Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice

PubMed Central

Baldwin, Jessie; Collins, Brian; Wolf, Patricia G.; Martinez, Kristina; Shen, Wan; Chuang, Chia-Chi; Zhong, Wei; Cooney, Paula; Cockrell, Chase; Chang, Eugene; Gaskins, H. Rex; McIntosh, Michael K.

2016-01-01

Our objective was to determine if consuming table grapes reduces adiposity and its metabolic consequences and alters gut microbiota in mice fed a high fat (HF), butter-rich diet. C57BL/6J mice were fed a low fat (LF) diet or HF diet with 3% or 5% grapes for 11 weeks. Total body and inguinal fat were moderately, but significantly reduced in mice fed both levels of grapes compared to their controls. Mice fed 5% grapes had lower liver weights and triglyceride levels, and decreased expression of glycerol-3-phosphate acyltransferase (Gpat1) compared to the 5% controls. Mice fed 3% grapes had lower hepatic mRNA levels of peroxisome proliferator-activated receptor gamma 2, sterol-CoA desaturase 1, fatty-acid binding protein 4, and Gpat1 compared to the 3% controls. Although grape feeding had only a minor impact on markers of inflammation or lipogenesis in adipose tissue or intestine, 3% grapes decreased the intestinal abundance of sulfidogenic Desulfobacter spp., and the Bilophila wadsworthia-specific dissimilatory sulfite reductase gene (dsrA-Bw), and tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls. Additionally, Bifidobacterium, Lactobacillus, Allobaculum, and several other genera correlated negatively with adiposity. Allobaculum in particular was increased in the LF and 3% grapes groups compared to the HF-fed controls. Notably, grape feeding attenuated the HF-induced impairment in epithelial localization of the intestinal tight junction protein zonula occludens. Collectively, these data indicate that some of the adverse health consequences of consuming a HF diet rich in saturated fat can be attenuated by table grape consumption. PMID:26423887

Table grape consumption reduces adiposity and markers of hepatic lipogenesis and alters gut microbiota in butter fat-fed mice.

PubMed

Baldwin, Jessie; Collins, Brian; Wolf, Patricia G; Martinez, Kristina; Shen, Wan; Chuang, Chia-Chi; Zhong, Wei; Cooney, Paula; Cockrell, Chase; Chang, Eugene; Gaskins, H Rex; McIntosh, Michael K

2016-01-01

Our objective was to determine if consuming table grapes reduces adiposity and its metabolic consequences and alters gut microbiota in mice fed a high-fat (HF), butter-rich diet. C57BL/6J mice were fed a low-fat (LF) diet or HF diet with 3% or 5% grapes for 11weeks. Total body and inguinal fat were moderately but significantly reduced in mice fed both levels of grapes compared to their controls. Mice fed 5% grapes had lower liver weights and triglyceride levels and decreased expression of glycerol-3-phosphate acyltransferase (Gpat1) compared to the 5% controls. Mice fed 3% grapes had lower hepatic mRNA levels of peroxisome proliferator-activated receptor gamma 2, sterol-CoA desaturase 1, fatty-acid binding protein 4 and Gpat1 compared to the 3% controls. Although grape feeding had only a minor impact on markers of inflammation or lipogenesis in adipose tissue or intestine, 3% of grapes decreased the intestinal abundance of sulfidogenic Desulfobacter spp. and the Bilophila wadsworthia-specific dissimilatory sulfite reductase gene and tended to increase the abundance of the beneficial bacterium Akkermansia muciniphila compared to controls. In addition, Bifidobacterium, Lactobacillus, Allobaculum and several other genera correlated negatively with adiposity. Allobaculum in particular was increased in the LF and 3% grapes groups compared to the HF-fed controls. Notably, grape feeding attenuated the HF-induced impairment in epithelial localization of the intestinal tight junction protein zonula occludens. Collectively, these data indicate that some of the adverse health consequences of consuming an HF diet rich in saturated fat can be attenuated by table grape consumption. Copyright © 2015 Elsevier Inc. All rights reserved.

A Postnatal Diet Containing Phospholipids, Processed to Yield Large, Phospholipid-Coated Lipid Droplets, Affects Specific Cognitive Behaviors in Healthy Male Mice.

PubMed

Schipper, Lidewij; van Dijk, Gertjan; Broersen, Laus M; Loos, Maarten; Bartke, Nana; Scheurink, Anton Jw; van der Beek, Eline M

2016-06-01

Infant cognitive development can be positively influenced by breastfeeding rather than formula feeding. The composition of breast milk, especially lipid quality, and the duration of breastfeeding have been linked to this effect. We investigated whether the physical properties and composition of lipid droplets in milk may contribute to cognitive development. From postnatal day (P) 16 to P44, healthy male C57BL/6JOlaHsd mice were fed either a control or a concept rodent diet, in which the dietary lipid droplets were large and coated with milk phospholipids, resembling more closely the physical properties and composition of breast milk lipids. Thereafter, all mice were fed an AIN-93M semisynthetic rodent diet. The mice were subjected to various cognitive tests during adolescence (P35-P44) and adulthood (P70-P101). On P102, mice were killed and brain phospholipids were analyzed. The concept diet improved performance in short-term memory tasks that rely on novelty exploration during adolescence (T-maze; spontaneous alternation 87% in concept-fed mice compared with 74% in mice fed control diet; P < 0.05) and adulthood (novel object recognition; preference index 0.48 in concept-fed mice compared with 0.05 in control-fed mice; P < 0.05). Cognitive performance in long-term memory tasks, however, was unaffected by diet. Brain phospholipid composition at P102 was not different between diet groups. Exposure to a diet with lipids mimicking more closely the structure and composition of lipids in breast milk improved specific cognitive behaviors in mice. These data suggest that lipid structure should be considered as a relevant target to improve dietary lipid quality in infant milk formulas. © 2016 American Society for Nutrition.

Intestinal epithelial cell surface glycosylation in mice. I. Effect of high-protein diet.

PubMed

Gupta, R; Jaswal, V M; Meenu Mahmood, A

1992-01-01

The effects of variation in dietary protein content have been investigated on brush border glycosylation and enzyme activities in mice small intestine. The comparison of different parameters was made between the mice fed 30% (high protein, HP) and 18% protein (pair-fed, PF, and ad libitum-fed) for 21 days. The activities of brush border sucrase, lactase, p-nitrophenyl (PNP)-beta-D-glucosidase and PNP-beta-D-galactosidase were reduced in the HP diet-fed mice compared to PF and ad libitum-fed controls. Alkaline phosphatase and leucine amino-peptidase activities were significantly enhanced while gamma-glutamyl transpeptidase activity was unaltered under these conditions. Total hexoses and sialic acid content in the brush borders were reduced significantly in the test group compared to the controls while hexosamine and fucose contents remained essentially similar in different groups. The results on the binding of wheat germ agglutinin and Ulex europaeus agglutininI to microvillus membranes corroborated the chemical analysis data on sialic acid and fucose contents of the membranes. Peanut agglutinin binding was enhanced in mice from the HP group. Incorporation of (14C)-mannose into membranes was significantly less in HP diet-fed mice. These results indicate that the feeding of HP diet to mice brings about marked alterations in small intestinal epithelial cell surface glycosylation and enzyme functions.

Oral feeding with polyunsaturated fatty acids fosters hematopoiesis and thrombopoiesis in healthy and bone marrow-transplanted mice.

PubMed

Limbkar, Kedar; Dhenge, Ankita; Jadhav, Dipesh D; Thulasiram, Hirekodathakallu V; Kale, Vaijayanti; Limaye, Lalita

2017-09-01

Hematopoietic stem cells play the vital role of maintaining appropriate levels of cells in blood. Therefore, regulation of their fate is essential for their effective therapeutic use. Here we report the role of polyunsaturated fatty acids (PUFAs) in regulating hematopoiesis which has not been explored well so far. Mice were fed daily for 10 days with n-6/n-3 PUFAs, viz. linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid and docosahexanoic acid (DHA) in four separate test groups with phosphate-buffered saline fed mice as control set. The bone marrow cells of PUFA-fed mice showed a significantly higher hematopoiesis as assessed using side population, Lin-Sca-1 + ckit+, colony-forming unit (CFU), long-term culture, CFU-spleen assay and engraftment potential as compared to the control set. Thrombopoiesis was also stimulated in PUFA-fed mice. A combination of DHA and AA was found to be more effective than when either was fed individually. Higher incorporation of PUFAs as well as products of their metabolism was observed in the bone marrow cells of PUFA-fed mice. A stimulation of the Wnt, CXCR4 and Notch1 pathways was observed in PUFA-fed mice. The clinical relevance of this study was evident when bone marrow-transplanted recipient mice, which were fed with PUFAs, showed higher engraftment of donor cells, suggesting that the bone marrow microenvironment may also be stimulated by feeding with PUFAs. These data indicate that oral administration of PUFAs in mice stimulates hematopoiesis and thrombopoiesis and could serve as a valuable supplemental therapy in situations of hematopoietic failure. Copyright © 2017 Elsevier Inc. All rights reserved.

Editor's Highlight: Perfluorooctane Sulfonate-Choline Ion Pair Formation: A Potential Mechanism Modulating Hepatic Steatosis and Oxidative Stress in Mice.

PubMed

Zhang, Limin; Krishnan, Prasad; Ehresman, David J; Smith, Philip B; Dutta, Mainak; Bagley, Bradford D; Chang, Shu-Ching; Butenhoff, John L; Patterson, Andrew D; Peters, Jeffrey M

2016-09-01

The mechanisms underlying perfluorooctane sulfonate (PFOS)-induced steatosis remain unclear. The hypothesis that PFOS causes steatosis and other hepatic effects by forming an ion pair with choline was examined. C57BL/6 mice were fed either a control diet or a marginal methionine/choline-deficient (mMCD) diet, with and without 0.003, 0.006, or 0.012% potassium PFOS. Dietary PFOS caused a dose-dependent decrease in body weight, and increases in the relative liver weight, hepatic triglyceride concentration and serum markers of liver toxicity and oxidative stress. Some of these effects were exacerbated in mice fed the mMCD diet supplemented with 0.012% PFOS compared with those fed the control diet supplemented with 0.012% PFOS. Surprisingly, serum PFOS concentrations were higher while liver PFOS concentrations were lower in mMCD-fed mice compared with corresponding control-fed mice. To determine if supplemental dietary choline could prevent PFOS-induced hepatic effects, C57BL/6 mice were fed a control diet, or a choline supplemental diet (1.2%) with or without 0.003% PFOS. Lipidomic analysis demonstrated that PFOS caused alterations in hepatic lipid metabolism in the PFOS-fed mice compared with controls, and supplemental dietary choline prevented these PFOS-induced changes. Interestingly, dietary choline supplementation also prevented PFOS-induced oxidative damage. These studies are the first to suggest that PFOS may cause hepatic steatosis and oxidative stress by effectively reducing the choline required for hepatic VLDL production and export by forming an ion pair with choline, and suggest that choline supplementation may prevent and/or treat PFOS-induced hepatic steatosis and oxidative stress. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Differential Effects of Dietary Fat Content and Protein Source on Bone Phenotype and Fatty Acid Oxidation in Female C57Bl/6 Mice

PubMed Central

Sawin, Emily A.; Stroup, Bridget M.; Murali, Sangita G.; O’Neill, Lucas M.; Ntambi, James M.

2016-01-01

Background Glycomacropeptide (GMP) is a 64-amino acid glycophosphopeptide released from κ-casein during cheesemaking that promotes satiety, reduces body fat, increases bone mass and infers prebiotic and anti-inflammatory effects. The impact of adiposity and gender on bone health is unclear. Objective To determine how feeding female mice diets providing 60% Fat Kcal (high-fat) or 13% Fat Kcal (control) with either GMP or casein as the protein source impacts: body composition, ex vivo fatty acid oxidation, bone (femoral) biomechanical performance, and the relationship between body composition and bone. Methods Weanling female C57Bl/6 mice were fed high-fat (60% Fat Kcal) or control diets (13% Fat Kcal) with GMP or casein from 3 to 32 weeks of age with assessment of body weight and food intake. Body composition was assessed by dual-energy X-ray absorptiometry (DXA). Fatty acid oxidation was measured in liver, muscle, and fat tissues using 14C-palmitate. Plasma concentrations of hormones and cytokines were determined. Bone biomechanical performance was assessed by the 3-point bending test. Results Female mice fed high-fat diets showed increased fatty acid oxidation capacity in both gastrocnemius muscle and brown adipose tissue compared to mice fed the control diets with a lower fat content. Despite increased fat mass in mice fed the high-fat diets, there was little evidence of glucose impairment or inflammation. Mice fed the high-fat diets had significantly greater total body bone mineral density (BMD), femoral BMD, and femoral cross-sectional area than mice fed the control diets. Femora of mice fed the high-fat diets had increased yield load and maximum load before fracture, consistent with greater bone strength, but reduced post-yield displacement or ductility, consistent with bone brittleness. Female mice fed a high-fat GMP diet displayed increased fat oxidation capacity in subcutaneous fat relative to mice fed the high-fat casein diet. Regardless of dietary fat content, GMP increased total body bone mineral content and femur length. The prebiotic properties of GMP may mediate the beneficial effects of GMP on bone. Conclusions Female mice adapt to high-fat feeding by increasing oxidative capacity in muscle tissue and to a lesser extent brown adipose tissue. High-fat feeding in female mice leads to development of a bone phenotype where femora show increased BMD and are stronger, yet more brittle. The increased brittleness of bone was associated with increased body fat content due to high-fat feeding. In summary, high-fat feeding in female mice increases mineralization of bone, but negatively impacts bone quality resulting in brittle bones. PMID:27695036

Iron restriction inhibits renal injury in aldosterone/salt-induced hypertensive mice.

PubMed

Sawada, Hisashi; Naito, Yoshiro; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Masuyama, Tohru

2015-05-01

Excess iron is associated with the pathogenesis of several renal diseases. Aldosterone is reported to have deleterious effects on the kidney, but there have been no reports of the role of iron in aldosterone/salt-induced renal injury. Therefore, we investigated the effects of dietary iron restriction on the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice. Ten-week-old male C57BL/6J mice were uninephrectomized and infused with aldosterone for four weeks. These were divided into two groups: one fed a high-salt diet (Aldo) and the other fed a high-salt with iron-restricted diet (Aldo-IR). Vehicle-infused mice without a uninephrectomy were also divided into two groups: one fed a normal diet (control) and the other fed an iron-restricted diet (IR) for 4 weeks. As compared with control and IR mice, Aldo mice showed an increase in both systolic blood pressure and urinary albumin/creatinine ratio, but these increases were reduced in the Aldo-IR group. In addition, renal histology revealed that Aldo mice exhibited glomerulosclerosis and tubulointerstitial fibrosis, whereas these changes were attenuated in Aldo-IR mice. Expression of intracellular iron transport protein transferrin receptor 1 was increased in the renal tubules of Aldo mice compared with control mice. Dietary iron restriction attenuated the development of hypertension and renal injury in aldosterone/salt-induced hypertensive mice.

FAT10 knock out mice livers fail to develop Mallory-Denk bodies in the DDC mouse model.

PubMed

French, S W; French, B A; Oliva, J; Li, J; Bardag-Gorce, F; Tillman, B; Canaan, A

2012-12-01

Mallory-Denk bodies (MDBs) are aggresomes composed of undigested ubiqutinated short lived proteins which have accumulated because of a decrease in the rate of their degradation by the 26s proteasome. The decrease in the activity of the proteasome is due to a shift in the activity of the 26s proteasome to the immunoproteasome triggered by an increase in expression of the catalytic subunits of the immunoproteasome which replaces the catalytic subunits of the 26s proteasome. This switch in the type of proteasome in liver cells is triggered by the binding of IFNγ to the IFNγ sequence response element (ISRE) located on the FAT10 promoter. To determine if either FAT10 or IFNγ are essential for the formation of MDBs we fed both IFNγ and FAT10 knock out (KO) mice DDC added to the control diet for 10weeks in order to induce MDBs. Mice fed the control diet and Wild type mice fed the DDC or control diet were compared. MDBs were located by immunofluorescent double stains using antibodies to ubiquitin to stain MDBs and FAT10 to localize the increased expression of FAT10 in MDB forming hepatocytes. We found that MDB formation occurred in the IFNγ KO mice but not in the FAT10 KO mice. Western blots showed an increase in the ubiquitin smears and decreases β 5 (chymotrypsin-like 26S proteasome subunit) in the Wild type mice fed DDC but not in the FAT10 KO mice fed DDC. To conclude, we have demonstrated that FAT10 is essential to the induction of MDB formation in the DDC fed mice. Copyright © 2012 Elsevier Inc. All rights reserved.

Dual specificity phosphatase 6 deficiency is associated with impaired systemic glucose tolerance and reversible weight retardation in mice

PubMed Central

Schriever, Sonja C.; Müller, Timo D.; Tschöp, Matthias H.

2017-01-01

Here, we aimed to investigate the potential role of DUSP6, a dual specificity phosphatase, that specifically inactivates extracellular signal-regulated kinase (ERK), for the regulation of body weight and glucose homeostasis. We further assessed whether metabolic challenges affect Dusp6 expression in selected brain areas or white adipose tissue. Hypothalamic Dusp6 mRNA levels remained unchanged in chow-fed lean vs. high fat diet (HFD) fed obese C57Bl/6J mice, and in C57Bl/6J mice undergoing prolonged fasting or refeeding with fat free diet (FFD) or HFD. Similarly, Dusp6 expression levels were unchanged in selected brain regions of Lepob mice treated with 1 mg/kg of leptin for 6 days, compared to pair-fed or saline-treated Lepob controls. Dusp6 expression levels remained unaltered in vitro in primary adipocytes undergoing differentiation, but were increased in eWAT of HFD-fed obese C57Bl/6J mice, compared to chow-fed lean controls. Global chow-fed DUSP6 KO mice displayed reduced body weight and lean mass and slightly increased fat mass at a young age, which is indicative for early-age weight retardation. Subsequent exposure to HFD led to a significant increase in lean mass and body weight in DUSP6 deficient mice, compared to WT controls. Nevertheless, after 26 weeks of high-fat diet exposure, we observed comparable body weight, fat and lean mass in DUSP6 WT and KO mice, suggesting overall normal susceptibility to develop obesity. In line with the increased weight gain to compensate for early-age weight retardation, HFD-fed DUSP6 KO displayed increased expression levels of anabolic genes involved in lipid and cholesterol metabolism in the epididymal white adipose tissue (eWAT), compared to WT controls. Glucose tolerance was perturbed in both chow-fed lean or HFD-fed obese DUSP6 KO, compared to their respective WT controls. Overall, our data indicate that DUSP6 deficiency has limited impact on the regulation of energy metabolism, but impairs systemic glucose tolerance. Our data are in conflict to earlier reports that propose protection from diet-induced obesity and glucose intolerance in DUSP6 deficient mice. Reasons for the discrepancies remain elusive, but may entail differential genetic backgrounds, environmental factors such as the type and source of HFD, or alterations in the gut microbiome between facilities. PMID:28873424

Microvascular dysfunction with increased vascular leakage response in mice systemically exposed to arsenic.

PubMed

Chen, Shih-Chieh; Huang, Shin-Yin; Lu, Chi-Yu; Hsu, Ya-Hung; Wang, Dean-Chuan

2014-09-01

The mechanisms underlying cardiovascular disease induced by arsenic exposure are not completely understood. The objectives of this study were to investigate whether arsenic-fed mice have an increased vascular leakage response to vasoactive agents and whether enhanced type-2 protein phosphatase (PP2A) activity is involved in mustard oil-induced leakage. ICR mice were fed water or sodium arsenite (20 mg/kg) for 4 or 8 weeks. The leakage response to vasoactive agents was quantified using the Evans blue (EB) technique or vascular labeling with carbon particles. Increased EB leakage and high density of carbon-labeled microvessels were detected in arsenic-fed mice treated with mustard oil. Histamine induced significantly higher vascular leakage in arsenic-fed mice than in water-fed mice. Pretreatment with the PP2A inhibitor okadaic acid or the neurokinin 1 receptor (NK1R) blocker RP67580 significantly reduced mustard oil-induced vascular leakage in arsenic-fed mice. The protein levels of PP2Ac and NK1R were similar in both groups. PP2A activity was significantly higher in the arsenic-fed mice compared with the control group. These findings indicate that microvessels generally respond to vasoactive agents, and that the increased PP2A activity is involved in mustard oil-induced vascular leakage in arsenic-fed mice. Arsenic may initiate endothelial dysfunction, resulting in vascular leakage in response to vasoactive agents.

MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes.

PubMed

Larter, Claire Z; Yeh, Matthew M; Williams, Jacqueline; Bell-Anderson, Kim S; Farrell, Geoffrey C

2008-09-01

In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched controls. MCD feeding increased serum ALT levels and induced hepatic steatosis, lobular inflammation and ballooning degeneration of hepatocytes, irrespective of dietary fat content. Hepatic triglyceride accumulation was similar between high and low-fat MCD-fed mice, but lipoperoxide levels were approximately 3-fold higher in the high-fat MCD-fed animals. Serum adiponectin levels increased in MCD-fed mice, although to a lesser extent in high-fat fed animals. AMPK phosphorylation was correspondingly increased in muscle of MCD-fed mice, but hepatic AMPK phosphorylation decreased, and there was little evidence of PPAR alpha activation, suggesting impaired adiponectin action in the livers of MCD-fed animals. Hepatocyte PPAR gamma mRNA levels increased in MCD-fed mice, and were associated with increased aP2 expression, indicating adipogenic transformation of hepatocytes. Increased dietary lipid intake did not alter steatohepatitis severity in MCD-fed mice despite increased lipoperoxide accumulation. Instead, steatohepatitis was associated with impaired hepatic adiponectin action, and adipogenic transformation of hepatocytes in both low and high-fat MCD-fed mice.

Characterisation of Atherogenic Effects of Low Carbohydrate, High Protein Diet (LCHP) in ApoE/LDLR-/- Mice.

PubMed

Kostogrys, R B; Johann, C; Czyżyńska, I; Franczyk-Żarów, M; Drahun, A; Maślak, E; Jasztal, A; Gajda, M; Mateuszuk, Ł; Wrobel, T P; Baranska, M; Wybrańska, I; Jezkova, K; Nachtigal, P; Chlopicki, S

2015-08-01

Low Carbohydrate High Protein diet represents a popular strategy to achieve weight loss. The aim of this study was to characterize effects of low carbohydrate, high protein diet (LCHP) on atherosclerotic plaque development in brachiocephalic artery (BCA) in apoE/LDLR-/- mice and to elucidate mechanisms of proatherogenic effects of LCHP diet. Atherosclerosis plaques in brachiocephalic artery (BCA) as well as in aortic roots, lipoprotein profile, inflammation biomarkers, expression of SREBP-1 in the liver as well as mortality were analyzed in Control diet (AIN-93G) or LCHP (Low Carbohydrate High Protein) diet fed mice. Area of atherosclerotic plaques in aortic roots or BCA from LCHP diet fed mice was substantially increased as compared to mice fed control diet and was characterized by increased lipids and cholesterol contents (ORO staining, FT-IR analysis), increased macrophage infiltration (MOMA-2) and activity of MMPs (zymography). Pro-atherogenic phenotype of LCHP fed apoE/LDLR-/- mice was associated with increased plasma total cholesterol concentration, and in LDL and VLDL fractions, increased TG contents in VLDL, and a modest increase in plasma urea. LCHP diet increased SCD-1 index, activated SREBP-1 transcription factor in the liver and triggered acute phase response as evidence by an increased plasma concentration of haptoglobin, CRP or AGP. Finally, in long-term experiment survival of apoE/LDLR-/- mice fed LCHP diet was substantially reduced as compared to their counterparts fed control diet suggesting overall detrimental effects of LCHP diet on health. The pro-atherogenic effect of LCHP diet in apoE/LDLR-/- mice is associated with profound increase in LDL and VLDL cholesterol, VLDL triglicerides, liver SREBP-1 upregulation, and systemic inflammation.

Fish oil prevents sucrose-induced fatty liver but exacerbates high-safflower oil-induced fatty liver in ddy mice.

PubMed

Yamazaki, Tomomi; Nakamori, Akiko; Sasaki, Eriko; Wada, Satoshi; Ezaki, Osamu

2007-12-01

Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). We analyzed the effects of dietary fish oil on fatty liver induced by sucrose, safflower oil, and butter in ddY mice. In experiment I, mice were fed a high-starch diet [70 energy% (en%) starch] plus 20% (wt/wt) sucrose in the drinking water or fed a high-safflower oil diet (60 en%) for 11 weeks. As a control, mice were fed a high-starch diet with drinking water. Fish oil (10 en%) was either supplemented or not. Mice supplemented with sucrose or fed safflower oil showed a 1.7-fold or 2.2-fold increased liver triglyceride content, respectively, compared with that of control mice. Fish oil completely prevented sucrose-induced fatty liver, whereas it exacerbated safflower oil-induced fatty liver. Sucrose increased SREBP-1c and target gene messenger RNAs (mRNAs), and fish oil completely inhibited these increases. In experiment II, mice were fed a high-safflower oil or a high-butter diet, with or without fish oil supplementation. Fish oil exacerbated safflower oil-induced fatty liver but did not affect butter-induced fatty liver. Fish oil increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and target CD36 mRNA in safflower oil-fed mice. These increases were not observed in sucrose-supplemented or butter-fed mice. The effects of dietary fish oil on fatty liver differ according to the cause of fatty liver; fish oil prevents sucrose-induced fatty liver but exacerbates safflower oil-induced fatty liver. The exacerbation of fatty liver may be due, at least in part, to increased expression of liver PPARgamma.

Loss of Junctional Adhesion Molecule A Promotes Severe Steatohepatitis in Mice on a Diet High in Saturated Fat, Fructose, and Cholesterol.

PubMed

Rahman, Khalidur; Desai, Chirayu; Iyer, Smita S; Thorn, Natalie E; Kumar, Pradeep; Liu, Yunshan; Smith, Tekla; Neish, Andrew S; Li, Hongliang; Tan, Shiyun; Wu, Pengbo; Liu, Xiaoxiong; Yu, Yuanjie; Farris, Alton B; Nusrat, Asma; Parkos, Charles A; Anania, Frank A

2016-10-01

There is evidence from clinical studies that compromised intestinal epithelial permeability contributes to the development of nonalcoholic steatohepatitis (NASH), but the exact mechanisms are not clear. Mice with disruption of the gene (F11r) encoding junctional adhesion molecule A (JAM-A) have defects in intestinal epithelial permeability. We used these mice to study how disruption of the intestinal epithelial barrier contributes to NASH. Male C57BL/6 (control) or F11r(-/-) mice were fed a normal diet or a diet high in saturated fat, fructose, and cholesterol (HFCD) for 8 weeks. Liver and intestinal tissues were collected and analyzed by histology, quantitative reverse-transcription polymerase chain reaction, and flow cytometry. Intestinal epithelial permeability was assessed in mice by measuring permeability to fluorescently labeled dextran. The intestinal microbiota were analyzed using 16S ribosomal RNA sequencing. We also analyzed biopsy specimens from proximal colons of 30 patients with nonalcoholic fatty liver disease (NAFLD) and 19 subjects without NAFLD (controls) undergoing surveillance colonoscopy. F11r(-/-) mice fed a HFCD, but not a normal diet, developed histologic and pathologic features of severe NASH including steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis, whereas control mice fed a HFCD developed only modest steatosis. Interestingly, there were no differences in body weight, ratio of liver weight:body weight, or glucose homeostasis between control and F11r(-/-) mice fed a HFCD. In these mice, liver injury was associated with significant increases in mucosal inflammation, tight junction disruption, and intestinal epithelial permeability to bacterial endotoxins, compared with control mice or F11r(-/-) mice fed a normal diet. The HFCD led to a significant increase in inflammatory microbial taxa in F11r(-/-) mice, compared with control mice. Administration of oral antibiotics or sequestration of bacterial endotoxins with sevelamer hydrochloride reduced mucosal inflammation and restored normal liver histology in F11r(-/-) mice fed a HFCD. Protein and transcript levels of JAM-A were significantly lower in the intestinal mucosa of patients with NAFLD than without NAFLD; decreased expression of JAM-A correlated with increased mucosal inflammation. Mice with defects in intestinal epithelial permeability develop more severe steatohepatitis after a HFCD than control mice, and colon tissues from patients with NAFLD have lower levels of JAM-A and higher levels of inflammation than subjects without NAFLD. These findings indicate that intestinal epithelial barrier function and microbial dysbiosis contribute to the development of NASH. Restoration of intestinal barrier integrity and manipulation of gut microbiota might be developed as therapeutic strategies for patients with NASH. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice.

PubMed

Philip, Bincy; Roland, Christina L; Daniluk, Jaroslaw; Liu, Yan; Chatterjee, Deyali; Gomez, Sobeyda B; Ji, Baoan; Huang, Haojie; Wang, Huamin; Fleming, Jason B; Logsdon, Craig D; Cruz-Monserrate, Zobeida

2013-12-01

Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but it is not clear how obesity contributes to pancreatic carcinogenesis. The oncogenic form of KRAS is expressed during early stages of PDAC development and is detected in almost all of these tumors. However, there is evidence that mutant KRAS requires an additional stimulus to activate its full oncogenic activity and that this stimulus involves the inflammatory response. We investigated whether the inflammation induced by a high-fat diet, and the accompanying up-regulation of cyclooxygenase-2 (COX2), increases Kras activity during pancreatic carcinogenesis in mice. We studied mice with acinar cell-specific expression of KrasG12D (LSL-Kras/Ela-CreERT mice) alone or crossed with COX2 conditional knockout mice (COXKO/LSL-Kras/Ela-CreERT). We also studied LSL-Kras/PDX1-Cre mice. All mice were fed isocaloric diets with different amounts of fat, and a COX2 inhibitor was administered to some LSL-Kras/Ela-CreERT mice. Pancreata were collected from mice and analyzed for Kras activity, levels of phosphorylated extracellular-regulated kinase, inflammation, fibrosis, pancreatic intraepithelial neoplasia (PanIN), and PDACs. Pancreatic tissues from LSL-Kras/Ela-CreERT mice fed high-fat diets (HFDs) had increased Kras activity, fibrotic stroma, and numbers of PanINs and PDACs than LSL-Kras/Ela-CreERT mice fed control diets; the mice fed the HFDs also had shorter survival times than mice fed control diets. Administration of a COX2 inhibitor to LSL-Kras/Ela-CreERT mice prevented these effects of HFDs. We also observed a significant reduction in survival times of mice fed HFDs. COXKO/LSL-Kras/Ela-CreERT mice fed HFDs had no evidence for increased numbers of PanIN lesions, inflammation, or fibrosis, as opposed to the increases observed in LSL-Kras/Ela-CreERT mice fed HFDs. In mice, an HFD can activate oncogenic Kras via COX2, leading to pancreatic inflammation and fibrosis and development of PanINs and PDAC. This mechanism might be involved in the association between risk for PDAC and HFDs. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice.

PubMed

Betancourt, Angela M; King, Adrienne L; Fetterman, Jessica L; Millender-Swain, Telisha; Finley, Rachel D; Oliva, Claudia R; Crowe, David R; Ballinger, Scott W; Bailey, Shannon M

2014-07-15

NAFLD (non-alcoholic fatty liver disease) involves significant changes in liver metabolism characterized by oxidative stress, lipid accumulation and fibrogenesis. Mitochondrial dysfunction and bioenergetic defects also contribute to NAFLD. In the present study, we examined whether differences in mtDNA influence NAFLD. To determine the role of mitochondrial and nuclear genomes in NAFLD, MNX (mitochondrial-nuclear exchange) mice were fed an atherogenic diet. MNX mice have mtDNA from C57BL/6J mice on a C3H/HeN nuclear background and vice versa. Results from MNX mice were compared with wild-type C57BL/6J and C3H/HeN mice fed a control or atherogenic diet. Mice with the C57BL/6J nuclear genome developed more macrosteatosis, inflammation and fibrosis compared with mice containing the C3H/HeN nuclear genome when fed the atherogenic diet. These changes were associated with parallel alterations in inflammation and fibrosis gene expression in wild-type mice, with intermediate responses in MNX mice. Mice with the C57BL/6J nuclear genome had increased State 4 respiration, whereas MNX mice had decreased State 3 respiration and RCR (respiratory control ratio) when fed the atherogenic diet. Complex IV activity and most mitochondrial biogenesis genes were increased in mice with the C57BL/6J nuclear or mitochondrial genome, or both fed the atherogenic diet. These results reveal new interactions between mitochondrial and nuclear genomes and support the concept that mtDNA influences mitochondrial function and metabolic pathways implicated in NAFLD.

Functional Deficits Precede Structural Lesions in Mice With High-Fat Diet–Induced Diabetic Retinopathy

PubMed Central

Rajagopal, Rithwick; Bligard, Gregory W.; Zhang, Sheng; Yin, Li; Lukasiewicz, Peter

2016-01-01

Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet–induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat–fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat–fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat–fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease. PMID:26740595

Tomato Lycopene Extract Prevents Lipopolysaccharide-Induced NF-κB Signaling but Worsens Dextran Sulfate Sodium-Induced Colitis in NF-κBEGFP Mice

PubMed Central

Joo, Young-Eun; Karrasch, Thomas; Mühlbauer, Marcus; Allard, Brigitte; Narula, Acharan; Herfarth, Hans H.; Jobin, Christian

2009-01-01

Background The impact of tomato lycopene extract (TLE) on intestinal inflammation is currently unknown. We investigated the effect of TLE on lipopolysaccharide (LPS)-induced innate signaling and experimental colitis. Methodology/Principal Findings Mice were fed a diet containing 0.5 and 2% TLE or isoflavone free control (AIN-76). The therapeutic efficacy of TLE diet was assessed using dextran sulfate sodium (DSS) exposed mice and IL-10−/−;NF-κBEGFP mice, representing an acute and spontaneous chronic colitis model respectively. A mini-endoscope was used to determine the extent of macroscopic mucosal lesions. Murine splenocytes and intestinal epithelial cells were used to determine the in vitro impact of TLE on LPS-induced NF-κB signaling. In vitro, TLE blocked LPS-induced IκBα degradation, RelA translocation, NF-κB transcriptional activity and MIP-2 mRNA accumulation in IEC-18 cells. Moreover, LPS-induced IL-12p40 gene expression was dose-dependently inhibited in TLE-treated splenocytes. Interestingly, DSS-induced acute colitis worsened in TLE-fed NF-κBEGFP mice compared to control diet as measured by weight loss, colonoscopic analysis and histological scores. In contrast, TLE-fed IL-10−/−;NF-κBEGFP mice displayed decreased colonic EGFP expression compared to control diet. IL-6, TNFα, and MCP-1 mRNA expression were increased in the colon of TLE-fed, DSS-exposed NF-κBEGFP mice compared to the control diet. Additionally, caspase-3 activation and TUNEL positive cells were enhanced in TLE diet-fed, DSS-exposed mice as compared to DSS control mice. Conclusions/ Significance These results indicate that TLE prevents LPS-induced proinflammatory gene expression by blocking of NF-κB signaling, but aggravates DSS-induced colitis by enhancing epithelial cell apoptosis. PMID:19234608

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition.

PubMed

Paul, Bidisha; Royston, Kendra J; Li, Yuanyuan; Stoll, Matthew L; Skibola, Christine F; Wilson, Landon S; Barnes, Stephen; Morrow, Casey D; Tollefsbol, Trygve O

2017-01-01

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition

PubMed Central

Paul, Bidisha; Royston, Kendra J.; Li, Yuanyuan; Stoll, Matthew L.; Skibola, Christine F.; Wilson, Landon S.; Barnes, Stephen; Morrow, Casey D.

2017-01-01

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients’ intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients’ post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth. PMID:29267377

Long-term ketogenic diet contributes to glycemic control but promotes lipid accumulation and hepatic steatosis in type 2 diabetic mice.

PubMed

Zhang, Xiaoyu; Qin, Juliang; Zhao, Yihan; Shi, Jueping; Lan, Rong; Gan, Yunqiu; Ren, Hua; Zhu, Bing; Qian, Min; Du, Bing

2016-04-01

The ketogenic diet (KD) has been widely used in weight and glycemic control, although potential side effects of long-term KD treatment have caused persistent concern. In this study, we hypothesized that the KD would ameliorate the progression of diabetes but lead to disruptions in lipid metabolism and hepatic steatosis in a mouse model of diabetes. In type 2 diabetic mouse model, mice were fed a high-fat diet and administered streptozotocin treatment before given the test diets for 8 weeks. Subsequently, ameliorated glucose and insulin tolerance in KD-fed diabetic mice was found, although the body weight of high-fat diet- and KD-fed mice was similar. Interestingly, the weight of adipose tissue in KD mice was greater than in the other groups. The KD diet resulted in higher serum triacylglycerol and cholesterol levels in diabetic mice. Moreover, the KD-fed mice showed greater hepatic lipid accumulation. Mice fed the KD showed significant changes in several key genes such as sterol regulatory element-binding protein, fibroblast growth factor 21, and peroxisome proliferator-activated receptor α, which are all important in metabolism. In summary, KD ameliorates glucose and insulin tolerance in a mouse model of diabetes, but severe hepatic lipid accumulation and hepatic steatosis were observed, which should be considered carefully in the long-term application of KD. Copyright © 2016 Elsevier Inc. All rights reserved.

Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice.

PubMed

Miyamoto, Junki; Watanabe, Keita; Taira, Satsuki; Kasubuchi, Mayu; Li, Xuan; Irie, Junichiro; Itoh, Hiroshi; Kimura, Ikuo

2018-01-01

Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.

Chromium (D-phenylalanine)3 supplementation alters glucose disposal, insulin signaling, and glucose transporter-4 membrane translocation in insulin-resistant mice.

PubMed

Dong, Feng; Kandadi, Machender Reddy; Ren, Jun; Sreejayan, Nair

2008-10-01

Chromium has gained popularity as a nutritional supplement for diabetic and insulin-resistant subjects. This study was designed to evaluate the effect of chronic administration of a novel chromium complex of d-phenylalanine [Cr(D-phe)(3)] in insulin-resistant, sucrose-fed mice. Whole-body insulin resistance was generated in FVB mice by 9 wk of sucrose feeding, following which they were randomly assigned to be unsupplemented (S group) or to receive oral Cr(D-phe)(3) in drinking water (SCr group) at a dose of 45 mug.kg(-1).d(-1) ( approximately 3.8 mug of elemental chromium.kg(-1).d(-1)). A control group (C) did not consume sucrose and was not supplemented. Sucrose-fed mice had an elevated serum insulin concentration compared with controls and this was significantly lower in sucrose-fed mice that received Cr(D-phe)(3), which did not differ from controls. Impaired glucose tolerance in sucrose-fed mice, evidenced by the poor glucose disposal rate following an intraperitoneal glucose tolerance test, was significantly improved in mice receiving Cr(D-phe)(3). Chromium supplementation significantly enhanced insulin-stimulated Akt phosphorylation and membrane-associated glucose transporter-4 in skeletal muscles of sucrose-fed mice. In cultured adipocytes rendered insulin resistant by chronic exposure to high concentrations of glucose and insulin, Cr(D-phe)(3) augmented Akt phosphorylation and glucose uptake. These results indicate that dietary supplementation with Cr(D-phe)(3) may have potential beneficial effects in insulin-resistant, prediabetic conditions.

Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice.

PubMed

Syed, Raisa; Shibata, Noreene M; Kharbanda, Kusum K; Su, Ruijun J; Olson, Kristin; Yokoyama, Amy; Rutledge, John C; Chmiel, Kenneth J; Kim, Kyoungmi; Halsted, Charles H; Medici, Valentina

2016-05-01

Previous studies indicated that nonpurified and purified commercially available control murine diets have different metabolic effects with potential consequences on hepatic methionine metabolism and liver histology. We compared the metabolic and histological effects of commercial nonpurified (13% calories from fat; 57% calories from carbohydrates with 38 grams/kg of sucrose) and purified control diets (12% calories from fat; 69% calories from carbohydrates with ∼500 grams/kg of sucrose) with or without choline supplementation administered to C3H mice with normal lipid and methionine metabolism. Diets were started 2 weeks before mating, continued through pregnancy and lactation, and continued in offspring until 24 weeks of age when we collected plasma and liver tissue to study methionine and lipid metabolism. Compared to mice fed nonpurified diets, the liver/body weight ratio was significantly higher in mice fed either purified diet, which was associated with hepatic steatosis and inflammation. Plasma alanine aminotransferase levels were higher in mice receiving the purified diets. The hepatic S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio was higher in female mice fed purified compared to nonpurified diet (4.6 ± 2 vs. 2.8 ± 1.9; P < 0.05). Choline supplementation was associated with improvement of some parameters of lipid and methionine metabolism in mice fed purified diets. Standard nonpurified and purified diets have significantly different effects on development of steatosis in control mice. These findings can help in development of animal models of fatty liver and in choosing appropriate laboratory control diets for control animals.

Anti-obesity and anti-diabetic effects of ethanol extract of Artemisia princeps in C57BL/6 mice fed a high-fat diet.

PubMed

Yamamoto, Norio; Kanemoto, Yuki; Ueda, Manabu; Kawasaki, Kengo; Fukuda, Itsuko; Ashida, Hitoshi

2011-01-01

Artemisia princeps is commonly used as a food ingredient and in traditional Asian medicine. In this study, we examined the effects of long-term administration of an ethanol extract of A. princeps (APE) on body weight, white adipose tissue, blood glucose, insulin, plasma and hepatic lipids, and adipocytokines in C57BL/6 mice fed a high-fat diet. Daily feeding of a 1% APE diet for 14 weeks normalized elevated body weight, white adipose tissue, and plasma glucose and insulin levels, and delayed impaired glucose tolerance in mice a fed high-fat diet. These events were not observed in mice fed a control diet containing 1% APE. Liver triglyceride and cholesterol levels were similar in mice fed a 1% APE-diet and those fed a control diet. In the high-fat diet groups, APE inhibited hepatic fatty acid synthase (FAS) and suppressed the elevation of plasma leptin, but had no effect on adiponectin levels. These findings suggest that the regulation of leptin secretion by APE may inhibit FAS activity with subsequent suppression of triglyceride accumulation in the liver and adipose tissues. Inhibition of lipid accumulation can, in turn, lead to improvements in impaired glucose tolerance.

Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXRα variant lacking the DNA-binding domain.

PubMed

Kosters, Astrid; Felix, Julio C; Desai, Moreshwar S; Karpen, Saul J

2014-02-01

Retinoid X Receptor α (RXRα) is the principal heterodimerization partner of class II Nuclear Receptors (NRs), and a major regulator of gene expression of numerous hepatic processes, including bile acid (BA) homeostasis through multiple partners. Specific contributions of hepatic RXRα domains in heterodimer function in response to either BA load or ductular cholestasis are not fully characterized. Wild-type (WT) mice and mice expressing a hepatocyte-specific RXRα lacking the DNA-Binding-Domain (hs-RxrαΔex4(-/-)), which retains partial ability to heterodimerize with its partners, were fed a 1% cholic acid (CA) diet for 5 days, a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet for 3 weeks, or control diet. Serum ALT (6.5-fold; p<0.05), AST (9.3-fold; p=0.06) and BA (2.8-fold; p<0.05) were increased in CA-fed hs-RxαΔex4(-/-) mice compared to CA-fed WT mice, but were equally induced between genotypes by DDC-feeding. CA-feeding elevated total (4.4-fold; p=0.06) and unconjugated (2.2-fold; p<0.02) bilirubin levels in hs-RxrαΔex4(-/-) mice compared to WT mice, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Increased necrosis and inflammation was observed in CA-fed, but not in DDC-fed hs-RxrαΔex4(-/-) mice. Apoptotic markers DR5, CK8, CK18 RNA were increased in CA- and DDC-fed hs-RxrαΔex4(-/-) mice. Cleaved caspase 3, CK18 and p-JNK protein were elevated in CA-fed but not in DDC-fed hs-RxrαΔex4(-/-) mice. Induction of Ostβ and Cyp2b10 RNA was impaired in CA-fed and DDC-fed hs-RxrαΔex4(-/-) mice. Surprisingly, DDC-fed hs-RxrαΔex4(-/-) mice showed attenuated fibrosis compared to DDC-fed WT mice. These two models of cholestasis identify common and injury-specific roles for RXRα heterodimers and the functional relevance of an intact RXRα-DBD in the hepatocytic adaptive cholestatic response. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Decreased production of interleukin-6 and prostaglandin E2 associated with inhibition of delta-5 desaturation of omega6 fatty acids in mice fed safflower oil diets supplemented with sesamol.

PubMed

Chavali, S R; Forse, R A

1999-12-01

The differences in the immune responses in mice fed sesame oil diets and those fed sesamin may be attributed to the presence of other lignans in the non-fat portion of the oil. The fatty acid composition (mean +/- SD mol. %) of liver membrane phospholipids and the levels of endotoxin-induced prostaglandin (PG) E2, interleukin (IL)-6, IL-10, IL-12 and tumor necrosis factor (TNF)-alpha were determined in mice fed diets supplemented with 5% safflower oil (SO) in the absence or presence of 1% sesamol. The levels of dihomo-gamma-linolenic acid (20:3omega6) were markedly higher (P<0.025) in the livers from mice fed sesamol supplemented SO diets (1.6 +/- 0.1) compared to the controls (1.4 +/- 0.1). These data suggest that sesamol or its metabolite could inhibit the in vivo delta-5 desaturation of omega6 fatty acids. Further, in animals fed sesamol supplemented SO diets, the levels of PGE2 (228 +/- 41 pg/ml) were markedly lower (P<0.01) compared to those fed SO diet alone (1355 +/- 188 pg/ml). Concomitantly, the concentrations of IL-6 were also lower (P<0.01) in mice fed sesamol diet (63 +/- 11 ng/ml) compared to the controls (143 +/- 22 ng/ml). A marked reduction in the levels of PGE2 in animals fed sesamol diets suggests that sesamol or its metabolite could inhibit the activity of cyclooxygenase enzyme.

Hepatic lipid profiling of deer mice fed ethanol using {sup 1}H and {sup 31}P NMR spectroscopy: A dose-dependent subchronic study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fernando, Harshica; Bhopale, Kamlesh K.; Boor, Paul J.

2012-11-01

Chronic alcohol abuse is a 2nd major cause of liver disease resulting in significant morbidity and mortality. Alcoholic liver disease (ALD) is characterized by a wide spectrum of pathologies starting from fat accumulation (steatosis) in early reversible stage to inflammation with or without fibrosis and cirrhosis in later irreversible stages. Previously, we reported significant steatosis in the livers of hepatic alcohol dehydrogenase (ADH)-deficient (ADH{sup −}) vs. hepatic ADH-normal (ADH{sup +}) deer mice fed 4% ethanol daily for 2 months [Bhopale et al., 2006, Alcohol 39, 179–188]. However, ADH{sup −} deer mice fed 4% ethanol also showed a significant mortality. Therefore,more » a dose-dependent study was conducted to understand the mechanism and identify lipid(s) involved in the development of ethanol-induced fatty liver. ADH{sup −} and ADH{sup +} deer mice fed 1, 2 or 3.5% ethanol daily for 2 months and fatty infiltration in the livers were evaluated by histology and by measuring dry weights of extracted lipids. Lipid metabolomic changes in extracted lipids were determined by proton ({sup 1}H) and {sup 31}phosphorus ({sup 31}P) nuclear magnetic resonance (NMR) spectroscopy. The NMR data was analyzed by hierarchical clustering (HC) and principle component analysis (PCA) for pattern recognition. Extensive vacuolization by histology and significantly increased dry weights of total lipids found only in the livers of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls suggest a dose-dependent formation of fatty liver in ADH{sup −} deer mouse model. Analysis of NMR data of ADH{sup −} deer mice fed 3.5% ethanol vs. pair-fed controls shows increases for total cholesterol, esterified cholesterol, fatty acid methyl esters (FAMEs), triacylglycerides and unsaturation, and decreases for free cholesterol, phospholipids and allylic and diallylic protons. Certain classes of neutral lipids (cholesterol esters, fatty acyl chain (-COCH{sub 2}-) and FAMEs) were also mildly increased in ADH{sup −} deer mice fed 1 or 2% ethanol. Only small increases were observed for allylic and diallylic protons, FAMEs and unsaturations in ADH{sup +} deer mice fed 3.5% ethanol vs. pair-fed controls. PCA of NMR data showed increased clustering by gradual separation of ethanol-fed ADH{sup −} deer mice groups from their respective pair-fed control groups and corresponding ethanol-fed ADH{sup +} deer mice groups. Our data indicate that dose of ethanol and hepatic ADH deficiency are two key factors involved in initiation and progression of alcoholic fatty liver disease. Further studies on characterization of individual lipid entities and associated metabolic pathways altered in our deer mouse model after different durations of ethanol feeding could be important to delineate mechanism(s) and identify potential biomarker candidate(s) of early stage ALD. -- Highlights: ► Dose-dependent ethanol-induced fatty liver was studied in deer mouse model. ► A NMR-based lipidomic approach with histology and dry lipid weights was used. ► We used principal component analysis (PCA) to analyze the NMR lipidomic data. ► Dose-dependent clustering patterns by PCA were compared among the groups.« less

Dietary supplementation of chinese ginseng prevents obesity and metabolic syndrome in high-fat diet-fed mice.

PubMed

Li, Xiaoxiao; Luo, Jing; Anandh Babu, Pon Velayutham; Zhang, Wei; Gilbert, Elizabeth; Cline, Mark; McMillan, Ryan; Hulver, Matthew; Alkhalidy, Hana; Zhen, Wei; Zhang, Haiyan; Liu, Dongmin

2014-12-01

Obesity and diabetes are growing health problems worldwide. In this study, dietary provision of Chinese ginseng (0.5 g/kg diet) prevented body weight gain in high-fat (HF) diet-fed mice. Dietary ginseng supplementation reduced body fat mass gain, improved glucose tolerance and whole body insulin sensitivity, and prevented hypertension in HF diet-induced obese mice. Ginseng consumption led to reduced concentrations of plasma insulin and leptin, but had no effect on plasma adiponectin levels in HF diet-fed mice. Body temperature was higher in mice fed the ginseng-supplemented diet but energy expenditure, respiration rate, and locomotive activity were not significantly altered. Dietary intake of ginseng increased fatty acid oxidation in the liver but not in skeletal muscle. Expression of several transcription factors associated with adipogenesis (C/EBPα and PPARγ) were decreased in the adipose tissue of HF diet-fed mice, effects that were mitigated in mice that consumed the HF diet supplemented with ginseng. Abundance of fatty acid synthase (FASN) mRNA was greater in the adipose tissue of mice that consumed the ginseng-supplemented HF diet as compared with control or un-supplemented HF diet-fed mice. Ginseng treatment had no effect on the expression of genes involved in the regulation of food intake in the hypothalamus. These data suggest that Chinese ginseng can potently prevent the development of obesity and insulin resistance in HF diet-fed mice.

Dietary fructose augments ethanol-induced liver pathology.

PubMed

Thomes, Paul G; Benbow, Jennifer H; Brandon-Warner, Elizabeth; Thompson, Kyle J; Jacobs, Carl; Donohue, Terrence M; Schrum, Laura W

2017-05-01

Certain dietary components when combined with alcohol exacerbate alcohol-induced liver injury (ALI). Here, we tested whether fructose, a major ingredient of the western diet, enhances the severity of ALI. We fed mice ethanol for 8 weeks in the following Lieber-DeCarli diets: (a) Regular (contains olive oil); (b) corn oil (contains corn oil); (c) fructose (contains fructose and olive oil) and (d) corn+fructose (contains fructose and corn oil). We compared indices of metabolic function and liver pathology among the different groups. Mice fed fructose-free and fructose-containing ethanol diets exhibited similar levels of blood alcohol, blood glucose and signs of disrupted hepatic insulin signaling. However, only mice given fructose-ethanol diets showed lower insulin levels than their respective controls. Compared with their respective pair-fed controls, all ethanol-fed mice exhibited elevated levels of serum ALT; the inflammatory cytokines TNF-α, MCP-1 and MIP-2; hepatic lipid peroxides and triglycerides. All the latter parameters were significantly higher in mice given fructose-ethanol diets than those fed fructose-free ethanol diets. Mice given fructose-free or fructose-containing ethanol diets each had higher levels of hepatic lipogenic enzymes than controls. However, the level of the lipogenic enzyme fatty acid synthase (FAS) was significantly higher in livers of mice given fructose control and fructose-ethanol diets than in all other groups. Our findings indicate that dietary fructose exacerbates ethanol-induced steatosis, oxidant stress, inflammation and liver injury, irrespective of the dietary fat source, to suggest that inclusion of fructose in or along with alcoholic beverages increases the risk of more severe ALI in heavy drinkers. Copyright © 2017 Elsevier Inc. All rights reserved.

Obese mice on a high-fat alternate-day fasting regimen lose weight and improve glucose tolerance.

PubMed

Joslin, P M N; Bell, R K; Swoap, S J

2017-10-01

Alternate-day fasting (ADF) causes body weight (BW) loss in humans and rodents. However, it is not clear that ADF while maintaining a high-fat (HF) diet results in weight loss and the accompanying improvement in control of circulating glucose. We tested the hypotheses that a high-fat ADF protocol in obese mice would result in (i) BW loss, (ii) improved glucose control, (iii) fluctuating phenotypes on 'fasted' days when compared to 'fed' days and (iv) induction of torpor on 'fasted days'. We evaluated the physiological effects of ADF in diet-induced obese mice for BW, heart rate (HR), body temperature (T b ), glucose tolerance, insulin responsiveness, blood parameters (leptin, insulin, free fatty acids) and hepatic gene expression. Diet-induced obese male C57BL/6J mice lost one-third of their pre-diet BW while on an ADF diet for 10 weeks consisting of HF food. The ADF protocol improved glucose tolerance and insulin sensitivity, although mice on a fast day were less glucose tolerant than the same mice on a fed day. ADF mice on a fast day had low circulating insulin, but had an enhanced response to an insulin-assisted glucose tolerance test, suggesting the impaired glucose tolerance may be a result of insufficient insulin production. On fed days, ADF mice were the warmest, had a high HR and displayed hepatic gene expression and circulating leptin that closely mimicked that of mice fed an ad lib HF diet. ADF mice never entered torpor as assessed by HR and T b . However, on fast days, they were the coolest, had the slowest HR, and displayed hepatic gene expression and circulating leptin that closely mimicked that of Chow-Fed mice. Collectively, the ADF regimen with a HF diet in obese mice results in weight loss, improved blood glucose control, and daily fluctuations in selected physiological and biochemical parameters in the mouse. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

Effect of sodium-alginate and laminaran on Salmonella Typhimurium infection in human enterocyte-like HT-29-Luc cells and BALB/c mice.

PubMed

Kuda, Takashi; Kosaka, Misa; Hirano, Shino; Kawahara, Miho; Sato, Masahiro; Kaneshima, Tai; Nishizawa, Makoto; Takahashi, Hajime; Kimura, Bon

2015-07-10

Brown algal polysaccharides such as alginate, polymers of uronic acids, and laminaran, beta-1,3 and 1,6-glucan, can be fermented by human intestinal microbiota. To evaluate the effects of these polysaccharides on infections caused by food poisoning pathogens, we investigated the adhesion and invasion of pathogens (Salmonella Typhimurium, Listeria monocytogenes and Vibrio parahaemolyticus) in human enterocyte-like HT-29-Luc cells and in infections caused in BALB/c mice. Both sodium Na-alginate and laminaran (0.1% each) inhibited the adhesion of the pathogens to HT-29-Luc cells by approximately 70-90%. The invasion of S. Typhimurium was also inhibited by approximately 70 and 80% by Na-alginate and laminaran, respectively. We observed that incubation with Na-alginate for 18 h increased the transepithelial electrical resistance of HT-29-Luc monolayer cells. Four days after inoculation with 7 log CFU/mouse of S. Typhimurium, the faecal pathogen count in mice that were not fed polysaccharides (control mice) was about 6.5 log CFU/g while the count in mice that were fed Na-alginate had decreased to 5.0 log CFU/g. The liver pathogen count, which was 4.1 log CFU/g in the control mice, was also decreased in mice that were fed Na-alginate. In contrast, the mice that were fed laminaran exhibited a more severe infection than that exhibited by control mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

Dissociation between diurnal cycles in locomotor activity, feeding behavior and hepatic PERIOD2 expression in chronic alcohol-fed mice

PubMed Central

Zhou, Peng; Werner, John H.; Lee, Donghoon; Sheppard, Aaron D.; Liangpunsakul, Suthat; Duffield, Giles E.

2015-01-01

Chronic alcohol consumption contributes to fatty liver disease. Our studies revealed that the hepatic circadian clock is disturbed in alcohol-induced hepatic steatosis, and effects of chronic alcohol administration upon the clock itself may contribute to steatosis. We extended these findings to explore the effects of chronic alcohol treatment on daily feeding and locomotor activity patterns. Mice were chronically pair-fed ad libitum for 4 weeks using the Lieber-DeCarli liquid diet, with calorie-controlled liquid and standard chow diets as control groups. Locomotor activity, feeding activity, and real-time bioluminescence recording of PERIOD2::LUCIFERASE expression in tissue explants were measured. Mice on liquid control and chow diets exhibited normal profiles of locomotor activity, with a ratio of 22:78% day/night activity and a peak during early night. This pattern was dramatically altered in alcohol-fed mice, marked by a 49:51% ratio and the absence of a distinct peak. While chow-diet fed mice had a normal 24:76% ratio of feeding activity, with a peak in the early night, this pattern was dramatically altered in both liquid-diet groups: mice had a 43:57% ratio, and an absence of a distinct peak. Temporal differences were also observed between the two liquid-diet groups during late day. Cosinor analysis revealed a ~4-h and ~6-h shift in the alcohol-fed group feeding and locomotor activity rhythms, respectively. Analysis of hepatic PER2 expression revealed that the molecular clock in alcohol-fed and control liquid-diet mice was shifted by ~11 h and ~6 h, respectively. No differences were observed in suprachiasmatic nucleus explants, suggesting that changes in circadian phase in the liver were generated independently from the central clock. These results suggest that chronic alcohol consumption and a liquid diet can differentially modulate the daily rhythmicity of locomotor and feeding behaviors, aspects that might contribute to disturbances in the circadian timing system and development of hepatic steatosis. PMID:25960184

Systemic metabolite changes in wild-type C57BL/6 mice fed black raspberries

PubMed Central

Pan, Pan; Skaer, Chad W.; Wang, Hsin-Tzu; Kreiser, Michael A.; Stirdivant, Steven M.; Oshima, Kiyoko; Huang, Yi-Wen; Young, Matthew R.; Wang, Li-Shu

2017-01-01

Introduction Freeze-dried black raspberries (BRBs) elicit chemopreventive effects against colorectal cancer in humans and in rodents. The study objective was to investigate potential BRB-caused metabolite changes using wild-type (WT) C57BL/6 mice. Methods and results WT mice were fed either control diet or control diet supplemented with 5% BRBs for 8 weeks. A non-targeted metabolomic analysis was conducted on colonic mucosa, liver, and fecal specimens collected from both diet groups. BRBs significantly changed the levels of 41 colonic mucosa metabolites, 40 liver metabolites and 34 fecal metabolites compared to control diet-fed mice. BRBs reduced 34 lipid metabolites in colonic mucosa and increased levels of amino acids in liver. One metabolite, 3-[3-(sulfooxy) phenyl] propanoic acid, might be a useful biomarker of BRB consumption. In addition, BRB powder was found to contain 30-fold higher levels of linolenate compared to control diets. Consistently, multiple omega-3 polyunsaturated fatty acids (ω-3 PUFAs), including stearidonate, docosapentaenoate (ω-3 DPA), eicosapentaenoate (EPA) and docosahexaenoate (DHA), were significantly elevated in livers of BRB-fed mice. Conclusion The data from the current study suggest that BRBs produce systemic metabolite changes in multiple tissue matrices, supporting our hypothesis that BRBs may serve as both a chemopreventive agent and a beneficial dietary supplement. PMID:28094560

Ufmylation and FATylation Pathways are Down Regulated in Human Alcoholic and Non Alcoholic Steatohepatitis, and Mice Fed DDC, where Mallory-Denk Bodies (MDBs) Form

PubMed Central

Liu, H; Li, J; Tillman, B; French, BA; French, SW

2014-01-01

We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly down regulated, both in DDC re-fed mice livers and patients’ livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was down regulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both up regulated as previously shown. An approximate 176- and 5-fold up regulation (respectively) of FAT10 were observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be down regulated both in patients’ livers and in the liver of DDC re-fed mice. Interestedly, the down regulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is down regulated. This was also shown in livers of DDC re-fed mice where MDBs had formed. PMID:24893112

Ufmylation and FATylation pathways are downregulated in human alcoholic and nonalcoholic steatohepatitis, and mice fed DDC, where Mallory-Denk bodies (MDBs) form.

PubMed

Liu, H; Li, J; Tillman, B; French, B A; French, S W

2014-08-01

We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly downregulated, both in DDC re-fed mice livers and patients' livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was downregulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both upregulated as previously shown. An approximate 176- and 5-fold upregulation (respectively) of FAT10 was observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be downregulated both in patients' livers and in the liver of DDC re-fed mice. Interestedly, the downregulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is downregulated. This was also shown in the livers of DDC re-fed mice where MDBs had formed. Copyright © 2014 Elsevier Inc. All rights reserved.

Effect of Powder Leaf Breadfruit Disposals (Arthocarpus Altilis) in Oil Mandar District and Polman Against Cholesterol and Glucose Mice (Mus Musculus)

NASA Astrophysics Data System (ADS)

Mu'nisa, A.; Asmawati, A.; Farida, A.; FA, Fressy; Erni

2018-01-01

The purpose of this study was to determine the effect of powdered leaves of breadfruit (Arthocarpus altilis) on oil is mandated origin of the Polman glucose and cholesterol levels in mice (Mus musculus). This study comprised 4 treatments and each treatment consisted of 5 replicates, ie groups of mice were fed a standard (negative control); 2 groups: group of mice fed with standard and cholesterol feed (positive control); Group 3 that mice fed with standard and Selayar oil; and group 4: group of mice fed with standard and Mandar oil that has been given powdered leaves of breadfruit. Measurement of glucose and blood cholesterol levels in mice done 3 times ie 2 weeks after the adaptation period (phase 1), 2 weeks after administration of the oil (phase 2) and 2 weeks after feeding cholesterol (stage 3). Based on the analysis of data both cholesterol and glucose levels showed that in a group of 4 decreased glucose and cholesterol levels in stage 2 but at stage 3 an increase in the group of mice given only the oil while in the group of mice given the oil and powdered leaves of breadfruit indicate glucose levels and normal cholesterol. The conclusion of this study show that the addition of powdered leaves of breadfruit into cooking oil Mandar influential in glucose levels and normalize blood cholesterol levels in mice.

Dietary flavonoids from modified apple reduce inflammation markers and modulate gut microbiota in mice.

PubMed

Espley, Richard V; Butts, Christine A; Laing, William A; Martell, Sheridan; Smith, Hannah; McGhie, Tony K; Zhang, Jingli; Paturi, Gunaranjan; Hedderley, Duncan; Bovy, Arnaud; Schouten, Henk J; Putterill, Joanna; Allan, Andrew C; Hellens, Roger P

2014-02-01

Apples are rich in polyphenols, which provide antioxidant properties, mediation of cellular processes such as inflammation, and modulation of gut microbiota. In this study we compared genetically engineered apples with increased flavonoids [myeloblastis transcription factor 10 (MYB10)] with nontransformed apples from the same genotype, "Royal Gala" (RG), and a control diet with no apple. Compared with the RG diet, the MYB10 diet contained elevated concentrations of the flavonoid subclasses anthocyanins, flavanol monomers (epicatechin) and oligomers (procyanidin B2), and flavonols (quercetin glycosides), but other plant secondary metabolites were largely unaltered. We used these apples to investigate the effects of dietary flavonoids on inflammation and gut microbiota in 2 mouse feeding trials. In trial 1, male mice were fed a control diet or diets supplemented with 20% MYB10 apple flesh and peel (MYB-FP) or RG apple flesh and peel (RG-FP) for 7 d. In trial 2, male mice were fed MYB-FP or RG-FP diets or diets supplemented with 20% MYB10 apple flesh or RG apple flesh for 7 or 21 d. In trial 1, the transcription levels of inflammation-linked genes in mice showed decreases of >2-fold for interleukin-2 receptor (Il2rb), chemokine receptor 2 (Ccr2), chemokine ligand 10 (Cxcl10), and chemokine receptor 10 (Ccr10) at 7 d for the MYB-FP diet compared with the RG-FP diet (P < 0.05). In trial 2, the inflammation marker prostaglandin E(2) (PGE(2)) in the plasma of mice fed the MYB-FP diet at 21 d was reduced by 10-fold (P < 0.01) compared with the RG-FP diet. In colonic microbiota, the number of total bacteria for mice fed the MYB-FP diet was 6% higher than for mice fed the control diet at 21 d (P = 0.01). In summary, high-flavonoid apple was associated with decreases in some inflammation markers and changes in gut microbiota when fed to healthy mice.

Effects of Nonpurified and Choline Supplemented or Nonsupplemented Purified Diets on Hepatic Steatosis and Methionine Metabolism in C3H Mice

PubMed Central

Syed, Raisa; Shibata, Noreene M.; Kharbanda, Kusum K.; Su, Ruijun J.; Olson, Kristin; Yokoyama, Amy; Rutledge, John C.; Chmiel, Kenneth J.; Kim, Kyoungmi; Halsted, Charles H.

2016-01-01

Abstract Background: Previous studies indicated that nonpurified and purified commercially available control murine diets have different metabolic effects with potential consequences on hepatic methionine metabolism and liver histology. Methods: We compared the metabolic and histological effects of commercial nonpurified (13% calories from fat; 57% calories from carbohydrates with 38 grams/kg of sucrose) and purified control diets (12% calories from fat; 69% calories from carbohydrates with ∼500 grams/kg of sucrose) with or without choline supplementation administered to C3H mice with normal lipid and methionine metabolism. Diets were started 2 weeks before mating, continued through pregnancy and lactation, and continued in offspring until 24 weeks of age when we collected plasma and liver tissue to study methionine and lipid metabolism. Results: Compared to mice fed nonpurified diets, the liver/body weight ratio was significantly higher in mice fed either purified diet, which was associated with hepatic steatosis and inflammation. Plasma alanine aminotransferase levels were higher in mice receiving the purified diets. The hepatic S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio was higher in female mice fed purified compared to nonpurified diet (4.6 ± 2 vs. 2.8 ± 1.9; P < 0.05). Choline supplementation was associated with improvement of some parameters of lipid and methionine metabolism in mice fed purified diets. Conclusions: Standard nonpurified and purified diets have significantly different effects on development of steatosis in control mice. These findings can help in development of animal models of fatty liver and in choosing appropriate laboratory control diets for control animals. PMID:26881897

Hepatic Src Homology Phosphatase 2 Regulates Energy Balance in Mice

PubMed Central

Nagata, Naoto; Matsuo, Kosuke; Bettaieb, Ahmed; Bakke, Jesse; Matsuo, Izumi; Graham, James; Xi, Yannan; Liu, Siming; Tomilov, Alexey; Tomilova, Natalia; Gray, Susan; Jung, Dae Young; Ramsey, Jon J.; Kim, Jason K.; Cortopassi, Gino; Havel, Peter J.

2012-01-01

The Src homology 2 domain-containing protein-tyrosine phosphatase Src homology phosphatase 2 (Shp2) is a negative regulator of hepatic insulin action in mice fed regular chow. To investigate the role of hepatic Shp2 in lipid metabolism and energy balance, we determined the metabolic effects of its deletion in mice challenged with a high-fat diet (HFD). We analyzed body mass, lipid metabolism, insulin sensitivity, and glucose tolerance in liver-specific Shp2-deficient mice (referred to herein as LSHKO) and control mice fed HFD. Hepatic Shp2 protein expression is regulated by nutritional status, increasing in mice fed HFD and decreasing during fasting. LSHKO mice gained less weight and exhibited increased energy expenditure compared with control mice. In addition, hepatic Shp2 deficiency led to decreased liver steatosis, enhanced insulin-induced suppression of hepatic glucose production, and impeded the development of insulin resistance after high-fat feeding. At the molecular level, LSHKO exhibited decreased hepatic endoplasmic reticulum stress and inflammation compared with control mice. In addition, tyrosine and serine phosphorylation of total and mitochondrial signal transducer and activator of transcription 3 were enhanced in LSHKO compared with control mice. In line with this observation and the increased energy expenditure of LSHKO, oxygen consumption rate was higher in liver mitochondria of LSHKO compared with controls. Collectively, these studies identify hepatic Shp2 as a novel regulator of systemic energy balance under conditions of high-fat feeding. PMID:22619361

Cow milk allergy symptoms are reduced in mice fed dietary synbiotics during oral sensitization with whey.

PubMed

Schouten, Bastiaan; van Esch, Betty C A M; Hofman, Gerard A; van Doorn, Suzan A C M; Knol, Jan; Nauta, Alma J; Garssen, Johan; Willemsen, Linette E M; Knippels, Léon M J

2009-07-01

Cow milk allergy is the most common food allergy in children. So far, no effective treatment is available to prevent or cure food allergy. The purpose of this study was to compare effects of dietary supplementation with a prebiotic mixture (Immunofortis), a probiotic strain [Bifidobacterium breve M-16V], or a synbiotic diet combining both on the outcome of the allergic response when provided during oral sensitization with whey in mice. Mice were fed diets containing 2% (wt:wt) Immunofortis and/or the B. breve M-16V (n = 6/group). The acute allergic skin response was determined by measuring ear swelling. Antigen-induced anaphylaxis was scored. Furthermore, whey-specific serum immunoglobulins and mouse mast cell protease-1 (mMCP-1) were determined. In mice fed the synbiotic mixture, the allergic skin response and the anaphylactic reaction were strongly reduced compared with whey-sensitized mice fed the control diet (P < 0.01). Immunofortis or B. breve M-16V alone were significantly less effective in reducing the allergic skin response than the synbiotic diet and did not reduce the anaphylactic reaction. The whey-specific IgE and IgG(1) responses were not affected; however, IgG(2a) was greater in all treated groups than in the control group (P < 0.05). Serum mMCP-1 concentrations, reflecting mucosal mast cell degranulation, were lower in mice fed synbiotics compared with those fed the control diet (P < 0.01). Dietary supplementation with Immunofortis, B. breve M-16V, and particularly the synbiotic mixture, provided during sensitization, reduces the allergic effector response in a murine model of IgE-mediated hypersensitivity that mimics the human route of sensitization. This model shows the potential for dietary intervention with synbiotics in reducing the allergic response to food allergens.

DNA Repair and the Accumulation of Oxidatively Damaged DNA Are Affected by Fruit Intake in Mice

PubMed Central

Croteau, Deborah L.; de Souza-Pinto, Nadja C.; Harboe, Charlotte; Keijzers, Guido; Zhang, Yongqing; Becker, Kevin; Sheng, Shan

2010-01-01

AGING is associated with elevated oxidative stress and DNA damage. To achieve healthy aging, we must begin to understand how diet affects cellular processes. We postulated that fruit-enriched diets might initiate a program of enhanced DNA repair and thereby improve genome integrity. C57Bl/6 J mice were fed for 14 weeks a control diet or a diet with 8% peach or nectarine extract. The activities of DNA repair enzymes, the level of DNA damage, and gene expression changes were measured. Our study showed that repair of various oxidative DNA lesions was more efficient in liver extracts derived from mice fed fruit-enriched diets. In support of these findings, gas chromatography–mass spectrometry analysis revealed that there was a decrease in the levels of formamidopyrimidines in peach-fed mice compared with the controls. Additionally, microarray analysis revealed that NTH1 was upregulated in peach-fed mice. Taken together, these results suggest that an increased intake of fruits might modulate the efficiency of DNA repair, resulting in altered levels of DNA damage. PMID:20847039

Western Diet-Induced Dysbiosis in Farnesoid X Receptor Knockout Mice Causes Persistent Hepatic Inflammation after Antibiotic Treatment.

PubMed

Jena, Prasant K; Sheng, Lili; Liu, Hui-Xin; Kalanetra, Karen M; Mirsoian, Annie; Murphy, William J; French, Samuel W; Krishnan, Viswanathan V; Mills, David A; Wan, Yu-Jui Yvonne

2017-08-01

Patients who have liver cirrhosis and liver cancer also have reduced farnesoid X receptor (FXR). The current study analyzes the effect of diet through microbiota that affect hepatic inflammation in FXR knockout (KO) mice. Wild-type and FXR KO mice were on a control (CD) or Western diet (WD) for 10 months. In addition, both CD- and WD-fed FXR KO male mice, which had hepatic lymphocyte and neutrophil infiltration, were treated by vancomycin, polymyxin B, and Abx (ampicillin, neomycin, metronidazole, and vancomycin). Mice were subjected to morphological analysis as well as gut microbiota and bile acid profiling. Male WD-fed FXR KO mice had the most severe steatohepatitis. FXR KO also had reduced Firmicutes and increased Proteobacteria, which could be reversed by Abx. In addition, Abx eliminated hepatic neutrophils and lymphocytes in CD-fed, but not WD-fed, FXR KO mice. Proteobacteria and Bacteroidetes persisted in WD-fed FXR KO mice even after Abx treatment. Only polymyxin B could reduce hepatic lymphocytes in WD-fed FXR KO mice. The reduced hepatic inflammation by antibiotics was accompanied by decreased free and conjugated secondary bile acids as well as changes in gut microbiota. Our data revealed that Lactococcus, Lactobacillus, and Coprococcus protect the liver from inflammation. Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Pomegranate polyphenols and extract inhibit nuclear factor of activated T-cell activity and microglial activation in vitro and in a transgenic mouse model of Alzheimer disease.

PubMed

Rojanathammanee, Lalida; Puig, Kendra L; Combs, Colin K

2013-05-01

Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract-supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression.

Pomegranate Polyphenols and Extract Inhibit Nuclear Factor of Activated T-Cell Activity and Microglial Activation In Vitro and in a Transgenic Mouse Model of Alzheimer Disease123

PubMed Central

Rojanathammanee, Lalida; Puig, Kendra L.; Combs, Colin K.

2013-01-01

Alzheimer disease (AD) brain is characterized by extracellular plaques of amyloid β (Aβ) peptide with reactive microglia. This study aimed to determine whether a dietary intervention could attenuate microgliosis. Memory was assessed in 12-mo-old male amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice via Barnes maze testing followed by division into either a control-fed group provided free access to normal chow and water or a treatment group provided free access to normal chow and drinking water supplemented with pomegranate extract (6.25 mL/L) for 3 mo followed by repeat Barnes maze testing for both groups. Three months of pomegranate feeding decreased the path length to escape of mice compared with their initial 12-mo values (P < 0.05) and their control-fed counterparts (P < 0.05). Brains of the 3-mo study pomegranate-fed mice had lower tumor necrosis factor α (TNF-α) concentrations (P < 0.05) and lower nuclear factor of activated T-cell (NFAT) transcriptional activity (P < 0.05) compared with controls. Brains of the 3-mo pomegranate or control mice were also compared with an additional control group of 12-mo-old mice for histologic analysis. Immunocytochemistry showed that pomegranate- but not control-fed mice had attenuated microgliosis (P < 0.05) and Aβ plaque deposition (P < 0.05) compared with 12-mo-old mice. An additional behavioral study again used 12-mo-old male APP/PS1 mice tested by T-maze followed by division into a control group provided with free access to normal chow and sugar supplemented drinking water or a treatment group provided with normal chow and pomegranate extract–supplemented drinking water (6.25 mL/L) for 1 mo followed by repeat T-maze testing in both groups. One month of pomegranate feeding increased spontaneous alternations versus control-fed mice (P < 0.05). Cell culture experiments verified that 2 polyphenol components of pomegranate extract, punicalagin and ellagic acid, attenuated NFAT activity in a reporter cell line (P < 0.05) and decreased Aβ-stimulated TNF-α secretion by murine microglia (P < 0.05). These data indicate that dietary pomegranate produces brain antiinflammatory effects that may attenuate AD progression. PMID:23468550

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

PubMed

Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

2015-01-01

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Vitamin A-Deficient Diet Accelerated Atherogenesis in Apolipoprotein E−/− Mice and Dietary β-Carotene Prevents This Consequence

PubMed Central

Relevy, Noa Zolberg; Harats, Dror; Harari, Ayelet; Ben-Amotz, Ami; Bitzur, Rafael; Rühl, Ralph; Shaish, Aviv

2015-01-01

Vitamin A is involved in regulation of glucose concentrations, lipid metabolism, and inflammation, which are major risk factors for atherogenesis. However, the effect of vitamin A deficiency on atherogenesis has not been investigated. Therefore, the objective of the current study was to examine whether vitamin A deficiency accelerates atherogenesis in apolipoprotein E-deficient mice (apoE−/−). ApoE−/− mice were allocated into the following groups: control, fed vitamin A-containing chow diet; BC, fed chow diet fortified with Dunaliella powder containing βc isomers; VAD, fed vitamin A-deficient diet; and VAD-BC group, fed vitamin A-deficient diet fortified with a Dunaliella powder. Following 15 weeks of treatment, liver retinol concentration had decreased significantly in the VAD group to about 30% that of control group. Vitamin A-deficient diet significantly increased both plasma cholesterol concentrations and the atherosclerotic lesion area at the aortic sinus (+61%) compared to the control group. Dietary βc fortification inhibited the elevation in plasma cholesterol and retarded atherogenesis in mice fed the vitamin A-deficient diet. The results imply that dietary vitamin A deficiency should be examined as a risk factor for atherosclerosis and that dietary βc, as a sole source of retinoids, can compensate for vitamin A deficiency. PMID:25802864

Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice

PubMed Central

Taira, Satsuki; Kasubuchi, Mayu; Li, Xuan; Irie, Junichiro; Itoh, Hiroshi

2018-01-01

Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs. PMID:29698465

Sex-dependent regulation of hypothalamic neuropeptide Y-Y1 receptor gene expression in moderate/high fat, high-energy diet-fed mice

PubMed Central

Zammaretti, Francesca; Panzica, Giancarlo; Eva, Carola

2007-01-01

In this study we investigated whether long-term consumption of a moderate/high fat (MHF), high-energy diet can affect the gene expression of the Y1 receptor (Y1R) for neuropeptide Y (NPY) in the dorsomedial (DMH), ventromedial (VMH), arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of male and female Y1R/LacZ transgenic mice, carrying the murine Y1R promoter linked to the LacZ gene. MHF diet-fed male mice showed an increased consumption of metabolizable energy that was associated with a significant increase in body weight as compared with chow-fed controls. In parallel, consumption of a MHF diet for 8 weeks significantly decreased Y1R/LacZ transgene expression in the DMH and VMH of male mice whereas no changes were found in the ARC and PVN. Leptin treatment reduced body weight of both MHF diet- and chow-fed male mice but failed to prevent the decrease in Y1R/LacZ transgene expression apparent in the DMH and VMH of male mice after 8 weeks of MHF diet intake. Conversely, no significant changes of metabolizable energy intake, body weight or hypothalamic β-galactosidase expression were found in MHF diet-fed female Y1R/LacZ transgenic mice. A gender-related difference of Y1R/LacZ transgenic mice was also observed in response to leptin treatment that failed to decrease body weight of both MHF diet- and chow-fed female mice. Results herein demonstrate that Y1R/LacZ FVB mice show a sexual dimorphism both on energy intake and on nucleus-specific regulation of the NPY Y1R system in the hypothalamus. Overall, these results provide new insights into the mechanism by which diet composition affects the hypothalamic circuit that controls energy homeostasis. PMID:17584829

The Major Green Tea Polyphenol, (−)-Epigallocatechin-3-Gallate, Inhibits Obesity, Metabolic Syndrome, and Fatty Liver Disease in High-Fat–Fed Mice1,2

PubMed Central

Bose, Mousumi; Lambert, Joshua D.; Ju, Jihyeung; Reuhl, Kenneth R.; Shapses, Sue A.; Yang, Chung S.

2008-01-01

In this study, we investigated the effects of the major green tea polyphenol, (−)-epigallocatechin-3-gallate (EGCG), on high-fat–induced obesity, symptoms of the metabolic syndrome, and fatty liver in mice. In mice fed a high-fat diet (60% energy as fat), supplementation with dietary EGCG treatment (3.2 g/kg diet) for 16 wk reduced body weight (BW) gain, percent body fat, and visceral fat weight (P < 0.05) compared with mice without EGCG treatment. The BW decrease was associated with increased fecal lipids in the high-fat–fed groups (r2 = 0.521; P < 0.05). EGCG treatment attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations in high-fat–fed mice (P < 0.05). EGCG treatment also decreased liver weight, liver triglycerides, and plasma alanine aminotransferase concentrations in high-fat–fed mice (P < 0.05). Histological analyses of liver samples revealed decreased lipid accumulation in hepatocytes in mice treated with EGCG compared with high-fat diet-fed mice without EGCG treatment. In another experiment, 3-mo-old high-fat–induced obese mice receiving short-term EGCG treatment (3.2 g/kg diet, 4 wk) had decreased mesenteric fat weight and blood glucose compared with high-fat–fed control mice (P < 0.05). Our results indicate that long-term EGCG treatment attenuated the development of obesity, symptoms associated with the metabolic syndrome, and fatty liver. Short-term EGCG treatment appeared to reverse preexisting high-fat–induced metabolic pathologies in obese mice. These effects may be mediated by decreased lipid absorption, decreased inflammation, and other mechanisms. PMID:18716169

Effect of peroxisome proliferator-activated receptor alpha activators on tumor necrosis factor expression in mice during endotoxemia.

PubMed

Hill, M R; Clarke, S; Rodgers, K; Thornhill, B; Peters, J M; Gonzalez, F J; Gimble, J M

1999-07-01

Inflammatory mediators orchestrate the host immune and metabolic response to acute bacterial infections and mediate the events leading to septic shock. Tumor necrosis factor (TNF) has long been identified as one of the proximal mediators of endotoxin action. Recent studies have implicated peroxisome proliferator-activated receptor alpha (PPARalpha) as a potential target to modulate regulation of the immune response. Since PPARalpha activators, which are hypolipidemic drugs, are being prescribed for a significant population of older patients, it is important to determine the impact of these drugs on the host response to acute inflammation. Therefore, we examined the role of PPARalpha activators on the regulation of TNF expression in a mouse model of endotoxemia. CD-1 mice treated with dietary fenofibrate or Wy-14,643 had fivefold-higher lipopolysaccharide (LPS)-induced TNF plasma levels than LPS-treated control-fed animals. Higher LPS-induced TNF levels in drug-fed animals were reflected physiologically in significantly lower glucose levels in plasma and a significantly lower 50% lethal dose than those in LPS-treated control-fed animals. Utilizing PPARalpha wild-type (WT) and knockout (KO) mice, we showed that the effect of fenofibrate on LPS-induced TNF expression was indeed mediated by PPARalpha. PPARalpha WT mice fed fenofibrate also had a fivefold increase in LPS-induced TNF levels in plasma compared to control-fed animals. However, LPS-induced TNF levels were significantly decreased and glucose levels in plasma were significantly increased in PPARalpha KO mice fed fenofibrate compared to those in control-fed animals. Data from peritoneal macrophage studies indicate that Wy-14,643 modestly decreased TNF expression in vitro. Similarly, overexpression of PPARalpha in 293T cells decreased activity of a human TNF promoter-luciferase construct. The results from these studies suggest that any anti-inflammatory activity of PPARalpha in vivo can be masked by other systemic effects of PPARalpha activators.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice

PubMed Central

Gutierrez-Orozco, Fabiola; Thomas-Ahner, Jennifer M.; Berman-Booty, Lisa D.; Galley, Jeffrey D.; Chitchumroonchokchai, Chureeporn; Mace, Thomas; Suksamrarn, Sunit; Bailey, Michael T.; Clinton, Steven K.; Lesinski, Gregory B.; Failla, Mark L.

2014-01-01

Scope Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. Methods and results Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3+ and F4/80+ cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. Conclusion α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk. PMID:24668769

Hepcidin regulation in wild-type and Hfe knockout mice in response to alcohol consumption: evidence for an alcohol-induced hypoxic response.

PubMed

Heritage, Mandy L; Murphy, Therese L; Bridle, Kim R; Anderson, Gregory J; Crawford, Darrell H G; Fletcher, Linda M

2009-08-01

Expression of Hamp1, the gene encoding the iron regulatory peptide hepcidin, is inappropriately low in HFE-associated hereditary hemochromatosis and Hfe knockout mice (Hfe(-/-)). Since chronic alcohol consumption is also associated with disturbances in iron metabolism, we investigated the effects of alcohol consumption on hepcidin mRNA expression in Hfe(-/-) mice. Hfe(-/-) and C57BL/6 (wild-type) mice were pair-fed either an alcohol liquid diet or control diet for up to 8 weeks. The mRNA levels of hepcidin and ferroportin were measured at the mRNA level by RT-PCR and protein expression of hypoxia inducible factor-1 alpha (HIF-1alpha) was measured by western blot. Hamp1 mRNA expression was significantly decreased and duodenal ferroportin expression was increased in alcohol-fed wild-type mice at 8 weeks. Time course experiments showed that the decrease in hepcidin mRNA was not immediate, but was significant by 4 weeks. Consistent with the genetic defect, Hamp1 mRNA was decreased and duodenal ferroportin mRNA expression was increased in Hfe(-/-) mice fed on the control diet compared with wild-type animals and alcohol further exacerbated these effects. HIF-1alpha protein levels were elevated in alcohol-fed wild-type animals compared with controls. Alcohol may decrease Hamp1 gene expression independently of the HFE pathway possibly via alcohol-induced hypoxia.

Soybean β-Conglycinin Prevents Age-Related Hearing Impairment.

PubMed

Tanigawa, Tohru; Shibata, Rei; Kondo, Kazuhisa; Katahira, Nobuyuki; Kambara, Takahiro; Inoue, Yoko; Nonoyama, Hiroshi; Horibe, Yuichiro; Ueda, Hiromi; Murohara, Toyoaki

2015-01-01

Obesity-related complications are associated with the development of age-related hearing impairment. β-Conglycinin (β-CG), one of the main storage proteins in soy, offers multiple health benefits, including anti-obesity and anti-atherosclerotic effects. Here, to elucidate the potential therapeutic application of β-CG, we investigated the effect of β-CG on age-related hearing impairment. Male wild-type mice (age 6 months) were randomly divided into β-CG-fed and control groups. Six months later, the body weight was significantly lower in β-CG-fed mice than in the controls. Consumption of β-CG rescued the hearing impairment observed in control mice. Cochlear blood flow also increased in β-CG-fed mice, as did the expression of eNOS in the stria vascularis (SV), which protects vasculature. β-CG consumption also ameliorated oxidative status as assessed by 4-HNE staining. In the SV, lipofuscin granules of marginal cells and vacuolar degeneration of microvascular pericytes were decreased in β-CG-fed mice, as shown by transmission electron microscopy. β-CG consumption prevented loss of spiral ganglion cells and reduced the frequencies of lipofuscin granules, nuclear invaginations, and myelin vacuolation. Our observations indicate that β-CG ameliorates age-related hearing impairment by preserving cochlear blood flow and suppressing oxidative stress.

Korean pine nut oil replacement decreases intestinal lipid uptake while improves hepatic lipid metabolism in mice

PubMed Central

Zhu, Shuang; Park, Soyoung; Lim, Yeseo; Shin, Sunhye

2016-01-01

BACKGROUND/OBJECTIVES Consumption of pine nut oil (PNO) was shown to reduce weight gain and attenuate hepatic steatosis in mice fed a high-fat diet (HFD). The aim of this study was to examine the effects of PNO on both intestinal and hepatic lipid metabolism in mice fed control or HFD. MATERIALS/METHODS Five-week-old C57BL/6 mice were fed control diets containing 10% energy fat from either Soybean Oil (SBO) or PNO, or HFD containing 15% energy fat from lard and 30% energy fat from SBO or PNO for 12 weeks. Expression of genes related to intestinal fatty acid (FA) uptake and channeling (Cd36, Fatp4, Acsl5, Acbp), intestinal chylomicron synthesis (Mtp, ApoB48, ApoA4), hepatic lipid uptake and channeling (Lrp1, Fatp5, Acsl1, Acbp), hepatic triacylglycerol (TAG) lipolysis and FA oxidation (Atgl, Cpt1a, Acadl, Ehhadh, Acaa1), as well as very low-density lipoprotein (VLDL) assembly (ApoB100) were determined by real-time PCR. RESULTS In intestine, significantly lower Cd36 mRNA expression (P < 0.05) and a tendency of lower ApoA4 mRNA levels (P = 0.07) was observed in PNO-fed mice, indicating that PNO consumption may decrease intestinal FA uptake and chylomicron assembly. PNO consumption tended to result in higher hepatic mRNA levels of Atgl (P = 0.08) and Cpt1a (P = 0.05). Significantly higher hepatic mRNA levels of Acadl and ApoB100 were detected in mice fed PNO diet (P < 0.05). These results suggest that PNO could increase hepatic TAG metabolism; mitochondrial fatty acid oxidation and VLDL assembly. CONCLUSIONS PNO replacement in the diet might function in prevention of excessive lipid uptake by intestine and improve hepatic lipid metabolism in both control diet and HFD fed mice. PMID:27698954

Gender Dimorphism in Aspartame-Induced Impairment of Spatial Cognition and Insulin Sensitivity

PubMed Central

Collison, Kate S.; Makhoul, Nadine J.; Zaidi, Marya Z.; Saleh, Soad M.; Andres, Bernard; Inglis, Angela; Al-Rabiah, Rana; Al-Mohanna, Futwan A.

2012-01-01

Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame, commencing in utero, may affect spatial cognition and glucose homeostasis in C57BL/6J mice, particularly in males. PMID:22509243

Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity.

PubMed

Collison, Kate S; Makhoul, Nadine J; Zaidi, Marya Z; Saleh, Soad M; Andres, Bernard; Inglis, Angela; Al-Rabiah, Rana; Al-Mohanna, Futwan A

2012-01-01

Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame, commencing in utero, may affect spatial cognition and glucose homeostasis in C57BL/6J mice, particularly in males.

Adipokine production in mice fed high-fat diets containing different types of dietary fats

USDA-ARS?s Scientific Manuscript database

The present study compared high-fat diets containing different types of dietary fats with various levels of linoleic acid (18:2n6, LA) and a-linolenic acid (18:3n3, ALA) on adipokine production in male C57BL/6 mice. Three-week old mice were fed AIN93G diet (15% of energy from corn oil, control) or ...

Functional Deficits Precede Structural Lesions in Mice With High-Fat Diet-Induced Diabetic Retinopathy.

PubMed

Rajagopal, Rithwick; Bligard, Gregory W; Zhang, Sheng; Yin, Li; Lukasiewicz, Peter; Semenkovich, Clay F

2016-04-01

Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet-induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat-fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat-fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat-fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effects of diet quality on vulnerability to mild subchronic social defeat stress in mice.

PubMed

Goto, Tatsuhiko; Kubota, Yoshifumi; Toyoda, Atsushi

2016-09-01

The chronic social defeat stress (CSDS) mouse model is a potentially useful system for understanding stress responses to social environments. We previously developed a mouse model of subchronic and mild social defeat stress (sCSDS) that exhibits increased body weight gain and food intake following polydipsia-like features. sCSDS mice also show avoidance behavior in a social interaction test. In this study, we examined the effects of diet quality on susceptibility to sCSDS by feeding these mice semi- and non-purified diets. Male C57BL/6J (B6; n = 82) mice were exposed to sCSDS using male ICR mice. The B6 mice were divided into four test groups: semi-purified pellet diet + sCSDS, non-purified pellet diet + sCSDS, semi-purified diet + control (no sCSDS), and non-purified diet + control. Although increased body weight, and food and water intake following sCSDS exposure were consistently observed in the groups that were fed semi- and non-purified diets, social avoidance behavior was influenced by food type (i.e., sCSDS mice fed semi-purified diet showed the greatest social avoidance behavior). In addition, the rates of stress susceptibility were estimated at 73.9 and 34.8% in sCSDS mice fed semi-purified and non-purified diets, respectively (P < 0.05). For comparison, the susceptible-like phenotype rates were estimated at 12.5 and 8.3% in healthy control mice fed semi-purified and non-purified diets, respectively. These results suggest that diet quality affects the vulnerability of mice to social defeat stress.

Pancreatic β-cell overexpression of the glucagon receptor gene results in enhanced β-cell function and mass

PubMed Central

Gelling, Richard W.; Vuguin, Patricia M.; Du, Xiu Quan; Cui, Lingguang; Rømer, John; Pederson, Raymond A.; Leiser, Margarita; Sørensen, Heidi; Holst, Jens J.; Fledelius, Christian; Johansen, Peter B.; Fleischer, Norman; McIntosh, Christopher H. S.; Nishimura, Erica; Charron, Maureen J.

2009-01-01

In addition to its primary role in regulating glucose production from the liver, glucagon has many other actions, reflected by the wide tissue distribution of the glucagon receptor (Gcgr). To investigate the role of glucagon in the regulation of insulin secretion and whole body glucose homeostasis in vivo, we generated mice overexpressing the Gcgr specifically on pancreatic β-cells (RIP-Gcgr). In vivo and in vitro insulin secretion in response to glucagon and glucose was increased 1.7- to 3.9-fold in RIP-Gcgr mice compared with controls. Consistent with the observed increase in insulin release in response to glucagon and glucose, the glucose excursion resulting from both a glucagon challenge and intraperitoneal glucose tolerance test (IPGTT) was significantly reduced in RIP-Gcgr mice compared with controls. However, RIP-Gcgr mice display similar glucose responses to an insulin challenge. β-Cell mass and pancreatic insulin content were also increased (20 and 50%, respectively) in RIP-Gcgr mice compared with controls. When fed a high-fat diet (HFD), both control and RIP-Gcgr mice developed similar degrees of obesity and insulin resistance. However, the severity of both fasting hyperglycemia and impaired glucose tolerance (IGT) were reduced in RIP-Gcgr mice compared with controls. Furthermore, the insulin response of RIP-Gcgr mice to an IPGTT was twice that of controls when fed the HFD. These data indicate that increased pancreatic β-cell expression of the Gcgr increased insulin secretion, pancreatic insulin content, β-cell mass, and, when mice were fed a HFD, partially protected against hyperglycemia and IGT. PMID:19602585

High-fat simple carbohydrate (HFSC) diet impairs hypothalamic and corpus striatal serotonergic metabolic pathway in metabolic syndrome (MetS) induced C57BL/6J mice.

PubMed

Stephen, DSouza Serena; Abraham, Asha

2017-07-26

To study the effect of specially formulated high-fat simple carbohydrate diet (HFSC) on the serotonin metabolic pathway in male C57BL/6J mice. Previous studies from our laboratory have shown that specially formulated HFSC induces metabolic syndrome in C57BL/6J mice. In the present investigation, 5-hydroxytryptophan, serotonin and 5-hydroxyindoleacetic acid were analyzed in two brain regions (hypothalamus, corpus striatum), urine and plasma of HFSC-fed mice on a monthly basis up to 5 months using high-performance liquid chromatography fitted with electrochemical detector. The data were analyzed using Graph pad Prism v7.3 by two-way ANOVA and post hoc Tukey's test (to assess the effect of time on the serotonergic metabolic pathway). HFSC feed was observed to lower the hypothalamic serotonergic tone as compared to the age-matched control-fed C57BL/6J mice. Although the hypothalamic serotonergic tone was unaltered over time due to consumption of diet per se, hypothalamic 5-HTP levels were observed to be lower on consumption of HFSC feed over duration of 5 months as compared to 1st month of consumption of HFSC feed. The striatal 5-HTP levels were lowered in the HFSC-fed mice after 4 months of feeding as compared to the age-matched control-fed mice. The striatal 5-HTP levels were also lower in both control and HFSC-fed mice due to consumption of the respective diet over a duration of 5 months. Increased plasma 5-HTP levels were observed due to consumption of HFSC feed over duration of 5 months in the HFSC-fed group. However, higher breakdown of serotonin was observed in both the plasma and urine of HFSC-fed C57BL/6J mice as per the turnover studies. The central and peripheral serotonergic pathway is affected differentially by both the type of diet consumed and the duration for which the diet is consumed. The hypothalamic, striatal and plasma serotonergic pathway were altered both by the type of feed consumed and the duration of feeding. The urine serotonergic pathway was affected by mainly the duration for which a particular diet was consumed. These findings may have implications in the feeding behavior, cognitive decline and depression associated with metabolic syndrome patients.

Changes in intestinal immunity, gut microbiota, and expression of energy metabolism-related genes explain adenoma growth in bilberry and cloudberry-fed ApcMin mice.

PubMed

Päivärinta, Essi; Niku, Mikael; Maukonen, Johanna; Storvik, Markus; Heiman-Lindh, Anu; Saarela, Maria; Pajari, Anne-Maria; Mutanen, Marja

2016-11-01

We showed previously that ellagitannin-rich cloudberries and anthocyanin-rich bilberries reduce the number of intestinal adenomas in multiple intestinal neoplasia/+ (Apc Min ) mice. We also found that cloudberries decreased the size of adenomas, whereas bilberries increased it. Here we hypothesized that the difference in adenoma growth could be explained by dissimilar effects of the berries on intestinal immune responses and gut microbiota, potentially driven by the distinct polyphenol compositions of the 2 berries. Our objectives were to investigate lymphocyte subtypes and the predominant cecal bacterial diversity in mice fed with bilberries and cloudberries, and to analyze global gene expression profiles in the intestinal mucosa. Immunostainings of CD3 + T lymphocytes, FoxP3 + regulatory T lymphocytes, and CD45R + B lymphocytes revealed a smaller ratio of intraepithelial to all mucosal CD3 + T lymphocytes in the cloudberry-fed mice compared with controls, suggesting an attenuation of inflammation. Bilberry feeding induced no changes in the density of any of the lymphocyte subtypes. The predominant bacterial diversity in cecal contents, analyzed using polymerase chain reaction-denaturating gradient gel electrophoresis, was higher in the bilberry group than in the control or cloudberry groups. The microbial profiles of cloudberry-fed mice clustered together and were associated with small adenoma size. Pathway analyses of gene expression data showed that cloudberry down-regulated and bilberry up-regulated the expression of energy metabolism-related genes in the intestinal mucosa. In conclusion, attenuation of intestinal inflammation, changes in microbial profiles, and down-regulation of mucosal energy metabolism may account for the smaller adenoma size in cloudberry-fed mice in comparison to bilberry-fed mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Hops (Humulus lupulus) Content in Beer Modulates Effects of Beer on the Liver After Acute Ingestion in Female Mice.

PubMed

Landmann, Marianne; Sellmann, Cathrin; Engstler, Anna Janina; Ziegenhardt, Doreen; Jung, Finn; Brombach, Christine; Bergheim, Ina

2017-01-01

Using a binge-drinking mouse model, we aimed to determine whether hops (Humulus lupulus) in beer is involved in the less damaging effects of acute beer consumption on the liver in comparison with ethanol. Female C57BL/6 J mice were either fed one iso-alcoholic and iso-caloric bolus dose of ethanol, beer, beer without hops (6 g ethanol/kg body weight) or an iso-caloric bolus of maltodextrin control solution. Markers of steatosis, intestinal barrier function, activation of toll-like receptor 4 signaling cascades, lipid peroxidation and lipogenesis were determined in liver, small intestine and plasma 2 h and 12 h after acute alcohol ingestion. Alcohol-induced hepatic fat accumulation was significantly attenuated in mice fed beer whereas in those fed beer without hops, hepatic fat accumulation was similar to that found in ethanol-fed mice. While markers of intestinal barrier function e.g. portal endotoxin levels and lipogenesis only differed slightly between groups, hepatic concentrations of myeloid differentiation primary response gene 88, inducible nitric oxide synthase (iNOS) and plasminogen-activator inhibitor 1 protein as well as of 4-hydroxynonenal and 3-nitrotyrosine protein adducts were similarly elevated in livers of mice fed ethanol or beer without hops when compared with controls. Induction of these markers was markedly attenuated in mice fed hops-containing beer. Taken together, our data suggest that hops in beer markedly attenuated acute alcohol-induced liver steatosis in female mice through mechanisms involving a suppression of iNOS induction in the liver. © The Author 2016. Medical Council on Alcohol and Oxford University Press. All rights reserved.

S100A8 Production in CXCR2-Expressing CD11b+Gr-1high Cells Aggravates Hepatitis in Mice Fed a High-Fat and High-Cholesterol Diet.

PubMed

Mukai, Kaori; Miyagi, Takuya; Nishio, Kumiko; Yokoyama, Yoshinobu; Yoshioka, Teppei; Saito, Yoshinobu; Tanaka, Satoshi; Shigekawa, Minoru; Nawa, Takatoshi; Hikita, Hayato; Sakamori, Ryotaro; Yoshihara, Harumasa; Imai, Yasuharu; Hiramatsu, Naoki; Tatsumi, Tomohide; Takehara, Tetsuo

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease with a spectrum of presentations. S100A8 has been suggested to play a pivotal role as an endogenous immune-activator in inflammatory diseases. In this study, we investigated the involvement of S100A8 in the development of NAFLD. We used a diet model of NAFLD, in which mice were fed either a high-fat and high-cholesterol diet (HFHCD) or a normal diet (ND) as a control. We also assessed liver tissues from patients with NAFLD, including patients with nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). HFHCD-fed mice, but not ND-fed mice, developed steatohepatitis. S100A8 expression was significantly elevated in the livers of HFHCD-fed mice compared with the controls. S100A8 was exclusively expressed in CXCR2-expressing CD11b(+)Gr-1(high) cells, which significantly increased in the livers of HFHCD-fed mice. These cells were F4/80 negative and did not possess a suppressor function. TNF-α expression was enhanced by S100A8 in primary liver leukocytes or a hepatocyte cell line and significantly elevated in the livers of HFHCD-fed mice. TNF-α was primarily produced from CD11b(+)F4/80(+) cells in liver leukocytes in response to S100A8. TNF-α deficiency attenuated hepatitis in HFHCD-fed mice. S100A8 was significantly more expressed in the liver tissues of patients with NASH than in those of patients with NAFL. In conclusion, these results suggest that S100A8 is primarily produced from CXCR2-expressing CD11b(+)Gr-1(high) cells, and it upregulates TNF-α production in CD11b(+)F4/80(+) cells through cellular cross-talk, which is an important mechanism in the development of NAFLD. Copyright © 2015 by The American Association of Immunologists, Inc.

Probiotic dahi containing Lactobacillus casei protects against Salmonella enteritidis infection and modulates immune response in mice.

PubMed

Jain, Shalini; Yadav, Hariom; Sinha, P R

2009-06-01

In the present study, effect of dahi containing probiotic Lactobacillus casei (probiotic dahi) was evaluated to modulate immune response against Salmonella enteritidis infection in mice. Animals were fed with milk products along with standard diet for 2 and 7 days prior to the S. enteritidis challenge and continued on the respective dairy food-supplemented diets during the postchallenge period. Translocation of S. enteritidis in spleen and liver, beta-galactosidase and beta-glucuronidase enzymatic activities and secretory IgA (sIgA) in intestinal fluid, lymphocyte proliferation, and cytokine (interleukin [IL]-2, IL-4, IL-6, and interferon-gamma [IFN-gamma]) production in cultured splenocytes were assessed on day 2, 5, and 8 of the postchallenge period. Colonization of S. enteritidis in liver and spleen was remarkably low in probiotic dahi-fed mice than mice fed milk and control dahi. The beta-galactosidase and beta-glucuronidase activities in intestinal fluid collected from mice prefed for 7 days with probiotic dahi were significantly lower at day 5 and 8 postchallenge than in mice fed milk and control dahi. Levels of sIgA and lymphocyte proliferation rate were also significantly increased in probiotic dahi-fed mice compared with the other groups. Production of IL-2, IL-6, and IFN-gamma increased, whereas IL-4 decreased in splenic lymphocytes collected from probiotic dahi-fed mice. Data showed that dahi prefed for 7 days before S. enteritidis challenge was more effective than when mice were prefed for 2 days with dahi. Moreover, probiotic dahi was more efficacious in protecting against S. enteritidis infection by enhancing innate and adaptive immunity than fermented milk and normal dahi. Results of the present study suggest that prefeeding of probiotic dahi may strengthen the consumer's immune system and may protect infectious agents like S. enteritidis.

Purified blueberry anthocyanins and blueberry juice alter development of obesity in mice fed an obesogenic high-fat diet.

PubMed

Prior, Ronald L; E Wilkes, Samuel; R Rogers, Theodore; Khanal, Ramesh C; Wu, Xianli; Howard, Luke R

2010-04-14

Male C57BL/6J mice (25 days of age) were fed either a low-fat diet (10% kcal from fat) (LF) or a high-fat diet (45% kcal from fat) (HF45) for a period of 72 days. Blueberry juice or purified blueberry anthocyanins (0.2 or 1.0 mg/mL) in the drinking water were included in LF or HF45 treatments. Sucrose was added to the drinking water of one treatment to test if the sugars in blueberry juice would affect development of obesity. Total body weights (g) and body fat (%) were higher and body lean tissue (%) was lower in the HF45 fed mice compared to the LF fed mice after 72 days, but in mice fed HF45 diet plus blueberry juice or blueberry anthocyanins (0.2 mg/mL), body fat (%) was not different from those mice fed the LF diet. Anthocyanins (ACNs) decreased retroperitoneal and epididymal adipose tissue weights. Fasting serum glucose concentrations were higher in mice fed the HF45 diet. However, it was reduced to LF levels in mice fed the HF45 diet plus 0.2 mg of ACNs/mL in the drinking water, but not with blueberry juice. beta cell function (HOMA-BCF) score was lowered with HF45 feeding but returned to normal levels in mice fed the HF45 diet plus purified ACNs (0.2 mg/mL). Serum leptin was elevated in mice fed HF45 diet, and feeding either blueberry juice or purified ACNs (0.2 mg/mL) decreased serum leptin levels relative to HF45 control. Sucrose in drinking water, when consumption was restricted to the volume of juice consumed, produced lower serum leptin and insulin levels, leptin/fat, and retroperitoneal and total fat (% BW). Blueberry juice was not as effective as the low dose of anthocyanins in the drinking water in preventing obesity. Additional studies are needed to determine factors responsible for the differing responses of blueberry juice and whole blueberry in preventing the development of obesity.

Making bread with sourdough improves iron bioavailability from reconstituted fortified wheat flour in mice.

PubMed

Chaoui, Asmaa; Faid, Mohamed; Belahsen, Rekia

2006-01-01

This study aimed to evaluate the effect of a diet prepared with traditional sourdough (TS) on iron status. Levels of blood hemoglobin (Hb), Hematocrite (Ht), serum ferritin and serum iron as well as excreted iron were determined in three groups of mice fed with: TS bread (TS group), baking yeast bread (BY group) or bread with no starters (control group), respectively. The results show that the levels of Hb, Ht, ferritin and iron were significantly higher in the TS compared to the BY and control groups. Also a significant decrease in the excreted iron levels was observed in the mice fed with TS compared to the others dietary groups. In conclusion, the study results indicate an improvement of iron status indicators in mice when they were fed sourdough bread as compared to baking yeast bread and bread with no starters.

Spontaneous liver fibrosis induced by long term dietary vitamin D deficiency in adult mice is related to chronic inflammation and enhanced apoptosis.

PubMed

Zhu, Longdong; Kong, Ming; Han, Yuan-Ping; Bai, Li; Zhang, Xiaohui; Chen, Yu; Zheng, Sujun; Yuan, Hong; Duan, Zhongping

2015-05-01

Epidemiological studies have revealed an association between vitamin D deficiency and various chronic liver diseases. However, it is not known whether lack of vitamin D can induce spontaneous liver fibrosis in an animal model. To study this, mice were fed either a control diet or a vitamin D deficient diet (VDD diet). For the positive control, liver fibrosis was induced with carbon tetrachloride. Here we show, for the first time, that liver fibrosis spontaneously developed in mice fed the VDD diet. Long-term administration of a VDD diet resulted in necro-inflammation and liver fibrosis. Inflammatory mediators including tumor necrosis factor-α, interleulin-1, interleukin-6, Toll-like-receptor 4, and monocyte chemotactic protein-1 were up-regulated in the livers of the mice fed the VDD diet. Conversely, the expression of Th2/M2 markers such as IL-10, IL-13, arginase 1, and heme oxygenase-1 were down-regulated in the livers of mice fed the VDD diet. Transforming growth factor-β1 and matrix metalloproteinase 13, which are important for fibrosis, were induced in the livers of mice fed the VDD diet. Moreover, the VDD diet triggered apoptosis in the parenchymal cells, in agreement with the increased levels of Fas and FasL, and decreased Bcl2 and Bclx. Thus, long-term vitamin D deficiency can provoke chronic inflammation that can induce liver apoptosis, which consequently activates hepatic stellate cells to initiate liver fibrosis.

A long-term high-fat diet changes iron distribution in the body, increasing iron accumulation specifically in the mouse spleen.

PubMed

Yamano, Noriko; Ikeda, Yasumasa; Sakama, Minoru; Izawa-Ishizawa, Yuki; Kihira, Yoshitaka; Ishizawa, Keisuke; Miyamoto, Licht; Tomita, Shuhei; Tsuchiya, Koichiro; Tamaki, Toshiaki

2015-01-01

Although iron is an essential trace metal, its presence in excess causes oxidative stress in the human body. Recent studies have indicated that iron storage is a risk factor for type 2 diabetes mellitus. Dietary iron restriction or iron chelation ameliorates symptoms of type 2 diabetes in mouse models. However, whether iron content in the body changes with the development of diabetes is unknown. Here, we investigated the dynamics of iron accumulation and changes in iron absorption-related genes in mice that developed obesity and diabetes by consuming a high-fat diet (HFD-fed mice). HFD-fed mice (18-20 wk) were compared with control mice for hematologic features, serum ferritin levels, and iron contents in the gastrocnemius muscle, heart, epididymal fat, testis, liver, duodenum, and spleen. In addition, the spleen was examined histologically. Iron absorption-related gene expression in the liver and duodenum was also examined. Hemoglobin and serum ferritin levels were increased in HFD-fed mice. The HFD-fed mice showed iron accumulation in the spleen, but not in the heart or liver. Increased percentages of the splenic red pulp and macrophages were observed in HFD-fed mice and iron accumulation in the spleen was found mainly in the splenic red pulp. The HFD-fed mice also showed decreased iron content in the duodenum. The mRNA expression of divalent metal transporter-1 (DMT-1), an iron absorption-related gene, was elevated in the duodenum of HFD-fed mice. These results indicate that iron accumulation (specifically accumulation in the spleen) is enhanced by the development of type 2 diabetes induced by HFD.

Human-relevant Levels of Added Sugar Consumption Increase Female Mortality and Lower Male Fitness in Mice

PubMed Central

Ruff, James S.; Suchy, Amanda K.; Hugentobler, Sara A.; Sosa, Mirtha M.; Schwartz, Bradley L.; Morrison, Linda C.; Gieng, Sin H.; Shigenaga, Mark K.; Potts, Wayne K.

2013-01-01

Consumption of added sugar has increased over recent decades and is correlated with numerous diseases. Rodent models have elucidated mechanisms of toxicity, but only at concentrations beyond typical human exposure. Here we show that comparatively low levels of added sugar consumption have substantial negative effects on mouse survival, competitive ability, and reproduction. Using Organismal Performance Assays (OPAs) – in which mice fed human-relevant concentrations of added sugar (25% Kcal from a mixture of fructose and glucose [F/G]) and control mice compete in seminatural enclosures for territories, resources and mates – we demonstrate that F/G-fed females experience a two-fold increase in mortality while F/G-fed males control 26% fewer territories and produce 25% less offspring. These findings represent the lowest level of sugar consumption shown to adversely affect mammalian health. Clinical defects of F/G-fed mice were decreased glucose clearance and increased fasting cholesterol. Our data highlight that physiological adversity can exist when clinical disruptions are minor, and suggest that OPAs represent a promising technique for unmasking negative effects of toxicants. PMID:23941916

Dietary supplementation with docosahexanoic acid (DHA) increases red blood cell membrane flexibility in mice with sickle cell disease.

PubMed

Wandersee, Nancy J; Maciaszek, Jamie L; Giger, Katie M; Hanson, Madelyn S; Zheng, Suilan; Guo, YiHe; Mickelson, Barbara; Hillery, Cheryl A; Lykotrafitis, George; Low, Philip S; Hogg, Neil

2015-02-01

Humans and mice with sickle cell disease (SCD) have rigid red blood cells (RBCs). Omega-3 fatty acids, such as docosahexanoic acid (DHA), may influence RBC deformability via incorporation into the RBC membrane. In this study, sickle cell (SS) mice were fed natural ingredient rodent diets supplemented with 3% DHA (DHA diet) or a control diet matched in total fat (CTRL diet). After 8weeks of feeding, we examined the RBCs for: 1) stiffness, as measured by atomic force microscopy; 2) deformability, as measured by ektacytometry; and 3) percent irreversibly sickled RBCs on peripheral blood smears. Using atomic force microscopy, it is found that stiffness is increased and deformability decreased in RBCs from SS mice fed CTRL diet compared to wild-type mice. In contrast, RBCs from SS mice fed DHA diet had markedly decreased stiffness and increased deformability compared to RBCs from SS mice fed CTRL diet. Furthermore, examination of peripheral blood smears revealed less irreversibly sickled RBCs in SS mice fed DHA diet as compared to CTRL diet. In summary, our findings indicate that DHA supplementation improves RBC flexibility and reduces irreversibly sickled cells by 40% in SS mice. These results point to potential therapeutic benefits of dietary omega-3 fatty acids in SCD. Copyright © 2014 Elsevier Inc. All rights reserved.

Influence of source and quantity of protein on the development of immunity and resistance to African trypanosomiasis.

PubMed Central

Norton, J D; Yang, S P; Diffley, P

1986-01-01

Although it is well documented that severe protein deprivation inhibits the development of the immune response and exacerbates certain infections, little has been done to study the effects of native diets on endemic diseases or immunity. Therefore, protein-restricted diets were formulated for mice to mimic the sources and amounts measured in human diets of the Batouri region of Cameroon, endemic for African trypanosomiasis. Weanling C57BL/6 female mice were fed a diet that contained 73% of the recommended daily allowance (RDA) of protein. The sources of protein were all plant (cornmeal), all animal (casein), or a ratio that reflected the native diet (2.2 parts plant to 1 part animal protein). Diets were isocaloric on a weight basis, equal in lipids, and adequate in vitamins and minerals. Control mice were fed laboratory chow or two times the RDA of animal protein (casein). Mice fed only cornmeal or the native diets consumed as much food but did not gain as much weight as mice fed only animal protein, indicating the poorer quality of protein in their diets. Upon infection with Trypanosoma brucei gambiense, however, significantly higher numbers of these mice controlled the first peak of parasitemia and survived the infection as compared with mice fed the other three diets. Since all mice developed patent infections and the parasite growth rate was unaffected by diet, innate immune factors were ruled out as the cause for the higher level of resistance to the parasite. To determine whether diet affected the development of the immune system, weanling mice were maintained on diets for 30 days before immunization with sheep erythrocytes or trinitrophenylated Ficoll. Mice fed only plant protein or native diets elicited higher direct plaque-forming-cell responses to both the T-cell-dependent and T-cell-independent antigens. Since variant-specific immunity which controls levels of African trypanosomes in the blood is a T-cell-independent humoral immunoglobulin M response, this suggests that cornmeal, a protein of poor quality, was adequate for the development of humoral immunity and resistance to African trypanosomiasis while casein, an animal protein of high quality, was not. This provides more evidence that diet plays an important role in infection and immunity. PMID:3484725

Cranberry extract attenuates hepatic inflammation in high fat-fed obese mice

PubMed Central

Glisan, Shannon L.; Ryan, Caroline; Neilson, Andrew P.; Lambert, Joshua D.

2016-01-01

Cranberry (Vaccinium macrocarpon) consumption has been associated with health beneficial effects. Non-alcoholic fatty liver disease (NAFLD) is a co-morbidity of obesity. In the present study, we investigated the effect of a polyphenol-rich cranberry extract (CBE) on hepatic inflammation in high fat-fed obese C57BL/6J mice. Following dietary treatment with 0.8% CBE for 10 weeks, we observed no change in body weight or visceral fat mass in CBE supplemented mice compared to high fat-fed control mice. We did observe a significant decrease in plasma alanine aminotransferase (31%) and histological severity of NAFLD (33% decrease in area of involvement, 29% decrease in lipid droplet size) compared to high fat-fed controls. Hepatic protein levels of tumor necrosis factor alpha and C-C chemokine ligand 2 were reduced by 28% and 19%, respectively, following CBE supplementation. CBE significantly decreased hepatic mRNA levels of toll-like receptor 4 (TLR4, 63%) and nuclear factorκ B (NFκB, 24%), as well as a number of genes related to the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome. In conclusion, CBE reduced NAFLD and hepatic inflammation in high fat-fed obese C57BL/6J mice. These effects appear to be related to mitigation of TLR4-NFκB related signaling, however further studies into the underlying mechanisms of these hepatoprotective effects are needed. PMID:27619543

Ethanol affects hepatitis C pathogenesis: humanized SCID Alb-uPA mouse model.

PubMed

Osna, Natalia A; Kharbanda, Kusum K; Sun, Yimin; Simpson, Ronda L; Poluektova, Larisa E; Ganesan, Murali; Wisecarver, James L; Mercer, David F

2014-07-18

Alcohol consumption exacerbates the course of hepatitis C viral (HCV) infection, worsens outcomes and contributes to the development of chronic infection that exhibits low anti-viral treatment efficiency. The lack of suitable in vivo models makes HCV-ethanol studies very difficult. Here, we examine whether chimeric SCID Alb-uPA mice transplanted with human hepatocytes and infected with HCV develop worsening pathology when fed ethanol. After 5 weeks of feeding, such mice fed chow+water (control) or chow+20% ethanol in water (EtOH) diets mice developed oxidative stress, decreased proteasome activity and increased steatosis. Importantly, HCV(+) mice in the control group cleared HCV RNA after 5 weeks, while the infection persisted in EtOH-fed mice at the same or even higher levels compared with pre-feeding HCV RNA. We conclude that in chimeric SCID Alb-uPA mice, EtOH exposure causes the complex biochemical and histological changes typical for alcoholic liver injury. In addition, ethanol feeding delays the clearance of HCV RNA thereby generating persistent infection and promoting liver injury. Overall, this model is appropriate for conducting HCV-ethanol studies. Published by Elsevier Inc.

Exacerbation of Acetaminophen Hepatotoxicity by the Anthelmentic Drug Fenbendazole

PubMed Central

Gardner, Carol R.; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

2012-01-01

Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8–12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole. PMID:22048645

Exacerbation of acetaminophen hepatotoxicity by the anthelmentic drug fenbendazole.

PubMed

Gardner, Carol R; Mishin, Vladimir; Laskin, Jeffrey D; Laskin, Debra L

2012-02-01

Fenbendazole is a broad-spectrum anthelmintic drug widely used to prevent or treat nematode infections in laboratory rodent colonies. Potential interactions between fenbendazole and hepatotoxicants such as acetaminophen are unknown, and this was investigated in this study. Mice were fed a control diet or a diet containing fenbendazole (8-12 mg/kg/day) for 7 days prior to treatment with acetaminophen (300 mg/kg) or phosphate buffered saline. In mice fed a control diet, acetaminophen administration resulted in centrilobular hepatic necrosis and increases in serum transaminases, which were evident within 12 h. Acetaminophen-induced hepatotoxicity was markedly increased in mice fed the fenbendazole-containing diet, as measured histologically and by significant increases in serum transaminase levels. Moreover, in mice fed the fenbendazole-containing diet, but not the control diet, 63% mortality was observed within 24 h of acetaminophen administration. Fenbendazole by itself had no effect on liver histology or serum transaminases. To determine if exaggerated hepatotoxicity was due to alterations in acetaminophen metabolism, we analyzed sera for the presence of free acetaminophen and acetaminophen-glucuronide. We found that there were no differences in acetaminophen turnover. We also measured cytochrome P450 (cyp) 2e1, cyp3a, and cyp1a2 activity. Whereas fenbendazole had no effect on the activity of cyp2e1 or cyp3a, cyp1a2 was suppressed. A prolonged suppression of hepatic glutathione (GSH) was also observed in acetaminophen-treated mice fed the fenbendazole-containing diet when compared with the control diet. These data demonstrate that fenbendazole exacerbates the hepatotoxicity of acetaminophen, an effect that is related to persistent GSH depletion. These findings are novel and suggest a potential drug-drug interaction that should be considered in experimental protocols evaluating mechanisms of hepatotoxicity in rodent colonies treated with fenbendazole.

Dietary α-mangostin, a xanthone from mangosteen fruit, exacerbates experimental colitis and promotes dysbiosis in mice.

PubMed

Gutierrez-Orozco, Fabiola; Thomas-Ahner, Jennifer M; Berman-Booty, Lisa D; Galley, Jeffrey D; Chitchumroonchokchai, Chureeporn; Mace, Thomas; Suksamrarn, Sunit; Bailey, Michael T; Clinton, Steven K; Lesinski, Gregory B; Failla, Mark L

2014-06-01

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. α-Mangostin (α-MG), the most abundant xanthone in mangosteen fruit, exerts anti-inflammatory and antibacterial activities in vitro. We evaluated the impact of dietary α-MG on murine experimental colitis and on the gut microbiota of healthy mice. Colitis was induced in C57BL/6J mice by administration of dextran sulfate sodium (DSS). Mice were fed control diet or diet with α-MG (0.1%). α-MG exacerbated the pathology of DSS-induced colitis. Mice fed diet with α-MG had greater colonic inflammation and injury, as well as greater infiltration of CD3(+) and F4/80(+) cells, and colonic myeloperoxidase, than controls. Serum levels of granulocyte colony-stimulating factor, IL-6, and serum amyloid A were also greater in α-MG-fed animals than in controls. The colonic and cecal microbiota of healthy mice fed α-MG but no DSS shifted to an increased abundance of Proteobacteria and decreased abundance of Firmicutes and Bacteroidetes, a profile similar to that found in human UC. α-MG exacerbated colonic pathology during DSS-induced colitis. These effects may be associated with an induction of intestinal dysbiosis by α-MG. Our results suggest that the use of α-MG-containing supplements by patients with UC may have unintentional risk. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Waksman, Ron; Pakala, Rajbabu; Burnett, Mary S.

Introduction: Inflammatory and immunological responses of vascular cells are known to play significant roles in atherosclerotic plaque development. Rapamycin with antiinflammatory, immunosuppressive and antiproliferative properties has been shown to reduce neointima formation when coated on stents. This study is designed to test the potential of oral rapamycin to inhibit atherosclerotic plaque development. Methods: Eight-week-old apoE knock-out mice were fed with 0.25% cholesterol supplemented diet (control diet), control diet containing 50 {mu}g/kg rapamycin (low-dose rapamycin) or 100 {mu}g/kg rapamycin (high-dose rapamycin) for 4 or 8 weeks. Subsets of mice from each group (n=10) were weighed and euthanized. Whole blood rapamycin levelsmore » were determined using HPLC-MS/MS, and histological analyses of atherosclerotic lesions in the aortic root were performed. Results: Mice fed with high-dose rapamycin did not gain weight (18.5{+-}1.5 vs. 20.6{+-}0.9 g, P=.01). Blood levels of rapamycin 117{+-}7 pg/ml were detected in the blood of mice fed with high-dose rapamycin for 8 weeks. The plaque area in mice fed with high dose oral rapamycin is significantly less as compared to control (0.168{+-}0.008 vs. 0.326{+-}0.013 mm{sup 2}, P=.001 at 4 weeks; 0.234{+-}0.013 vs. 0.447{+-}0.011 mm{sup 2}, P=.001 at 8 weeks). Lumen area was inversely proportional to the plaque area. Conclusions: The results indicate that oral rapamycin is effective in attenuating the progression of atherosclerotic plaque in the mice.« less

Mitochondrial-nuclear genome interactions in nonalcoholic fatty liver disease in mice

PubMed Central

Betancourt, Angela M.; King, Adrienne L.; Fetterman, Jessica L.; Millender-Swain, Telisha; Finley, Rachel D.; Oliva, Claudia R.; Crowe, David Ralph; Ballinger, Scott W.; Bailey, Shannon M.

2014-01-01

Nonalcoholic fatty liver disease (NAFLD) involves significant changes in liver metabolism characterized by oxidative stress, lipid accumulation, and fibrogenesis. Mitochondrial dysfunction and bioenergetic defects also contribute to NAFLD. Herein, we examined whether differences in mtDNA influence NAFLD. To determine the role of mitochondrial and nuclear genomes in NAFLD, Mitochondrial-Nuclear eXchange (MNX) mice were fed an atherogenic diet. MNX mice have mtDNA from C57BL/6J mice on a C3H/HeN nuclear background and vice versa. Results from MNX mice were compared to wild-type C57BL/6J and C3H/HeN mice fed a control or atherogenic diet. Mice with the C57BL/6J nuclear genome developed more macrosteatosis, inflammation, and fibrosis compared with mice containing the C3H/HeN nuclear genome when fed the atherogenic diet. These changes were associated with parallel alterations in inflammation and fibrosis gene expression in wild-type mice, with intermediate responses in MNX mice. Mice with the C57BL/6J nuclear genome had increased State 4 respiration, whereas MNX mice had decreased State 3 respiration and RCR when fed the atherogenic diet. Complex IV activity and most mitochondrial biogenesis genes were increased in mice with the C57BL/6J nuclear or mitochondrial genome, or both fed the atherogenic diet. These results reveal new interactions between mitochondrial and nuclear genomes and support the concept that mtDNA influences mitochondrial function and metabolic pathways implicated in NAFLD. PMID:24758559

NASA Rodent Foodbar: Long Term Effects in Swiss Webster Mice

NASA Technical Reports Server (NTRS)

Santiago, D. L.; Yu, D. S.; Naficy, N. H.; Roghani, P. M.; Dalton, B. P.; Barrett, J. E.; Dalton, Bonnie (Technical Monitor)

2001-01-01

Swiss Webster male and female mice (150 of each) were fed NASA Rodent Foodbar for more than 110 days to test the diet's nutritional adequacy for use in future long-term studies aboard the International Space Station. Mice were grouped three to a cage (one cage = one sample) and cages were assigned to either Foodbar or Purina Chow #5001 (control) diet groups. Body weights, food intake, and water intake were obtained throughout the study. There were no significant differences in body weights between male Foodbar fed and Chow fed males (p=0.58), and at 15 weeks into the female mouse study there appear to be no significant body weight differences. Both male and female Foodbar fed groups consumed more food and less water than their Chow controls, both factors thought to be attributable to the high moisture content of the Foodbars (26% versus 10% for Chow). All differences in gross food and water consumption had p-values of less than 0.01. When food and water intake were adjusted for the moisture content in the food, both male and female Foodbar fed animals consumed less food, but still had a lower water intake rate than their controls. (p is less than 0.01). Preliminary analysis on blood samples from male and female halfway point dissections suggests differences in glucose and fat metabolism. In both male and female Foodbar fed animals, blood glucose values were significantly lower (p is less than 0.01) but there were no significant differences in cholesterol levels (p=0.51). In Foodbar fed females, triglycerides were significantly higher (p is less than 0.01). These data suggest that Foodbars allow for normal growth in Swiss Webster mice, but affect some blood chemistry parameters.

Eucaloric Ketogenic Diet Reduces Hypoglycemia and Inflammation in Mice with Endotoxemia.

PubMed

Nandivada, Prathima; Fell, Gillian L; Pan, Amy H; Nose, Vania; Ling, Pei-Ra; Bistrian, Bruce R; Puder, Mark

2016-06-01

Dietary strategies to alter the immune response to acute inflammation have the potential to improve outcomes in critically ill patients. A eucaloric ketogenic diet (EKD), composed predominantly of fat with very small amounts of carbohydrate, can provide adequate caloric support while minimizing spikes in blood glucose and reducing oxidative stress. The purpose of this study was to evaluate the effects of an EKD on glycemic control and the inflammatory response after acute endotoxemia in mice. Mice received either an EKD or a carbohydrate-based control diet (CD) for 4 weeks. Animals subsequently underwent either a 2-h fast (postprandial) or an overnight fast (postabsorptive), and half of the animals in each diet group were randomized to receive either intraperitoneal lipopolysaccharide (1 mg/kg) or an equivalent volume of saline. Glycemic response, insulin resistance, inflammatory cytokine levels, and the expression of key inflammatory and metabolic genes were measured. After endotoxin challenge, hypoglycemia was more frequent in mice fed a CD than an EKD in the postprandial period. This was due in part to the preservation of hepatic glycogen stores despite endotoxin exposure and prolonged fasting in mice fed an EKD. Furthermore, mice fed the CD had higher levels of IL-6 and TNF-α in the postabsorptive period, with a fivefold higher expression of hepatic NFκB compared to mice fed the EKD in both fasting periods. These results suggest that the unique metabolic state induced by an EKD can alter the response to acute inflammation in mice.

Dietary phytosterols modulate T-helper immune response but do not induce apparent anti-inflammatory effects in a mouse model of acute, aseptic inflammation.

PubMed

Calpe-Berdiel, Laura; Escolà-Gil, Joan Carles; Benítez, Sonia; Bancells, Cristina; González-Sastre, Francesc; Palomer, Xavier; Blanco-Vaca, Francisco

2007-05-01

Although most studies have focused on the cholesterol-lowering activity of phytosterols, other biological actions have been ascribed to these plant sterol compounds, one of which is a potential immune modulatory effect. To gain insight into this issue, we used a mouse model of acute, aseptic inflammation induced by a single subcutaneous turpentine injection. Hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)) mice, fed with or without a 2% phytosterol supplement, were treated with turpentine or saline and euthanized 48 h later. No differences were observed in spleen lymphocyte subsets between phytosterol- and control-fed apoE(-/-) mice. However, cultured spleen lymphocytes of apoE(-/-) mice fed with phytosterols and treated with turpentine showed increased IL-2 and IFN-gamma secretion (T-helper type1, Th1 lymphocyte cytokines) compared with turpentine-treated, control-fed animals. In contrast, there was no change in Th2 cytokines IL-4 and IL-10. Phytosterols also inhibit intestinal cholesterol absorption in wild-type C57BL/6J mice but, in this case, without decreasing plasma cholesterol. Spleen lymphocytes of turpentine-treated C57BL/6J mice fed with phytosterols also showed increased IL-2 production, but IFN-gamma, IL-4 and IL-10 production was unchanged. The Th1/Th2 ratio was significantly increased both in phytosterol-fed apoE(-/-) and C57BL/6J mice. We conclude that phytosterols modulate the T-helper immune response in vivo, in part independently of their hypocholesterolemic effect in a setting of acute, aseptic inflammation. Further study of phytosterol effects on immune-based diseases characterized by an exacerbated Th2 response is thus of interest.

A study of the comparative effects of hawthorn fruit compound and simvastatin on lowering blood lipid levels.

PubMed

Xu, Hong; Xu, Hou-En; Ryan, Damien

2009-01-01

This project studied the lowering blood lipids effect in atherosclerotic ApoE-deficient mice. Group A mice (n = 6), fed with a normal diet, served as the negative control. The experimental groups used mice fed with a high cholesterol diet (HCD) for eight weeks, and then selected for inclusion in the study on the basis of high blood lipid levels and the formation of atherosclerotic lesion plaque, which was indicated by an ultrasound biomicroscopy test. Eighteen mice met the selection criteria (atherosclerotic mice with high blood lipid levels) and these were randomly assigned into three groups B, C and D (n = 6). Group B fed with a HCD, served as the positive control. The intervention Group C was fed with HCD and Simvastatin. The intervention Group D was fed with a HCD and Hawthorn fruit compound (HFC includes Hawthorn and Kiwi fruit extract) for eight weeks. The results showed that after feeding on a HCD, Group B had significantly higher blood lipid levels compared to Group A and this confirmed the validity of Group A and Group B controls in this study. The results also showed that compared to Group B, in both Group C and D, there was a significant reduction in triglyceride and in the ratio between low-density lipoprotein cholesterol (LDL-C) and serum cholesterol. Moreover a reduction of LDL-C was evident in Group D, whereas a similar effect did not occur in Group C. The results indicate that HFC can be considered for the treatment of hyperlipidemia and prevention of atherosclerosis.

HEPATIC LIPOGENESIS IN D$sub 2$O-FED MICE

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabinowitz, J.L.; Defendi, V.; Langan, J.

1960-11-25

Swiss mice were maintained on a regimen of 25% D/sub 2/O for three weeks. The mice were slightly smaller than H/sub 2/O-fed controls, but the liver weight to body weight ratio was greater. There were no significant differences in liver lipid or cholesterol. Histologic examination showed progressive vacuolization and loss of basophilia, with changes in the mitochondrial distribution in the cytoplasm. These alterations did not show any specific localization in the hepatic lobule. There was a progressive reduction in the ability of liver homogenates from D/sub 2/O-fed mice to convert acetate-2-C-14 to cholesterol and fatty acid. Incubation of normal mousemore » livers in media containing 75% D/sub 2/O resulted in significant enhancement of cholestero1 and fatty acid biosynthetic capacity. This reduced lipogenesis in D/sub 2/O-fed mice appears to be due to derangements in cell structure, rather than to inhibition of enzyme activity. (auth)« less

Effect of GPR84 deletion on obesity and diabetes development in mice fed long chain or medium chain fatty acid rich diets.

PubMed

Du Toit, Eugene; Browne, Liam; Irving-Rodgers, Helen; Massa, Helen M; Fozzard, Nicolette; Jennings, Michael P; Peak, Ian R

2017-04-20

Although there is good evidence showing that diets rich in medium chain fatty acids (MCFAs) have less marked obesogenic and diabetogenic effects than diets rich in long chain fatty acids (LCFAs), the role of the pro-inflammatory, medium chain fatty acid receptor (GPR84) in the aetiology of obesity and glucose intolerance is not well characterised. We set out to determine whether GPR84 expression influences obesity and glucose intolerance susceptibility in MCFA and LCFA rich diet fed mice. Wild type (WT) and GPR84 knockout (KO) mice were fed a control, MCFA or LCFA diet, and body mass, heart, liver and epididymal fat mass was assessed, as well as glucose tolerance and adipocyte size. LCFA diets increased body mass and decreased glucose tolerance in both WT and GPR84 KO animals while MCFA diets had no effect on these parameters. There were no differences in body weight when comparing WT and GPR84 KO mice on the respective diets. Glucose tolerance was also similar in WT and GPR84 KO mice irrespective of diet. Liver mass was increased following LCFA feeding in WT but not GPR84 KO mice. Hepatic triglyceride content was increased in GPR84 KO animals fed MCFA, and myocardial triglyceride content was increased in GPR84 KO animals fed LCFA. GPR84 deletion had no effects on body weight or glucose tolerance in mice fed either a high MCFA or LCFA diet. GPR84 may influence lipid metabolism, as GPR84 KO mice had smaller livers and increased myocardial triglyceride accumulation when fed LCFA diets, and increased liver triglyceride accumulation in responses to increased dietary MCFAs.

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice.

PubMed

Maekawa, Ryuya; Seino, Yusuke; Ogata, Hidetada; Murase, Masatoshi; Iida, Atsushi; Hosokawa, Kaori; Joo, Erina; Harada, Norio; Tsunekawa, Shin; Hamada, Yoji; Oiso, Yutaka; Inagaki, Nobuya; Hayashi, Yoshitaka; Arima, Hiroshi

2017-11-01

Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and β-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

A Mitochondrial-Targeted Coenzyme Q Analog Prevents Weight Gain and Ameliorates Hepatic Dysfunction in High-Fat–Fed Mice

PubMed Central

Fink, Brian D.; Herlein, Judith A.; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J.; Yu, Liping; Grobe, Justin L.; Rahmouni, Kamal; Kerns, Robert J.

2014-01-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. PMID:25301169

A mitochondrial-targeted coenzyme q analog prevents weight gain and ameliorates hepatic dysfunction in high-fat-fed mice.

PubMed

Fink, Brian D; Herlein, Judith A; Guo, Deng Fu; Kulkarni, Chaitanya; Weidemann, Benjamin J; Yu, Liping; Grobe, Justin L; Rahmouni, Kamal; Kerns, Robert J; Sivitz, William I

2014-12-01

We hypothesized that the mitochondrial-targeted antioxidant, mitoquinone (mitoQ), known to have mitochondrial uncoupling properties, might prevent the development of obesity and mitigate liver dysfunction by increasing energy expenditure, as opposed to reducing energy intake. We administered mitoQ or vehicle (ethanol) to obesity-prone C57BL/6 mice fed high-fat (HF) or normal-fat (NF) diets. MitoQ (500 µM) or vehicle (ethanol) was added to the drinking water for 28 weeks. MitoQ significantly reduced total body mass and fat mass in the HF-fed mice but had no effect on these parameters in NF mice. Food intake was reduced by mitoQ in the HF-fed but not in the NF-fed mice. Average daily water intake was reduced by mitoQ in both the NF- and HF-fed mice. Hypothalamic expression of neuropeptide Y, agouti-related peptide, and the long form of the leptin receptor were reduced in the HF but not in the NF mice. Hepatic total fat and triglyceride content did not differ between the mitoQ-treated and control HF-fed mice. However, mitoQ markedly reduced hepatic lipid hydroperoxides and reduced circulating alanine aminotransferase, a marker of liver function. MitoQ did not alter whole-body oxygen consumption or liver mitochondrial oxygen utilization, membrane potential, ATP production, or production of reactive oxygen species. In summary, mitoQ added to drinking water mitigated the development of obesity. Contrary to our hypothesis, the mechanism involved decreased energy intake likely mediated at the hypothalamic level. MitoQ also ameliorated HF-induced liver dysfunction by virtue of its antioxidant properties without altering liver fat or mitochondrial bioenergetics. U.S. Government work not protected by U.S. copyright.

A beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion in mice.

PubMed

Attané, Camille; Peyot, Marie-Line; Lussier, Roxane; Poursharifi, Pegah; Zhao, Shangang; Zhang, Dongwei; Morin, Johane; Pineda, Marco; Wang, Shupei; Dumortier, Olivier; Ruderman, Neil B; Mitchell, Grant A; Simons, Brigitte; Madiraju, S R Murthy; Joly, Erik; Prentki, Marc

2016-12-01

To directly assess the role of beta cell lipolysis in insulin secretion and whole-body energy homeostasis, inducible beta cell-specific adipose triglyceride lipase (ATGL)-deficient (B-Atgl-KO) mice were studied under normal diet (ND) and high-fat diet (HFD) conditions. Atgl flox/flox mice were cross-bred with Mip-Cre-ERT mice to generate Mip-Cre-ERT /+ ;Atgl flox/flox mice. At 8 weeks of age, these mice were injected with tamoxifen to induce deletion of beta cell-specific Atgl (also known as Pnpla2), and the mice were fed an ND or HFD. ND-fed male B-Atgl-KO mice showed decreased insulinaemia and glucose-induced insulin secretion (GSIS) in vivo. Changes in GSIS correlated with the islet content of long-chain saturated monoacylglycerol (MAG) species that have been proposed to be metabolic coupling factors for insulin secretion. Exogenous MAGs restored GSIS in B-Atgl-KO islets. B-Atgl-KO male mice fed an HFD showed reduced insulinaemia, glycaemia in the fasted and fed states and after glucose challenge, as well as enhanced insulin sensitivity. Moreover, decreased insulinaemia in B-Atgl-KO mice was associated with increased energy expenditure, and lipid metabolism in brown (BAT) and white (WAT) adipose tissues, leading to reduced fat mass and body weight. ATGL in beta cells regulates insulin secretion via the production of signalling MAGs. Decreased insulinaemia due to lowered GSIS protects B-Atgl-KO mice from diet-induced obesity, improves insulin sensitivity, increases lipid mobilisation from WAT and causes BAT activation. The results support the concept that fuel excess can drive obesity and diabetes via hyperinsulinaemia, and that an islet beta cell ATGL-lipolysis/adipose tissue axis controls energy homeostasis and body weight via insulin secretion.

Dietary Intake of Structured Lipids with Different Contents of Medium-Chain Fatty Acids on Obesity Prevention in C57BL/6J Mice.

PubMed

Zhou, Shengmin; Wang, Yueqiang; Jiang, Yuanrong; Zhang, Zhongfei; Sun, Xiangjun; Yu, Liangli Lucy

2017-08-01

Three medium- and long-chain triacylglycerols (MLCT) with different contents of medium-chain fatty acids (MCFA) (10% to 30%, w/w) were prepared and evaluated for their anti-obesity potential in C57BL/6J mice. The group fed with a high fat diet of MLCT containing 30% (w/w) MCFA showed significantly decreased body weight and fat mass (P < 0.05) relative to the control mice fed an obesity-inducing high fat rapeseed oil diet. In addition, serum parameters including triacylglycerols, total cholesterol, glucose, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein A1 and apolipoprotein B in the treatment group fed with 30% (w/w) MCFA were close to those of mice fed with a low fat rapeseed oil diet, but significantly different (P < 0.05) from those of the obesity control group. Moreover, the intake of MLCT with high content of MCFA reduced the size of adipocytes. In addition, the visceral fat and liver weights, as well as the liver triacylglycerol for 3 treatment groups were lower than those of the obesity control group. These results demonstrate the great potential of MLCT with high content of MCFA in weight loss. © 2017 Institute of Food Technologists®.

Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice

PubMed Central

Deshpande, Krutika T.; Liu, Shinlan; McCracken, Jennifer M.; Jiang, Lu; Gaw, Ta Ehpaw; Kaydo, Lindsey N.; Richard, Zachary C.; O’Neil, Maura F.; Pritchard, Michele T.

2016-01-01

Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure. PMID:26751492

Enterobacter cloacae administration induces hepatic damage and subcutaneous fat accumulation in high-fat diet fed mice.

PubMed

Keskitalo, Anniina; Munukka, Eveliina; Toivonen, Raine; Hollmén, Maija; Kainulainen, Heikki; Huovinen, Pentti; Jalkanen, Sirpa; Pekkala, Satu

2018-01-01

Accumulating evidence indicates that gut microbiota plays a significant role in obesity, insulin resistance and associated liver disorders. Family Enterobacteriaceae and especially Enterobacter cloacae strain B29 have been previously linked to obesity and hepatic damage. The underlying mechanisms, however, remain unclear. Therefore, we comprehensively examined the effects of E. cloacae subsp. cloacae (ATCC® 13047™) administration on host metabolism of mice fed with high-fat diet (HFD). C57BL/6N mice were randomly divided into HFD control, chow control, and E. cloacae treatment groups. The E. cloacae treatment group received live bacterial cells in PBS intragastrically twice a week, every other week for 13 weeks. Both control groups received PBS intragastrically. After the 13-week treatment period, the mice were sacrificed for gene and protein expression and functional analyses. Our results show that E. cloacae administration increased subcutaneous fat mass and the relative proportion of hypertrophic adipocytes. Both subcutaneous and visceral fat had signs of decreased insulin signaling and elevated lipolysis that was reflected in higher serum glycerol levels. In addition, E. cloacae -treated mice had significantly higher hepatic AST and AST/ALT ratio, and their liver histology indicated fibrosis, demonstrating that E. cloacae subsp. cloacae administration promotes hepatic damage in HFD fed mice.

Effects of a galacto-oligosaccharide-rich diet on fecal microbiota and metabolite profiles in mice.

PubMed

Cheng, W; Lu, J; Lin, W; Wei, X; Li, H; Zhao, X; Jiang, A; Yuan, J

2018-03-01

Galacto-oligosaccharides (GOS) are prebiotics that positively affect the host's gut microbiota, which is important for the health of the host. Most previous studies focused on specific flora components (e.g. Bifidobacterium and Lactobacillus); very few have investigated the relationship between flora and metabolites. Here, we used 16S rRNA analysis and metabolomics to analyze the effect of GOS on microbiota and metabolites. Results show that the abundance of Ruminococcaceae and Oscillibacter decreased significantly in GOS-fed mice. Twenty-one metabolites, including oleic acid, arachidic acid, and behenic acid, decreased significantly in the GOS-fed mice. Fatty acid synthesis and blood triglyceride content significantly decreased in the GOS-fed mice compared with those in the control mice, suggesting that GOS may improve lipid metabolism in mice. Additionally, after three weeks of a GOS-rich diet, the mouse microbiota was significantly enriched in Alloprevotella, Bacteroides, and Parasutterella. The blood glucose level of the GOS-fed group was significantly higher than that of the control group, whereas the abundance of Coprococcus and Odoribacter (butyrate-producing bacteria) was significantly decreased. The metabolism of butyrate, known to reduce plasma glucose levels, was significantly downregulated in the GOS-fed mice, an effect potentially detrimental to the glucose metabolism of the host. This dual-omics analysis provided important information on the changes in host-microbe-metabolite interactions resulting from GOS supplementation. Our results provide evidence that GOS may improve lipid metabolism, and that long-term GOS supplementation had a detrimental effect on the host's glucose metabolism, which could be important for optimizing methods of prebiotic supplementation and developing approaches to prevent diseases using prebiotic interventions.

Oral Supplementation of Glutamine Attenuates the Progression of Nonalcoholic Steatohepatitis in C57BL/6J Mice.

PubMed

Sellmann, Cathrin; Baumann, Anja; Brandt, Annette; Jin, Cheng Jun; Nier, Anika; Bergheim, Ina

2017-11-01

Background: Universally accepted therapeutic strategies for the treatment of nonalcoholic steatohepatitis (NASH) are still lacking. Studies suggest a preventive effect of oral Gln supplementation on the development of NASH; however, whether Gln also has therapeutic potential for pre-existing NASH has not yet been clarified. Objective: The aim of the present study was to determine whether Gln prevents the progression of diet-induced NASH in mice. Methods: For 8 wk, female C57BL/6J mice (6-8 wk old) were pair-fed a liquid Western-style diet [WSD, 25% of energy from fat, 50% wt:wt fructose, 0.16% wt:wt cholesterol] or control diet (C diet) to induce liver damage. From week 8 to 13, they were pair-fed the C diet or WSD alone or supplemented with l-Gln to provide 2.1 g/kg body weight (C diet + Gln or WSD + Gln). Energy intake was adjusted to the group with the lowest energy intake. Indexes of liver damage and inflammation, intestinal barrier function, and toll-like receptor 4 ( Tlr4 ) signaling in the liver were determined. Results: The liver histology scores significantly increased from 8 to 13 wk (+31%) in WSD-fed mice and were significantly higher than in controls ( P ≤ 0.05 for both time comparisons), whereas scores did not differ between C diet-fed and WSD + Gln-fed mice after 13 wk of feeding. The occludin protein concentrations in the small intestinal tissue were similarly reduced in both WSD-fed groups when compared with controls [WSD compared with C diet (-53%) and C diet + Gln (-42%), P ≤ 0.05; WSD + Gln compared with C diet + Gln (-34%), P ≤ 0.05] after 13 wk, whereas the expression of myeloid differentiation primary response gene 88 mRNA and concentration of inducible nitric oxide synthase and 4-hydroxynonenal protein adducts were significantly higher only in livers of WSD-fed mice ( P ≤ 0.05 for the WSD group compared with all other groups; WSD + Gln group compared with the C diet groups: NS). Conclusion: Taken together, our data suggest that oral Gln supplementation protects mice from the progression of pre-existing, WSD-induced NASH. © 2017 American Society for Nutrition.

Epidermal growth factor improves intestinal integrity and survival in murine sepsis following chronic alcohol ingestion

PubMed Central

Klingensmith, Nathan J.; Yoseph, Benyam P.; Liang, Zhe; Lyons, John D.; Burd, Eileen M.; Margoles, Lindsay M.; Koval, Michael; Ford, Mandy L.; Coopersmith, Craig M.

2016-01-01

Epidermal growth factor (EGF) is a cytoprotective protein that improves survival in preclinical models of sepsis through its beneficial effects on intestinal integrity. Alcohol use disorder worsens intestinal integrity and is associated with increased morbidity and mortality in critical illness. We sought to determine whether chronic alcohol ingestion alters the host response to systemic administration of EGF in sepsis. Six week old FVB/N mice were randomized to receive 20% alcohol or water for 12 weeks. All mice then underwent cecal ligation and puncture (CLP) to induce polymicrobial sepsis. Mice were then randomized to receive either intraperitoneal injection of EGF (150 μg/kg/day) or normal saline. Water-fed mice given EGF mice had decreased seven-day mortality compared to water-fed mice (18% vs. 55%). Alcohol-fed mice given EGF also had decreased seven day mortality compared to alcohol-fed mice (48% vs. 79%). Notably, while systemic EGF improved absolute survival to a similar degree in both water-fed and alcohol-fed mice, mortality was significantly higher in alcohol+EGF mice compared to water+EGF mice. Compared to water-fed septic mice, alcohol-fed septic mice had worsened intestinal integrity with intestinal hyperpermeability, increased intestinal epithelial apoptosis, decreased proliferation and shorter villus length. Systemic administration of EGF to septic alcohol-fed mice decreased intestinal permeability compared to septic alcohol-fed mice given vehicle, with increased levels of the tight junction mediators claudin-5 and JAM-A. Systemic administration of EGF to septic alcohol-fed mice also decreased intestinal apoptosis with an improvement in the Bax/Bcl-2 ratio. EGF also improved both crypt proliferation and villus length in septic alcohol-fed mice. EGF administration resulted in lower levels of both pro- and anti-inflammatory cytokines MCP-1, TNF and IL-10 in alcohol-fed mice. EGF is therefore effective at improving both intestinal integrity and mortality following sepsis in mice with chronic alcohol ingestion. However, the efficacy of EGF in sepsis is blunted in the setting of chronic alcohol ingestion, as intestinal integrity and mortality in alcohol-fed mice given EGF improves animals to levels seen in water-fed mice given vehicle but does not approach levels seen in water-fed mice given EGF. PMID:27465753

Dietary lactosucrose suppresses influenza A (H1N1) virus infection in mice

PubMed Central

KISHINO, Eriko; TAKEMURA, Naho; MASAKI, Hisaharu; ITO, Tetsuya; NAKAZAWA, Masatoshi

2015-01-01

This study examined the effects of lactosucrose (4G-β-D-galactosylsucrose) on influenza A virus infections in mice. First, the effects of lactosucrose on fermentation in the cecum and on immune function were investigated. In female BALB/c mice, lactosucrose supplementation for 6 weeks promoted cecal fermentation and increased both secretory IgA (SIgA) levels in feces and total IgA and IgG2a concentrations in serum. Both the percentage of CD4+ T cells in Peyer’s patches and the cytotoxic activity of splenic natural killer (NK) cells increased significantly in response to lactosucrose. Next, we examined the effects of lactosucrose on low-dose influenza A virus infection in mice. After 2 weeks of dietary supplementation with lactosucrose, the mice were infected with low-dose influenza A virus. At 7 days post infection, a comparison with control mice showed that weight loss was suppressed, as were viral titers in the lungs. In the spleens of lactosucrose-fed mice, there was an increase in the percentage of NK cells. Lastly, mice fed lactosucrose were challenged with a lethal dose of influenza A virus. The survival rate of these mice was significantly higher than that of mice fed a control diet. These results suggested that lactosucrose supplementation suppresses influenza A virus infection by augmenting innate immune responses and enhancing cellular and mucosal immunity. PMID:26594606

Quercetin and rutin as inhibitors of azoxymethanol-induced colonic neoplasia.

PubMed

Deschner, E E; Ruperto, J; Wong, G; Newmark, H L

1991-07-01

Dietary quercetin (QU) and rutin (RU), phenolic flavonoids commonly found in many fruits and vegetables, were provided to CF1 female mice for 50 weeks to assess the ability of these compounds to inhibit azoxymethanol (AOM)-induced colonic neoplasia. In addition to a control group fed an AIN 76A diet, five other groups received that diet to which was added either 0.1, 0.5 or 2.0% QU and 1.0 or 4.0% RU. Acute studies revealed that, among saline controls, no alteration of any proliferative parameters of colonic epithelial cells was observed among those groups receiving any dose of QU or RU. However, among the AOM-treated mice, both 2% QU and 4% RU significantly reduced hyperproliferation and inhibited the shift of S-phase cells to the middle and upper portion of crypts. Moreover, mice fed these concentrations of QU and RU had significantly fewer AOM-induced focal areas of dysplasia (FADs) than those fed the control diet (0.2 +/- 0.4 and 0.4 +/- 0.5 versus 3.6 +/- 2.3 respectively). Tumors occurred more frequently in the distal half of the colon, regardless of treatment. Compared with controls, mice fed 2% QU had a significantly reduced tumor incidence (25.0% versus 5.9%, P = 0.03). Those fed 4% RU showed only a trend toward inhibition (25% versus 9.7%, P = 0.11). Nevertheless, both 2% QU and 4% RU suppressed tumor multiplicity, i.e. fewer tumors/animal arose in these groups than in the AOM-treated control mice (1.2 versus 2.3, P = 0.005; 1.1 versus 2.3, P = 0.003 respectively). Clearly, QU and RU exhibit significant activity in reducing AOM-induced hyperproliferation of colonic epithelial cells and FAD incidence. This behavior successfully forecast the ability of both flavonoids to suppress tumor multiplicity and ultimately tumor development.

Protection of brain and pancreas from high-fat diet: effects of catechin and caffeine.

PubMed

Unno, Keiko; Yamamoto, Hiroyuki; Maeda, Ken-Ichi; Takabayashi, Fumiyo; Yoshida, Hirotoshi; Kikunaga, Naomi; Takamori, Nina; Asahina, Shunsuke; Iguchi, Kazuaki; Sayama, Kazutoshi; Hoshino, Minoru

2009-02-16

To investigate the effect of a high-fat diet on brain and pancreas functions, we used SAMP10 mice that have characteristics of brain atrophy and cognitive dysfunction with aging. Simultaneously, we investigated the effect of green tea catechin consumption on high-fat diet feeding, because green tea catechin has been reported to improve brain atrophy, brain dysfunction and obesity. The body weight of mice fed a high-fat diet from 2 to 12 months was higher than that of the control, although the calorie intake was not. The high-fat diet also increased insulin secretion; however, the hypersecretion of insulin and obesity were suppressed when mice were fed a high-fat diet with green tea catechin and caffeine. Furthermore, brain atrophy was suppressed and the working memory, tested using Y-maze, improved in mice fed a high-fat diet containing green tea catechin and caffeine. The secretion of insulin might affect both obesity and brain function. A strong correlation was found between working memory and insulin release in mice fed a high-fat diet with green tea catechin and/or caffeine. The results indicate the protective effect of green tea catechin and caffeine on the functions of brain and pancreas in mice fed a high-fat diet.

Cranberry extract attenuates hepatic inflammation in high-fat-fed obese mice.

PubMed

Glisan, Shannon L; Ryan, Caroline; Neilson, Andrew P; Lambert, Joshua D

2016-11-01

Cranberry (Vaccinium macrocarpon) consumption has been associated with health beneficial effects. Nonalcoholic fatty liver disease (NAFLD) is a comorbidity of obesity. In the present study, we investigated the effect of a polyphenol-rich cranberry extract (CBE) on hepatic inflammation in high fat (HF)-fed obese C57BL/6J mice. Following dietary treatment with 0.8% CBE for 10 weeks, we observed no change in body weight or visceral fat mass in CBE-supplemented mice compared to HF-fed control mice. We did observe a significant decrease in plasma alanine aminotransferase (31%) and histological severity of NAFLD (33% decrease in area of involvement, 29% decrease in lipid droplet size) compared to HF-fed controls. Hepatic protein levels of tumor necrosis factor α and C-C chemokine ligand 2 were reduced by 28% and 19%, respectively, following CBE supplementation. CBE significantly decreased hepatic mRNA levels of toll-like receptor 4 (TLR4, 63%) and nuclear factor κB (NFκB, 24%), as well as a number of genes related to the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3 inflammasome. In conclusion, CBE reduced NAFLD and hepatic inflammation in HF-fed obese C57BL/6J mice. These effects appear to be related to mitigation of TLR4-NFκB related signaling; however, further studies into the underlying mechanisms of these hepatoprotective effects are needed. Copyright © 2016 Elsevier Inc. All rights reserved.

Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice.

PubMed

Niemiec, T; Sikorska, J; Harrison, A; Szmidt, M; Sawosz, E; Wirth-Dzieciolowska, E; Wilczak, J; Pierzynowski, S

2011-02-01

The objective of this study was to evaluate the effect of α-ketoglutarate on redox state parameters and arterial elasticity in elderly mice. Mice in the control group were fed with standard diet, while the experimental animals received the diet supplemented either with calcium (Ca-AKG) or sodium salt of α-ketoglutarate (Na-AKG). The experimental animals were divided into 4 groups with 10 individuals in each: control I (12 months old), control II (2 months old), experimental group I fed with Ca-AKG (12 months old) and experimental group II fed with Na-AKG (12 months old). Mice treated with Ca-AKG as well as the control II animals demonstrated significantly higher level of total antioxidant status (TAS), comparing to the control I animals and those treated with Ca-AKG. Thiobarbituric acid reactive substances (TBARS) level in blood plasma was found significantly lower in young and Ca-AKG treated mice. TBARS liver concentration was significantly different in each examined group. The study also demonstrates the decrease in TBARS level in Ca-AKG treated animals. Treatment with Na-AKG significantly increased glutathione peroxidase activity and decreased the activity of superoxide dismutase. The presented results suggest that Ca-AKG protects the organism against the free radicals related elderly processes. The study presents also the effect of Ca-AKG treatment on arterial elastic characteristics in elderly mice. The beneficial effect of Ca-AKG on ageing organisms was confirmed via redox state stabilization and blood vessel elasticity improvement.

Epidermal Growth Factor Improves Intestinal Integrity and Survival in Murine Sepsis Following Chronic Alcohol Ingestion.

PubMed

Klingensmith, Nathan J; Yoseph, Benyam P; Liang, Zhe; Lyons, John D; Burd, Eileen M; Margoles, Lindsay M; Koval, Michael; Ford, Mandy L; Coopersmith, Craig M

2017-02-01

Epidermal growth factor (EGF) is a cytoprotective protein that improves survival in preclinical models of sepsis through its beneficial effects on intestinal integrity. Alcohol use disorder worsens intestinal integrity and is associated with increased morbidity and mortality in critical illness. We sought to determine whether chronic alcohol ingestion alters the host response to systemic administration of EGF in sepsis. Six-week-old FVB/N mice were randomized to receive 20% alcohol or water for 12 weeks. All mice then underwent cecal ligation and puncture to induce polymicrobial sepsis. Mice were then randomized to receive either intraperitoneal injection of EGF (150 μg/kg/day) or normal saline. Water-fed mice given EGF had decreased 7-day mortality compared with water-fed mice (18% vs. 55%). Alcohol-fed mice given EGF also had decreased 7-day mortality compared with alcohol-fed mice (48% vs. 79%). Notably, while systemic EGF improved absolute survival to a similar degree in both water-fed and alcohol-fed mice, mortality was significantly higher in alcohol+EGF mice compared with water+EGF mice. Compared with water-fed septic mice, alcohol-fed septic mice had worsened intestinal integrity with intestinal hyperpermeability, increased intestinal epithelial apoptosis, decreased proliferation and shorter villus length. Systemic administration of EGF to septic alcohol-fed mice decreased intestinal permeability compared with septic alcohol-fed mice given vehicle, with increased levels of the tight junction mediators claudin-5 and JAM-A. Systemic administration of EGF to septic alcohol-fed mice also decreased intestinal apoptosis with an improvement in the Bax/Bcl-2 ratio. EGF also improved both crypt proliferation and villus length in septic alcohol-fed mice. EGF administration resulted in lower levels of both pro- and anti-inflammatory cytokines monocyte chemoattractant protein-1, tumor necrosis factor, and interleukin 10 in alcohol-fed mice. EGF is therefore effective at improving both intestinal integrity and mortality following sepsis in mice with chronic alcohol ingestion. However, the efficacy of EGF in sepsis is blunted in the setting of chronic alcohol ingestion, as intestinal integrity and mortality in alcohol-fed mice given EGF improves animals to levels seen in water-fed mice given vehicle but does not approach levels seen in water-fed mice given EGF.

Consumption of Walnuts in Combination with Other Whole Foods Produces Physiologic, Metabolic, and Gene Expression Changes in Obese C57BL/6J High-Fat-Fed Male Mice.

PubMed

Luo, Ting; Miranda-Garcia, Omar; Adamson, Allysa; Hamilton-Reeves, Jill; Sullivan, Debra K; Kinchen, Jason M; Shay, Neil F

2016-09-01

Although a reductionist approach has sought to understand the roles of individual nutrients and biochemicals in foods, it has become apparent that there can be differences when studying food components in isolation or within the natural matrix of a whole food. The objective of this study was to determine the ability of whole-food intake to modulate the development of obesity and other metabolic dysfunction in mice fed a high-fat (HF), Western-style obesogenic diet. To test the hypothesis that an n-3 (ω-3) polyunsaturated fatty acid-rich food could synergize with other, largely polyphenol-rich foods by producing greater reductions in metabolic disease conditions, the intake of English walnuts was evaluated in combination with 9 other whole foods. Eight-week-old male C57Bl/6J mice were fed low-fat (LF; 10% fat) and HF control diets, along with an HF diet with 8.6% (wt:wt) added walnuts for 9 wk. The HF control diet contained 46% fat with added sucrose (10.9%, wt:wt) and cholesterol (1%, wt:wt); the added sucrose and cholesterol were not present in the LF diet. Other groups were provided the walnut diet with a second whole food-raspberries, apples, cranberries, tart cherries, broccoli sprouts, olive oil, soy protein, or green tea. All of the energy-containing whole foods were added at an energy level equivalent to 1.5 servings/d. Body weights, food intake, and glucose tolerance were determined. Postmortem, serum lipids and inflammatory markers, hepatic fat, gene expression, and the relative concentrations of 594 biochemicals were measured. The addition of walnuts with either raspberries, apples, or green tea reduced glucose area under the curve compared with the HF diet alone (-93%, -64%, and -54%, respectively, P < 0.05). Compared with HF-fed mice, mice fed walnuts with either broccoli sprouts or green tea (-49% and -61%, respectively, P < 0.05) had reduced hepatic fat concentrations. There were differences in global gene expression patterns related to whole-food content, with many examples of differences in LF- and HF-fed mice, HF- and walnut-fed mice, and mice fed walnuts and walnuts plus other foods. The mean ± SEM increase in relative hepatic concentrations of the n-3 fatty acids α-linolenic acid, eicosapentanoic acid, and docosapentanoic acid in all walnut-fed groups was 124% ± 13%, 159% ± 11%, and 114% ± 10%, respectively (P < 0.0001), compared with LF- and HF-fed mice not consuming walnuts. In obese male mice, walnut consumption with an HF Western-style diet caused changes in hepatic fat concentrations, gene expression patterns, and fatty acid concentrations. The addition of a second whole food in combination with walnuts produced other changes in metabolite concentrations and gene expression patterns and other physiologic markers. Importantly, these substantial changes occurred in mice fed typical amounts of intake, representing only 1.5 servings each food/d. © 2016 American Society for Nutrition.

Supplementation of Mice with Specific Nondigestible Oligosaccharides during Pregnancy or Lactation Leads to Diminished Sensitization and Allergy in the Female Offspring.

PubMed

Hogenkamp, Astrid; Knippels, Leon M J; Garssen, Johan; van Esch, Betty C A M

2015-05-01

The maternal environment and early life exposure affect immune development in offspring. We investigated whether development of food allergy in offspring is affected by supplementing pregnant or lactating sensitized or nonsensitized mice with a mixture of nondigestible oligosaccharides. Dams were sensitized intragastrically with ovalbumin before mating, with use of cholera toxin (CT) as an adjuvant. Nonsensitized dams received CT only. Dams were fed a control diet or a diet supplemented with short-chain galacto oligosaccharides (scGOSs), long-chain fructo oligosaccharides (lcFOSs), and pectin-derived acidic oligosaccharides (pAOSs) in a ratio of 9:1:2 at a dose of 2% during pregnancy or lactation, resulting in 7 experimental groups. After weaning, offspring were fed a control diet and ovalbumin-CT sensitized. Acute allergic skin responses (ASRs), shock symptoms, body temperature, and specific plasma immunoglobulins were measured upon intradermal ovalbumin challenge. Th2/Th1- and regulatory T cells were analyzed with use of quantitative polymerase chain reaction and flow cytometric analysis in spleen, mesenteric lymph nodes, and blood. Supplementing sensitized pregnant or lactating dams with scGOS/lcFOS/pAOS resulted in lower ASRs in the offspring [offspring of sensitized female mice fed experimental diet during pregnancy (S-Preg): 48 ± 2.1 μm; offspring of sensitized female mice fed experimental diet during lactation (S-Lact): 60 ± 6.2 μm] compared with the sensitized control group (119 ± 13.9 μm). In the S-Lact group, this coincided with an absence of shock symptoms compared with the offspring of sensitized female mice fed control food during pregnancy and lactation (S-Con) and S-Preg groups, and lower ovalbumin-IgG1 [S-Con: 3.8 ± 0.1 arbitrary units (AUs); S-Preg: 3.3 ± 0.1 AUs; S-Lact: 2.4 ± 0.1 AUs] and higher ovalbumin-IgG2a concentrations (S-Con: 1.1 ± 0.1 AUs; S-Preg: 0.8 ± 0.1 AUs; S-Lact: 2.0 ± 0.1 AUs). Supplementing nonsensitized pregnant or lactating dams with scGOS/lcFOS/pAOS resulted in lower plasma ovalbumin-IgE [offspring of nonsensitized female mice fed experimental diet during pregnancy (NS-Preg): 1.6 ± 0.4 AUs; offspring of nonsensitized female mice fed experimental diet during lactation (NS-Lact): 0.3 ± 0.1 AUs vs. offspring of nonsensitized female mice fed control food during pregnancy and lactation (NS-Con): 3.1 ± 0.6 AUs] and ovalbumin-IgG1 (NS-Lact: 2.3 ± 0.3 AUs vs. NS-Con: 3.4 ± 0.3 AUs) concentrations in offspring. Ovalbumin-IgG2a plasma concentrations were higher in offspring of scGOS/lcFOS/pAOS-supplemented dams (NS-Preg: 1.1 ± 0.1 AUs; NS-Lact: 1.1 ± 0.1 AUs) than in those of unsupplemented, nonsensitized controls (0.4 ± 0.0 AUs). These data show impaired sensitization in offspring of scGOS/lcFOS/pAOS-supplemented mice. A number of the analyzed variables are differentially affected by whether supplementation occurs during pregnancy or lactation, and the outcome of dietary supplementation is affected by whether the mother has been sensitized to ovalbumin and CT. © 2015 American Society for Nutrition.

Experimental Nonalcoholic Steatohepatitis and Liver Fibrosis Are Ameliorated by Pharmacologic Activation of Nrf2 (NF-E2 p45-Related Factor 2).

PubMed

Sharma, Ritu S; Harrison, David J; Kisielewski, Dorothy; Cassidy, Diane M; McNeilly, Alison D; Gallagher, Jennifer R; Walsh, Shaun V; Honda, Tadashi; McCrimmon, Rory J; Dinkova-Kostova, Albena T; Ashford, Michael L J; Dillon, John F; Hayes, John D

2018-03-01

Nonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis. Nrf2 +/+ and Nrf2 -/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control. Measures of whole-body glucose homeostasis, histologic assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis, and oxidative stress were performed in livers from these animals. TBE-31 treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31 treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, while increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31 treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis, and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in livers of HFFr-fed Nrf2-null mice. Pharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

Improving glucose tolerance by reducing weight gain in a polygenic obese mouse model: use of a high protein diet.

PubMed

Blair, A R; Strube, M L; Proietto, J; Andrikopoulos, S

2015-03-01

Diets to decrease body weight have limited success in achieving and importantly maintaining this weight loss long-term. It has recently been suggested that energy intake can be regulated by the amount of protein ingested, termed the protein leverage hypothesis. In this study, we determined whether a high protein diet would be effective in achieving and maintaining weight loss in a genetically obese model, the New Zealand Obese (NZO) mouse. NZO and C57BL/6J (C57) control mice were fed a high protein or chow diet for 5 weeks from weaning (3 weeks of age). Body weight and food intake were determined. Mice on the same diet were bred to produce offspring that were fed either a chow or high protein diet. Body weight, food intake, and glucose tolerance were determined. Feeding NZO and C57 mice a high protein diet for 5 weeks resulted in reduced food intake and consequently energy intake and body weight gain compared with mice on a chow diet. NZO mice fed a high protein diet showed a significant improvement in glucose tolerance compared with their chow-fed counterparts, while no difference was seen in C57 mice fed chow or protein diet. The offspring of NZO mice that were fed a high protein diet during gestation and weaning were also lighter and displayed improved glucose tolerance compared with chow fed animals. We conclude that a high protein diet is a reasonable strategy to reduce body weight gain and improve glucose tolerance in the NZO mouse, a polygenic model of obesity. © Georg Thieme Verlag KG Stuttgart · New York.

Excessive Vitamin E Intake Does Not Cause Bone Loss in Male or Ovariectomized Female Mice Fed Normal or High-Fat Diets.

PubMed

Ikegami, Hiroko; Kawawa, Rie; Ichi, Ikuyo; Ishikawa, Tomoko; Koike, Taisuke; Aoki, Yoshinori; Fujiwara, Yoko

2017-10-01

Background: Animal studies on the effects of vitamin E on bone health have yielded conflicting and inconclusive results, and to our knowledge, no studies have addressed the effect of vitamin E on bone in animals consuming a high-fat diet (HFD). Objective: This study aimed to evaluate the effect of excessive vitamin E on bone metabolism in normal male mice and ovariectomized female mice fed a normal diet (ND) or HFD. Methods: In the first 2 experiments, 7-wk-old male mice were fed an ND (16% energy from fat) containing 75 (control), 0 (vitamin E-free), or 1000 (high vitamin E) mg vitamin E/kg (experiment 1) or an HFD (46% energy from fat) containing 0, 200, 500, or 1000 mg vitamin E/kg (experiment 2) for 18 wk. In the third experiment, 7-wk-old sham-operated or ovariectomized female mice were fed the ND (75 mg vitamin E/kg) or HFD containing 0 or 1000 mg vitamin E/kg for 8 wk. At the end of the feeding period, blood and femurs were collected to measure bone turnover markers and analyze histology and microcomputed tomography. Results: In experiments 1 and 2, vitamin E intake had no effect on plasma alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP) activity, or bone formation, resorption, or volume in femurs in mice fed the ND or HFDs. In experiment 3, bone volume was significantly reduced (85%) in ovariectomized mice compared with that in sham-operated mice ( P < 0.05), but it did not differ among mice fed the 3 diets. Plasma ALP and TRAP activities and bone formation and resorption in femur were similar among ovariectomized mice fed the HFD containing 0 or 1000 mg vitamin E/kg. Conclusions: The results suggest that excess vitamin E intake does not cause bone loss in normal male mice or in ovariectomized or sham-operated female mice, regardless of dietary fat content. © 2017 American Society for Nutrition.

Incidence of pancreatic cancer is dramatically increased by a high fat, high calorie diet in KrasG12D mice.

PubMed

Chang, Hui-Hua; Moro, Aune; Takakura, Kazuki; Su, Hsin-Yuan; Mo, Allen; Nakanishi, Masako; Waldron, Richard T; French, Samuel W; Dawson, David W; Hines, O Joe; Li, Gang; Go, Vay Liang W; Sinnett-Smith, James; Pandol, Stephen J; Lugea, Aurelia; Gukovskaya, Anna S; Duff, Michael O; Rosenberg, Daniel W; Rozengurt, Enrique; Eibl, Guido

2017-01-01

Epidemiologic data has linked obesity to a higher risk of pancreatic cancer, but the underlying mechanisms are poorly understood. To allow for detailed mechanistic studies in a relevant model mimicking diet-induced obesity and pancreatic cancer, a high-fat, high-calorie diet (HFCD) was given to P48+/Cre;LSL-KRASG12D (KC) mice carrying a pancreas-specific oncogenic Kras mutation. The mice were randomly allocated to a HFCD or control diet (CD). Cohorts were sacrificed at 3, 6, and 9 months and tissues were harvested for further analysis. Compared to CD-fed mice, HFCD-fed animals gained significantly more weight. Importantly, the cancer incidence was remarkably increased in HFCD-fed KC mice, particularly in male KC mice. In addition, KC mice fed the HFCD showed more extensive inflammation and fibrosis, and more advanced PanIN lesions in the pancreas, compared to age-matched CD-fed animals. Interestingly, we found that the HFCD reduced autophagic flux in PanIN lesions in KC mice. Further, exome sequencing of isolated murine PanIN lesions identified numerous genetic variants unique to the HFCD. These data underscore the role of sustained inflammation and dysregulated autophagy in diet-induced pancreatic cancer development and suggest that diet-induced genetic alterations may contribute to this process. Our findings provide a better understanding of the mechanisms underlying the obesity-cancer link in males and females, and will facilitate the development of interventions targeting obesity-associated pancreatic cancer.

Effects of pyridoxine on a high-fat diet-induced reduction of cell proliferation and neuroblast differentiation depend on cyclic adenosine monophosphate response element binding protein in the mouse dentate gyrus.

PubMed

Yoo, Dae Young; Kim, Woosuk; Yoo, Ki-Yeon; Nam, Sung Min; Chung, Jin Young; Yoon, Yeo Sung; Won, Moo-Ho; Hwang, In Koo

2012-08-01

In this study, we challenged pyridoxine to mice fed a high-fat diet (HFD) and investigated the effects of pyridoxine on HFD-induced phenotypes such as blood glucose, reduction of cell proliferation and neuroblast differentiation in the dentate gyrus using Ki67 and doublecortin (DCX), respectively. Mice were fed a commercially available low-fat diet (LFD) as control diet or HFD (60% fat) for 8 weeks. After 5 weeks of LFD or HFD treatment, 350 mg/kg pyridoxine was administered for 3 weeks. The administration of pyridoxine significantly decreased body weight in the HFD-treated group. In addition, there were no significant differences in hepatic histology and pancreatic insulin-immunoreactive (-ir) and glucagon-ir cells of the HFD-treated group after pyridoxine treatment. In the HFD-fed group, Ki67-positive nuclei and DCX-ir neuroblasts were significantly decreased in the dentate gyrus compared with those in the LFD-fed mice. However, the administration of pyridoxine significantly increased Ki67-positive nuclei and DCX-ir neuroblasts in the dentate gyrus in both LFD- and HFD-fed mice. In addition, the administration of pyridoxine significantly increased the protein levels of glutamic acid decarboxylase 67 (GAD67) and brain-derived neurotrophic factor (BDNF) and the immunoreactivity of phosphorylated cyclic AMP response element binding protein (pCREB) compared with the vehicle-treated LFD- and HFD-fed mice. In contrast, the administration of pyridoxine significantly decreased HFD-induced malondialdehyde (MDA) levels in the hippocampus. These results showed that pyridoxine supplement reduced the HFD-induced reduction of cell proliferation and neuroblast differentiation in the dentate gyrus via controlling the levels of GAD67, pCREB, BDNF, and MDA. Copyright © 2012 Wiley Periodicals, Inc.

Profiling of hepatic gene expression of mice fed with edible japanese mushrooms by DNA microarray analysis: comparison among Pleurotus ostreatus, Grifola frondosa, and Hypsizigus marmoreus.

PubMed

Sato, Mayumi; Tokuji, Yoshihiko; Yoneyama, Shozo; Fujii-Akiyama, Kyoko; Kinoshita, Mikio; Ohnishi, Masao

2011-10-12

To compare and estimate the effects of dietary intake of three kinds of mushrooms (Pleurotus ostreatus, Grifola frondosa, and Hypsizigus marmoreus), mice were fed a diet containing 10-14% of each mushroom for 4 weeks. Triacylglycerol in the liver and plasma decreased and plasma cholesterol increased in the P. ostreatus-fed group compared with those in the control group. Cholesterol in the liver was lower in the G. frondosa-fed group than in the control group, but no changes were found in the H. marmoreus-fed group. DNA microarray analysis of the liver revealed differences of gene expression patterns among mushrooms. Ctp1a and Fabp families were upregulated in the P. ostreatus-fed group, which were considered to promote lipid transport and β-oxidation. In the G. frondosa-fed group, not only the gene involved in signal transduction of innate immunity via TLR3 and interferon but also virus resistance genes, such as Mx1, Rsad2, and Oas1, were upregulated.

Short Term High Fat Diet Induces Obesity-Enhancing Changes in Mouse Gut Microbiota That are Partially Reversed by Cessation of the High Fat Diet.

PubMed

Shang, Yue; Khafipour, Ehsan; Derakhshani, Hooman; Sarna, Lindsei K; Woo, Connie W; Siow, Yaw L; O, Karmin

2017-06-01

The gut microbiota is proposed as a "metabolic organ" involved in energy utilization and is associated with obesity. Dietary intervention is one of the approaches for obesity management. Changes in dietary components have significant impacts on host metabolism and gut microbiota. In the present study, we examined the influence of dietary fat intervention on the modification of gut mucosa-associated microbiota profile along with body weight and metabolic parameter changes. Male C57BL/6J mice (6-week old) were fed a low fat diet (10% kcal fat) as a control or a high fat diet (HFD 60% kcal fat) for 7 weeks. In another group, mice were fed HFD for 5 weeks followed by low fat control diet for 2 weeks (HFD + Control). At 7 weeks, body weight gain, blood glucose and hepatic triacylglycerol levels of mice fed a HFD were significantly higher than that of the control group and the HFD + Control group. There were significant differences in the diversity and predicted functional properties of microbiota in the cecum and colon mucosa between the control group and the HFD group. HFD feeding reduced the ratio of Bacteroidetes to Firmicutes, a microbiota pattern often associated with obesity. The HFD + Control diet partially restored the diversity and composition of microbiota in the cecum to the pattern observed in mice fed a control diet. These results suggest that short-term high fat diet withdrawal can restore metabolic changes and prevent excess body weight gain, however, long-term dietary intervention may be required to optimize the restoration of gut microbiota in mouse.

Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV.

PubMed Central

Cohen, R D; Castellani, L W; Qiao, J H; Van Lenten, B J; Lusis, A J; Reue, K

1997-01-01

Transgenic mouse lines carrying several copies of the mouse apo A-IV gene were produced. Lipoprotein composition and function, and aortic lesion development were examined. Apo A-IV levels in the plasma of transgenic mice were elevated threefold compared with nontransgenic littermates on a chow diet, and sixfold in mice fed an atherogenic diet. Plasma concentrations of total cholesterol, HDL cholesterol, triglycerides, and free fatty acids were similar in transgenic and control mice fed a chow diet. However, with the atherogenic diet, male transgenic mice exhibited significantly higher levels of plasma triglycerides (P < 0.05), total cholesterol (P < 0.01), HDL cholesterol (P < 0.0001), and free fatty acids (P < 0.05), and lower levels of unesterified cholesterol (P < 0.05), than nontransgenic littermates. Expression of the apo A-IV transgene had a protective effect against the formation of diet-induced aortic lesions, with transgenics exhibiting lesion scores of approximately 30% those seen in control mice. HDL-sized lipoproteins isolated from transgenic mice fed the atherogenic diet promoted cholesterol efflux from cholesterol-loaded human monocytes more efficiently than comparable lipoproteins from nontransgenic counterparts. Plasma from transgenics also exhibited higher endogenous cholesterol esterification rates. Taken together, these results suggest that apo A-IV levels influence the metabolism and antiatherogenic properties of HDL. PMID:9109435

Costaria costata Extract Suppresses Development of Atopic Dermatitis in chloro-2,4-dinitrobenzene-treated NC/Nga Mice.

PubMed

Kim, Ok-Kyung; Lee, Minhee; Kwon, Han Ol; Lee, Dasom; Park, Jeongjin; Kim, Eungpil; You, Yanghee; Lim, Young Tae; Jun, Woojin; Lee, Jeongmin

2018-05-23

We investigated the potential effects of Costaria costata (CC) on atopic dermatitis (AD) development in chloro-2,4-dinitrobenzene (DNCB)-treated NC/Nga mice. CC is a brown alga distributed across the seas of Korea, China, and Japan. A total of 40 mice were randomly assigned to 5 groups with 8 mice per group: untreated Balb/c mice, AD control (0.1% w/v DNCB-treated NC/Nga mice), positive control (i.e., DNCB-treated NC/Nga mice fed a dietary supplement of 66.6 mg/kg of body weight [b.w.] of CJLP133), DNCB-treated NC/Nga mice fed a dietary supplement of 100 mg/kg b.w. of CCE10 (CCE10 100), and DNCB-treated mice fed a dietary supplement of 300 mg/kg b.w. of CCE10 (CCE10 300) groups. The CCE10 100 and CCE10 300 treatment groups suppressed AD development including clinical and histopathological changes and a reduction in skin hydration induced by DNCB. In addition, Th2 cytokine production in primary splenocytes, serum IgE and histamine production, and mast cell infiltration into the skin were suppressed in the CCE10 300 mice compared to the CCE10 100 mice. Our finding demonstrated an inhibitory effect of CCE10 in AD development by means of improving the Th1/Th2 cytokine balance and anti-inflammatory effect in an in vivo model. © 2018 S. Karger AG, Basel.

Obesity alters immune and metabolic profiles: new insight from obese-resistant mice on high fat diet

PubMed Central

Boi, Shannon K.; Buchta, Claire M.; Pearson, Nicole A.; Francis, Meghan B.; Meyerholz, David K.; Grobe, Justin L.; Norian, Lyse A.

2016-01-01

Objective Diet-induced obesity has been shown to alter immune function in mice, but distinguishing the effects of obesity from changes in diet composition is complicated. We hypothesized that immunological differences would exist between diet-induced obese (DIO) and obese-resistant (OB-Res) mice fed the same high-fat diet (HFD). Methods BALB/c mice were fed either standard chow or HFD to generate lean or DIO and OB-Res mice, respectively. Resulting mice were analyzed for serum immunologic and metabolic profiles, and cellular immune parameters. Results BALB/c mice on HFD can be categorized as DIO or OB-Res, based on body weight versus lean controls. DIO mice are physiologically distinct from OB-Res mice, whose serum Insulin, Leptin, GIP, and Eotaxin concentrations remain similar to lean controls. DIO mice have increased macrophage+ crown-like structures in white adipose tissue, although macrophage percentages were unchanged from OB-Res and lean mice. DIO mice also have decreased splenic CD4+ T cells, elevated serum GM-CSF, and increased splenic CD11c+ dendritic cells, but impaired dendritic cell stimulatory capacity (p < 0.05 versus lean controls). These parameters were unaltered in OB-Res mice versus lean controls. Conclusions Diet-induced obesity results in alterations in immune and metabolic profiles that are distinct from effects caused by HFD alone. PMID:27515998

Effect of Canavalia gladiata Extract Fermented with Aspergillus oryzae on the Development of Atopic Dermatitis in NC/Nga Mice.

PubMed

Kim, Ok-Kyung; Chang, Jee-Yun; Nam, Da-Eun; Park, Yoo Kyoung; Jun, Woojin; Lee, Jeongmin

2015-01-01

Canavalia gladiata has been used as a Chinese traditional folk medicine for its anti-inflammatory properties. However, the use of C. gladiata is limited because it contains antinutritional and allergy-causing proteins. We fermented C. gladiata with Aspergillus oryzae and investigated the effects of fermented C. gladiata (FCG) on the development of atopic dermatitis (AD) in mice. The mice were divided into five groups: untreated Balb/c mice; AD control (NC/Nga mice); FCGH (NC/Nga mice fed a dietary supplement of 300 mg/kg fermented C. gladiata water extract); FCG30 (NC/Nga mice fed a dietary supplement of 300 mg/kg of fermented C. gladiata 30% ethanol extract), and FCG80 (NC/Nga mice fed a dietary supplement of 300 mg/kg of fermented C. gladiata 80% ethanol extract). We found increases in the nonessential amino acids and essential amino acid in the FCG compared with the non-FCG. FCG attenuated macroscopic and histopathological changes in dorsal skin of mice when compared with the AD control group. The FCG30 and FCG80 groups, in particular, showed significant decreases in scratching episodes when compared with the AD control group. FCG improved immune responses, including increases in IgE and histamine for AD, through attenuation of Th1/Th2 cytokine imbalance and the production of proinflammatory cytokines and chemokines. We suggest that FCG may have benefits for improvement of AD function by improving the balance of Th1/Th2 cytokines and by producing anti-inflammatory effects. © 2015 S. Karger AG, Basel.

Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae.

PubMed

Samuelson, Derrick R; Shellito, Judd E; Maffei, Vincent J; Tague, Eric D; Campagna, Shawn R; Blanchard, Eugene E; Luo, Meng; Taylor, Christopher M; Ronis, Martin J J; Molina, Patricia E; Welsh, David A

2017-06-01

Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these results suggest that alterations in the intestinal immune response as a consequence of alcohol-induced dysbiosis contribute to increased host susceptibility to Klebsiella pneumonia.

Alcohol-associated intestinal dysbiosis impairs pulmonary host defense against Klebsiella pneumoniae

PubMed Central

Campagna, Shawn R.; Blanchard, Eugene E.; Ronis, Martin J. J.

2017-01-01

Chronic alcohol consumption perturbs the normal intestinal microbial communities (dysbiosis). To investigate the relationship between alcohol-mediated dysbiosis and pulmonary host defense we developed a fecal adoptive transfer model, which allows us to investigate the impact of alcohol-induced gut dysbiosis on host immune response to an infectious challenge at a distal organ, independent of prevailing alcohol use. Male C57BL/6 mice were treated with a cocktail of antibiotics (ampicillin, gentamicin, neomycin, vancomycin, and metronidazole) via daily gavage for two weeks. A separate group of animals was fed a chronic alcohol (or isocaloric dextrose pair-fed controls) liquid diet for 10 days. Microbiota-depleted mice were recolonized with intestinal microbiota from alcohol-fed or pair-fed (control) animals. Following recolonization groups of mice were sacrificed prior to and 48 hrs. post respiratory infection with Klebsiella pneumoniae. Klebsiella lung burden, lung immunology and inflammation, as well as intestinal immunology, inflammation, and barrier damage were examined. Results showed that alcohol-associated susceptibility to K. pneumoniae is, in part, mediated by gut dysbiosis, as alcohol-naïve animals recolonized with a microbiota isolated from alcohol-fed mice had an increased respiratory burden of K. pneumoniae compared to mice recolonized with a control microbiota. The increased susceptibility in alcohol-dysbiosis recolonized animals was associated with an increase in pulmonary inflammatory cytokines, and a decrease in the number of CD4+ and CD8+ T-cells in the lung following Klebsiella infection but an increase in T-cell counts in the intestinal tract following Klebsiella infection, suggesting intestinal T-cell sequestration as a factor in impaired lung host defense. Mice recolonized with an alcohol-dysbiotic microbiota also had increased intestinal damage as measured by increased levels of serum intestinal fatty acid binding protein. Collectively, these results suggest that alterations in the intestinal immune response as a consequence of alcohol-induced dysbiosis contribute to increased host susceptibility to Klebsiella pneumonia. PMID:28604843

β-carotene 9’,10’ oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model

PubMed Central

Tan, Hsueh-Li; Thomas-Ahner, Jennifer M.; Moran, Nancy E.; Cooperstone, Jessica L.; Erdman, John W.; Young, Gregory S.; Clinton, Steven K.

2017-01-01

The hypothesis that dietary tomato consumption or the intake of the carotenoid lycopene inhibits prostate cancer arose from epidemiologic studies and is supported by preclinical rodent experiments and in vitro mechanistic studies. We hypothesize that variation in activity of carotenoid cleavage enzymes, such as β-carotene 9’,10’-oxygenase (BCO2), may alter the impact of dietary tomato and lycopene on prostate carcinogenesis and therefore examined this relationship in the TRAMP model. Starting at three weeks of age, TRAMP:Bco2+/+ and TRAMP:Bco2−/− mice were fed either AIN-93G control, or semi-purified diets containing 10% tomato powder or 0.25% lycopene beadlets until 18 weeks of age. Both tomato- and lycopene-fed TRAMP:Bco2−/− mice had significantly greater serum concentrations of total, 5-cis, other cis, and all-trans lycopene than TRAMP:Bco2+/+ mice. Tomato- and lycopene-fed mice had a lower incidence of prostate cancer compared to the control-fed mice. While Bco2 genotype alone did not significantly change prostate cancer outcome in the control AIN-93G-fed mice, the abilities of lycopene and tomato feeding to inhibit prostate carcinogenesis were significantly attenuated by the loss of Bco2 (interaction p=0.0004 and p=0.0383, respectively). Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a Bco2 genotype-specific manner, potentially implicating the anticancer activity of lycopene cleavage products. This study suggests that genetic variables impacting carotenoid metabolism and accumulation can impact anti-cancer activity and that future efforts devoted to understanding the interface between tomato carotenoid intake, host genetics, and metabolism will be necessary to clearly elucidate their interactive roles in human prostate carcinogenesis. PMID:27807077

β-Carotene 9',10' Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model.

PubMed

Tan, Hsueh-Li; Thomas-Ahner, Jennifer M; Moran, Nancy E; Cooperstone, Jessica L; Erdman, John W; Young, Gregory S; Clinton, Steven K

2017-02-01

The hypothesis that dietary tomato consumption or the intake of the carotenoid lycopene inhibits prostate cancer arose from epidemiologic studies and is supported by preclinical rodent experiments and in vitro mechanistic studies. We hypothesize that variation in activity of carotenoid cleavage enzymes, such as β-carotene 9',10'-oxygenase (BCO2), may alter the impact of dietary tomato and lycopene on prostate carcinogenesis and therefore examined this relationship in the TRAMP model. Starting at 3 weeks of age, TRAMP:Bco2 +/+ and TRAMP:Bco2 -/- mice were fed either AIN-93G control, or semipurified diets containing 10% tomato powder or 0.25% lycopene beadlets until 18 weeks of age. Both tomato- and lycopene-fed TRAMP:Bco2 -/- mice had significantly greater serum concentrations of total, 5-cis, other cis, and all-trans lycopene than TRAMP:Bco2 +/+ mice. Tomato- and lycopene-fed mice had a lower incidence of prostate cancer compared with the control-fed mice. Although Bco2 genotype alone did not significantly change prostate cancer outcome in the control AIN-93G-fed mice, the abilities of lycopene and tomato feeding to inhibit prostate carcinogenesis were significantly attenuated by the loss of Bco2 (P interaction = 0.0004 and 0.0383, respectively). Overall, dietary tomato and lycopene inhibited the progression of prostate cancer in TRAMP in a Bco2 genotype-specific manner, potentially implicating the anticancer activity of lycopene cleavage products. This study suggests that genetic variables impacting carotenoid metabolism and accumulation can impact anticancer activity and that future efforts devoted to understanding the interface between tomato carotenoid intake, host genetics, and metabolism will be necessary to clearly elucidate their interactive roles in human prostate carcinogenesis. Cancer Prev Res; 10(2); 161-9. ©2016 AACR. ©2016 American Association for Cancer Research.

The antifibrinolytic drug tranexamic acid reduces liver injury and fibrosis in a mouse model of chronic bile duct injury.

PubMed

Joshi, Nikita; Kopec, Anna K; Towery, Keara; Williams, Kurt J; Luyendyk, James P

2014-06-01

Hepatic fibrin deposition has been shown to inhibit hepatocellular injury in mice exposed to the bile duct toxicant α-naphthylisothiocyanate (ANIT). Degradation of fibrin clots by fibrinolysis controls the duration and extent of tissue fibrin deposition. Thus, we sought to determine the effect of treatment with the antifibrinolytic drug tranexamic acid (TA) and plasminogen activator inhibitor-1 (PAI-1) deficiency on ANIT-induced liver injury and fibrosis in mice. Plasmin-dependent lysis of fibrin clots was impaired in plasma from mice treated with TA (1200 mg/kg i.p., administered twice daily). Prophylactic TA administration reduced hepatic inflammation and hepatocellular necrosis in mice fed a diet containing 0.025% ANIT for 2 weeks. Hepatic type 1 collagen mRNA expression and deposition increased markedly in livers of mice fed ANIT diet for 4 weeks. To determine whether TA treatment could inhibit this progression of liver fibrosis, mice were fed ANIT diet for 4 weeks and treated with TA for the last 2 weeks. Interestingly, TA treatment largely prevented increased deposition of type 1 collagen in livers of mice fed ANIT diet for 4 weeks. In contrast, biliary hyperplasia/inflammation and liver fibrosis were significantly increased in PAI-1(-/-) mice fed ANIT diet for 4 weeks. Overall, the results indicate that fibrinolytic activity contributes to ANIT diet-induced liver injury and fibrosis in mice. In addition, these proof-of-principle studies suggest the possibility that therapeutic intervention with an antifibrinolytic drug could form a novel strategy to prevent or reduce liver injury and fibrosis in patients with liver disease.

Loss of Toll-Like Receptor 4 Function Partially Protects against Peripheral and Cardiac Glucose Metabolic Derangements During a Long-Term High-Fat Diet.

PubMed

Jackson, Ellen E; Rendina-Ruedy, Elisabeth; Smith, Brenda J; Lacombe, Veronique A

2015-01-01

Diabetes is a chronic inflammatory disease that carries a high risk of cardiovascular disease. However, the pathophysiological link between these disorders is not well known. We hypothesize that TLR4 signaling mediates high fat diet (HFD)-induced peripheral and cardiac glucose metabolic derangements. Mice with a loss-of-function mutation in TLR4 (C3H/HeJ) and age-matched control (C57BL/6) mice were fed either a high-fat diet or normal diet for 16 weeks. Glucose tolerance and plasma insulin were measured. Protein expression of glucose transporters (GLUT), AKT (phosphorylated and total), and proinflammatory cytokines (IL-6, TNF-α and SOCS-3) were quantified in the heart using Western Blotting. Both groups fed a long-term HFD had increased body weight, blood glucose and insulin levels, as well as impaired glucose tolerance compared to mice fed a normal diet. TLR4-mutant mice were partially protected against long-term HFD-induced insulin resistance. In control mice, feeding a HFD decreased cardiac crude membrane GLUT4 protein content, which was partially rescued in TLR4-mutant mice. TLR4-mutant mice fed a HFD also had increased expression of GLUT8, a novel isoform, compared to mice fed a normal diet. GLUT8 content was positively correlated with SOCS-3 and IL-6 expression in the heart. No significant differences in cytokine expression were observed between groups, suggesting a lack of inflammation in the heart following a HFD. Loss of TLR4 function partially restored a healthy metabolic phenotype, suggesting that TLR4 signaling is a key mechanism in HFD-induced peripheral and cardiac insulin resistance. Our data further suggest that TLR4 exerts its detrimental metabolic effects in the myocardium through a cytokine-independent pathway.

Shen-Yuan-Dan Capsule Inhibiting Inflammatory Reaction by Regulating Insulin Receptor Substrate 1/PI3K/Akt/NF-κB Signaling Pathway in Apoliprotein E Knockout Mice Fed with a High-Fat Diet.

PubMed

Zhou, Mingxue; Li, Ping; Kang, Qunfu; Zhang, Lei; Shang, Juju; Liu, Weihong; Liu, Hongxu

2017-05-01

Shen-Yuan-Dan Capsule (SYDC), a traditional Chinese medicine, is proposed to have the capacity to prevent angina pectoris. However, the effects and the related mechanisms of SYDC on atherosclerosis (AS) are still unknown. This study was designed to investigate the effects of SYDC on AS and inflammatory reaction in the apoliprotein E-knockout (ApoE -/- ) mice fed with a high-fat diet. Thirty eight-week-old male ApoE -/- mice were randomly divided into three groups (n = 10) 6 weeks after being fed with a high-fat diet: the control group, the lipitor group, and the SYDC group. The hearts were collected for hematoxylin and eosin (HE) or Van Gieson (VG) staining, and the aortas were collected for quantitative reverse transcription polymerase chain reaction (RT-PCR) and western-blotting. The data showed that the levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), atherosclerotic indexes (AI) and the corrected areas of atherosclerotic plaque of the mice on SYDC group were significantly decreased compared with those of the mice in the control group (p < 0.01, p < 0.05). SYDC can significantly increase collagen proportion in plaques as compared to the untreated mice (p < 0.01). In addition, the messenger ribonucleic acid (mRNA) expressions of insulin receptor substrate 1 (IRS-1), PI3K, Akt, NF-κB and tumor necrosis factor-α (TNF-α) in the mice fed with a high-fat diet were significantly reduced by SYDC (p < 0.05, p < 0.01). SYDC can exert an anti-atherosclerotic effect on ApoE -/- mice fed with a high-fat diet. The action mechanism of SYDC was attributed to its ability to inhibit inflammatory reaction by regulating IRS-1/PI3K/Akt/NF-κB signaling pathway.

Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

PubMed Central

Sáinz, Neira; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Ramírez, Beatriz; Lancha, Andoni; Burgos-Ramos, Emma; Gómez-Ambrosi, Javier; Frühbeck, Gema

2012-01-01

Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4. PMID:22253718

STIM1fl/fl Ksp-Cre Mouse has Impaired Renal Water Balance

PubMed Central

Cebotaru, Liudmila; Cebotaru, Valeriu; Wang, Hua; Arend, Lois J.; Guggino, William B.

2016-01-01

Background/AIM STIM1 is as an essential component in store operated Ca2+entry. However give the paucity of information on the role of STIM1 in kidney, the aim was to study the function of STIM1 in the medulla of the kidney. Methods we crossed a Ksp-cre mouse with another mouse containing two loxP sites flanking Exon 6 of STIM1. The Ksp-cre mouse is based upon the Ksp-cadherin gene promoter which expresses cre recombinase in developing nephrons, collecting ducts (SD) and thick ascending limbs (TAL) of the loop of Henle. Results The offspring of these mice are viable without gross morphological changes, however, we noticed that the STIM1 Ksp-cre knockout mice produced more urine compared to control. To examine this more carefully, we fed mice low (LP) and high protein (HP) diets respectively. When mice were fed HP diet STIM1 ko mice had significantly increased urinary volume and lower specific gravity compared to wt mice. In STIM1 ko mice fed HP diet urine creatinine and urea were significantly lower compared to wt mice fed HP diet, however the fractional excretion was the same. Conclusion These data support the idea that STIM1 ko mice have impaired urinary concentrating ability when challenged with HP diet is most likely caused by impaired Ca2+-dependent signal transduction through the vasopressin receptor cascade. PMID:27336410

Diet-induced obesity, energy metabolism and gut microbiota in C57BL/6J mice fed Western diets based on lean seafood or lean meat mixtures.

PubMed

Holm, Jacob Bak; Rønnevik, Alexander; Tastesen, Hanne Sørup; Fjære, Even; Fauske, Kristin Røen; Liisberg, Ulrike; Madsen, Lise; Kristiansen, Karsten; Liaset, Bjørn

2016-05-01

High protein diets may protect against diet-induced obesity, but little is known regarding the effects of different protein sources consumed at standard levels. We investigated how a mixture of lean seafood or lean meat in a Western background diet modulated diet-induced obesity, energy metabolism and gut microbiota. Male C57BL/6J mice fed a Western diet (WD) containing a mixture of lean seafood (seafood WD) for 12weeks accumulated less fat mass than mice fed a WD containing a mixture of lean meat (meat WD). Meat WD-fed mice exhibited increased fasting blood glucose, impaired glucose clearance, elevated fasting plasma insulin and increased plasma and liver lipid levels. We observed no first choice preference for either of the WDs, but over time, mice fed the seafood WD consumed less energy than mice fed the meat WD. Mice fed the seafood WD exhibited higher spontaneous locomotor activity and a lower respiratory exchange ratio (RER) than mice fed the meat WD. Thus, higher activity together with the decreased energy intake contributed to the different phenotypes observed in mice fed the seafood WD compared to mice fed the meat WD. Comparison of the gut microbiomes of mice fed the two WDs revealed significant differences in the relative abundance of operational taxonomic units (OTUs) belonging to the orders Bacteroidales and Clostridiales, with genes involved in metabolism of aromatic amino acids exhibiting higher relative abundance in the microbiomes of mice fed the seafood WD. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential effects of PPAR-{gamma} activation versus chemical or genetic reduction of DPP-4 activity on bone quality in mice.

PubMed

Kyle, Kimberly A; Willett, Thomas L; Baggio, Laurie L; Drucker, Daniel J; Grynpas, Marc D

2011-02-01

Patients with type 2 diabetes mellitus have an increased risk of fracture that can be further exacerbated by thiazolidinediones. A new class of antidiabetic agents control glucose through reduction of dipeptidyl peptidase-4 (DPP-4) activity; however the importance of DPP-4 for the control of bone quality has not been extensively characterized. We compared the effects of the thiazolidinedione pioglitazone and the DPP-4 inhibitor sitagliptin on bone quality in high-fat diet (HFD)-fed wild-type mice. In complementary studies, we examined bone quality in Dpp4(+/+) vs. Dpp4(-/-) mice. Pioglitazone produced yellow bones with greater bone marrow adiposity and significantly reduced vertebral bone mechanics in male, female, and ovariectomized (OVX) HFD fed female mice. Pioglitazone negatively affected vertebral volumetric bone mineral density, trabecular architecture, and mineral apposition rate in male mice. Sitagliptin treatment of HFD-fed wild-type mice significantly improved vertebral volumetric bone mineral density and trabecular architecture in female mice, but these improvements were lost in females after OVX. Genetic inactivation of Dpp4 did not produce a major bone phenotype in male and female Dpp4(-/-) mice; however, OVX Dpp4(-/-) mice exhibited significantly reduced femoral size and mechanics. These findings delineate the skeletal consequences of pharmacological and genetic reduction of DPP-4 activity and reveal significant differences in the effects of pioglitazone vs. sitagliptin vs. genetic Dpp4 inactivation on bone mechanics in mice.

Exercise improves adipose function and inflammation and ameliorates fatty liver disease in obese diabetic mice.

PubMed

Haczeyni, Fahrettin; Barn, Vanessa; Mridha, Auvro R; Yeh, Matthew M; Estevez, Emma; Febbraio, Mark A; Nolan, Christopher J; Bell-Anderson, Kim S; Teoh, Narci C; Farrell, Geoffrey C

2015-09-01

Adipose inflammation and dysfunction underlie metabolic obesity. Exercise improves glycemic control and metabolic indices, but effects on adipose function and inflammation are less clear. Accordingly, it was hypothesized that exercise improves adipose morphometry to reduce adipose inflammation in hyperphagic obese mice. Alms1 mutant foz/foz mice housed in pairs were fed an atherogenic or chow diet; half the cages were fitted with a computer-monitored wheel for voluntary exercise. Insulin-induced AKT-phosphorylation, adipocyte size distribution, and inflammatory recruitment were studied in visceral versus subcutaneous depots, and severity of fatty liver disease was determined. Exercise prevented obesity and diabetes development in chow-fed foz/foz mice and delayed their onset in atherogenic-fed counterparts. Insulin-stimulated phospho-AKT levels in muscle were improved with exercise, but not in adipose or liver. Exercise suppressed adipose inflammatory recruitment, particularly in visceral adipose, associated with an increased number of small adipocyte subpopulations, and enhanced expression of beige adipocyte factor PRDM16 in subcutaneous fat. In atherogenic-fed foz/foz mice liver, exercise suppressed development of nonalcoholic steatohepatitis and related liver fibrosis. Exercise confers metabo-protective effects in atherogenic-fed hyperphagic mice by preventing early onset of obesity and diabetes in association with enhanced muscle insulin sensitivity, improved adipose morphometry, and suppressed adipose and liver inflammation. © 2015 The Obesity Society.

Diet-induced obesity causes ghrelin resistance in reward processing tasks.

PubMed

Lockie, Sarah H; Dinan, Tara; Lawrence, Andrew J; Spencer, Sarah J; Andrews, Zane B

2015-12-01

Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Splenic Immune Response Is Down-Regulated in C57BL/6J Mice Fed Eicosapentaenoic Acid and Docosahexaenoic Acid Enriched High Fat Diet.

PubMed

Soni, Nikul K; Ross, Alastair B; Scheers, Nathalie; Savolainen, Otto I; Nookaew, Intawat; Gabrielsson, Britt G; Sandberg, Ann-Sofie

2017-01-10

Dietary n -3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with reduction of inflammation, although the mechanisms are poorly understood, especially how the spleen, as a secondary lymphoid organ, is involved. To investigate the effects of EPA and DHA on spleen gene expression, male C57BL/6J mice were fed high fat diets (HFD) differing in fatty acid composition, either based on corn oil (HFD-CO), or CO enriched with 2 g/100 g EPA and DHA (HFD-ED), for eight weeks. Spleen tissue was analyzed using transcriptomics and for fatty acids profiling. Biological processes (BPs) related to the immune response, including T-cell receptor signaling pathway, T-cell differentiation and co-stimulation, myeloid dendritic cell differentiation, antigen presentation and processing, and the toll like receptor pathway were downregulated by HFD-ED compared with control and HFD-CO. These findings were supported by the down-regulation of NF-κB in HFD-ED compared with HFD-CO fed mice. Lower phospholipid arachidonic acid levels in HFD-ED compared with HFD-CO, and control mice suggest attenuation of pathways via prostaglandins and leukotrienes. The HFD-ED also upregulated BPs related to erythropoiesis and hematopoiesis compared with control and HFD-CO fed mice. Our findings suggest that EPA and DHA down-regulate the splenic immune response induced by HFD-CO, supporting earlier work that the spleen is a target organ for the anti-inflammatory effects of these n -3 fatty acids.

Splenic Immune Response Is Down-Regulated in C57BL/6J Mice Fed Eicosapentaenoic Acid and Docosahexaenoic Acid Enriched High Fat Diet

PubMed Central

Soni, Nikul K.; Ross, Alastair B.; Scheers, Nathalie; Savolainen, Otto I.; Nookaew, Intawat; Gabrielsson, Britt G.; Sandberg, Ann-Sofie

2017-01-01

Dietary n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with reduction of inflammation, although the mechanisms are poorly understood, especially how the spleen, as a secondary lymphoid organ, is involved. To investigate the effects of EPA and DHA on spleen gene expression, male C57BL/6J mice were fed high fat diets (HFD) differing in fatty acid composition, either based on corn oil (HFD-CO), or CO enriched with 2 g/100 g EPA and DHA (HFD-ED), for eight weeks. Spleen tissue was analyzed using transcriptomics and for fatty acids profiling. Biological processes (BPs) related to the immune response, including T-cell receptor signaling pathway, T-cell differentiation and co-stimulation, myeloid dendritic cell differentiation, antigen presentation and processing, and the toll like receptor pathway were downregulated by HFD-ED compared with control and HFD-CO. These findings were supported by the down-regulation of NF-κB in HFD-ED compared with HFD-CO fed mice. Lower phospholipid arachidonic acid levels in HFD-ED compared with HFD-CO, and control mice suggest attenuation of pathways via prostaglandins and leukotrienes. The HFD-ED also upregulated BPs related to erythropoiesis and hematopoiesis compared with control and HFD-CO fed mice. Our findings suggest that EPA and DHA down-regulate the splenic immune response induced by HFD-CO, supporting earlier work that the spleen is a target organ for the anti-inflammatory effects of these n-3 fatty acids. PMID:28075380

Dietary lipids containing gangliosides reduce Giardia muris infection in vivo and survival of Giardia lamblia trophozoites in vitro.

PubMed

Suh, M; Belosevic, M; Clandinin, M T

2004-06-01

We examined whether a ganglioside supplemented diet affected the course of Giardia muris infection in mice and survival of Giardia lamblia trophozoites in vitro. Female CD-1 mice were fed 1 of 5 experimental diets: standard lab chow as a control diet; semi-synthetic diets containing 20% (w/w) triglyceride based on the fat composition of a conventional infant formula; triglyceride diet; triglyceride diet containing a low level of ganglioside (0.1% w/w); and triglyceride diet containing a high level of ganglioside (1.0% w/w of diet). After 2 weeks of feeding, mice were inoculated with G. muris by gastric intubation and fed the experimental diets during the course of the infection. Cysts released in the faeces and trophozoites present in the small intestine were enumerated at various times post-infection. The average cyst output and the number of trophozoites during the course of the infection in mice fed ganglioside-containing diet were found to be significantly lower (3-log10 reduction) compared to animals fed control diets. The results of in vitro growth studies indicated that gangliosides may be directly toxic to the parasites. Thus, gangliosides have a protective effect against G. muris infection in vivo and affect the survival of G. lamblia trophozoites in vitro.

Simvastatin inhibited cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice fed a “Western-style diet” by increasing PPAR α and γ expression and reducing TC, MMP-9, and Cat S levels

PubMed Central

Qin, Yan-wen; Ye, Ping; He, Ji-qiang; Sheng, Li; Wang, Lu-ya; Du, Jie

2010-01-01

Aim: The examine the cardiac hypertrophy and fibrosis in apolipoprotein E-deficient mice (ApoE−/− mice) fed a “Western-style diet” and the effect of simvastatin intervention. Methods: Male ApoE−/− mice (n=36) were fed a “Western-style diet” from the age of 8 weeks. After 16 weeks, they were randomly given either simvastatin (25 mg·kg−1·d−1) or normal saline (control group) by gavage for 8, 16, or 24 weeks. The left ventricular (LV) wall thickness and diameter of the myocardial cells were determined with Hematoxylin-Eosin stain, and the level of fibrosis of the myocardial matrix was assessed with Masson stain. Real-time quantitative polymerase chain reaction and Western blotting analysis were used to determine the mRNA and protein expression of matrix metalloproteinase-9 (MMP-9), Cathepsin S (Cat S), and the peroxisome proliferator-activated receptors (PPARs) in the myocardium of ApoE−/− mice. Results: ApoE−/− mice fed a “Western-style diet” showed an significant age-dependent increase in total cholesterol (TC), LV wall thickness, myocardial cell diameter and LV collagen content (P<0.05). The simvastatin treatment group showed significantly reduced LV wall thickness, myocardial cell diameters and LV collagen content at 40 weeks when compared with the control group (P<0.05). Furthermore, treatment with simvastatin also significantly inhibited the mRNA and protein expressions of MMP-9 and Cat S as well as increased the mRNA and protein expressions of PPAR alpha and PPAR gamma at 32 and 40 weeks compared with the control group (P<0.05). Conclusion: ApoE−/− mice fed a “Western-style diet” had cardiac hypertrophy and fibrosis, which worsened with age. Simvastatin treatment inhibits the development of cardiac hypertrophy and fibrosis, and this effect may be mediated through increased levels of PPAR alpha and PPAR gamma and reduced levels of TC, MMP-9, and Cat S. PMID:20835264

Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.

PubMed

Sataranatarajan, Kavithalakshmi; Ikeno, Yuji; Bokov, Alex; Feliers, Denis; Yalamanchili, Himabindu; Lee, Hak Joo; Mariappan, Meenalakshmi M; Tabatabai-Mir, Hooman; Diaz, Vivian; Prasad, Sanjay; Javors, Martin A; Ghosh Choudhury, Goutam; Hubbard, Gene B; Barnes, Jeffrey L; Richardson, Arlan; Kasinath, Balakuntalam S

2016-07-01

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment. © The Author 2015. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Ca2+ mobilization in the aortic endothelium in streptozotocin-induced diabetic and cholesterol-fed mice.

PubMed

Kamata, K; Nakajima, M

1998-04-01

1. Experiments were performed to compare Ca2+ mobilization in the aortic endothelium in streptozotocin (STZ)-induced diabetic and cholesterol-fed mice with that in age-matched controls. 2. The intracellular free Ca2+ ([Ca2+]i) in the fura PE-3 loaded endothelium of aortic rings was dose-dependently increased by cumulative administration of acetylcholine (ACh). ACh caused a transient rise in [Ca2+]i in Ca2+-free medium. The ACh-induced increase in [Ca2+]i in normal or Ca2+-free medium was significantly weaker in both STZ-induced diabetic and cholesterol-fed mice. 3. The weaker [Ca2+]i response in Ca2+-containing medium in STZ-induced diabetic and cholesterol-fed mice was normalized by chronic administration of cholestyramine. 4. The increased low density lipoprotein (LDL) levels seen in both STZ-induced diabetic and cholesterol-fed mice were normalized by the same chronic administration of cholestyramine (300 mg kg(-1), p.o. daily for 10 weeks). Chronic administration of cholestyramine had no effect on the plasma glucose level. 5. Lysophosphatidylcholine (LPC) decreased the [Ca2+]i responses to ACh in the aortic endothelium from normal mice. 6. These results suggest that ACh increases both Ca2+ influx and Ca2+ release from storage in the aortic endothelium. The weaker [Ca2+]i influx seen in the endothelium of aortae from both STZ-induced diabetic and cholesterol-fed mice was improved by the chronic administration of cholestyramine, and we suggest that this improvement is due, at least in part, to a lowering of the plasma LDL level. It is further suggested that LPC may have an important influence over Ca2+ mobilization in the endothelium.

Dietary β-conglycinin prevents fatty liver induced by a high-fat diet by a decrease in peroxisome proliferator-activated receptor γ2 protein.

PubMed

Yamazaki, Tomomi; Kishimoto, Kyoko; Miura, Shinji; Ezaki, Osamu

2012-02-01

Diets high in sucrose/fructose or fat can result in hepatic steatosis (fatty liver). Mice fed a high-fat diet, especially that of saturated-fat-rich oil, develop fatty liver with an increase in peroxisome proliferator-activated receptor (PPAR) γ2 protein in liver. The fatty liver induced by a high-fat diet is improved by knockdown of liver PPARγ2. In this study, we investigated whether β-conglycinin (a major protein of soy protein) could reduce PPARγ2 protein and prevent high-fat-diet-induced fatty liver in ddY mice. Mice were fed a high-starch diet (70 energy% [en%] starch) plus 20% (wt/wt) sucrose in their drinking water or a high-safflower-oil diet (60 en%) or a high-butter diet (60 en%) for 11 weeks, by which fatty liver is developed. As a control, mice were fed a high-starch diet with drinking water. Either β-conglycinin or casein (control) was given as dietary protein. β-Conglycinin supplementation completely prevented fatty liver induced by each type of diet, along with a reduction in adipose tissue weight. β-Conglycinin decreased sterol regulatory element-binding protein (SREBP)-1c and carbohydrate response element-binding protein (ChREBP) messenger RNAs (mRNAs) in sucrose-supplemented mice, whereas it decreased PPARγ2 mRNA (and its target genes CD36 and FSP27), but did not decrease SREBP-1c and ChREBP mRNAs, in mice fed a high-fat diet. β-Conglycinin decreased PPARγ2 protein and liver triglyceride (TG) concentration in a dose-dependent manner in mice fed a high-butter diet; a significant decrease in liver TG concentration was observed at a concentration of 15 en%. In conclusion, β-conglycinin effectively prevents fatty liver induced by a high-fat diet through a decrease in liver PPARγ2 protein. Copyright © 2012 Elsevier Inc. All rights reserved.

Activation of Estrogen Response Element–Independent ERα Signaling Protects Female Mice From Diet-Induced Obesity

PubMed Central

Yasrebi, Ali; Rivera, Janelle A.; Krumm, Elizabeth A.; Yang, Jennifer A.

2017-01-01

17β-estradiol (E2) regulates central and peripheral mechanisms that control energy and glucose homeostasis predominantly through estrogen receptor α (ERα) acting via receptor binding to estrogen response elements (EREs). ERα signaling is also involved in mediating the effects of E2 on diet-induced obesity (DIO), although the roles of ERE-dependent and -independent ERα signaling in reducing the effects of DIO remain largely unknown. We hypothesize that ERE-dependent ERα signaling is necessary to ameliorate the effects of DIO. We addressed this question using ERα knockout (KO) and ERα knockin/knockout (KIKO) female mice, the latter expressing an ERα that lacks a functional ERE binding domain. Female mice were ovariectomized, fed a low-fat diet (LFD) or a high-fat diet (HFD), and orally dosed with vehicle or estradiol benzoate (EB) (300 μg/kg). After 9 weeks, body composition, glucose and insulin tolerance, peptide hormone and inflammatory cytokine levels, and hypothalamic arcuate nucleus and liver gene expression were assessed. EB reduced body weight and body fat in wild-type (WT) female mice, regardless of diet, and in HFD-fed KIKO female mice, in part by reducing energy intake and feeding efficiency. EB reduced fasting glucose levels in KIKO mice fed both diets but augmented glucose tolerance only in HFD-fed KIKO female mice. Plasma insulin and interleukin 6 were elevated in KIKO and KO female mice compared with LFD-fed WT female mice. Expression of arcuate neuropeptide and receptor genes and liver fatty acid biosynthesis genes was altered by HFD and by EB through ERE-dependent and -independent mechanisms. Therefore, ERE-independent signaling mechanisms in both the brain and peripheral organs mediate, in part, the effects of E2 during DIO. PMID:27901601

Chronic alcohol ingestion increases mortality and organ injury in a murine model of septic peritonitis.

PubMed

Yoseph, Benyam P; Breed, Elise; Overgaard, Christian E; Ward, Christina J; Liang, Zhe; Wagener, Maylene E; Lexcen, Daniel R; Lusczek, Elizabeth R; Beilman, Greg J; Burd, Eileen M; Farris, Alton B; Guidot, David M; Koval, Michael; Ford, Mandy L; Coopersmith, Craig M

2013-01-01

Patients admitted to the intensive care unit with alcohol use disorders have increased morbidity and mortality. The purpose of this study was to determine how chronic alcohol ingestion alters the host response to sepsis in mice. Mice were randomized to receive either alcohol or water for 12 weeks and then subjected to cecal ligation and puncture. Mice were sacrificed 24 hours post-operatively or followed seven days for survival. Septic alcohol-fed mice had a significantly higher mortality than septic water-fed mice (74% vs. 41%, p = 0.01). This was associated with worsened gut integrity in alcohol-fed mice with elevated intestinal epithelial apoptosis, decreased crypt proliferation and shortened villus length. Further, alcohol-fed mice had higher intestinal permeability with decreased ZO-1 and occludin protein expression in the intestinal tight junction. The frequency of splenic and bone marrow CD4+ T cells was similar between groups; however, splenic CD4+ T cells in septic alcohol-fed mice had a marked increase in both TNF and IFN-γ production following ex vivo stimulation. Neither the frequency nor function of CD8+ T cells differed between alcohol-fed and water-fed septic mice. NK cells were decreased in both the spleen and bone marrow of alcohol-fed septic mice. Pulmonary myeloperoxidase levels and BAL levels of G-CSF and TFG-β were higher in alcohol-fed mice. Pancreatic metabolomics demonstrated increased acetate, adenosine, xanthine, acetoacetate, 3-hydroxybutyrate and betaine in alcohol-fed mice and decreased cytidine, uracil, fumarate, creatine phosphate, creatine, and choline. Serum and peritoneal cytokines were generally similar between alcohol-fed and water-fed mice, and there were no differences in bacteremia, lung wet to dry weight, or pulmonary, liver or splenic histology. When subjected to the same septic insult, mice with chronic alcohol ingestion have increased mortality. Alterations in intestinal integrity, the host immune response, and pancreatic metabolomics may help explain this differential response.

Protective effects of n-6 fatty acids-enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor

PubMed Central

Gobbetti, T; Ducheix, S; le Faouder, P; Perez, T; Riols, F; Boue, J; Bertrand-Michel, J; Dubourdeau, M; Guillou, H; Perretti, M; Vergnolle, N; Cenac, N

2015-01-01

Background and Purpose Long-term intake of dietary fatty acids is known to predispose to chronic inflammation, but their effects on acute intestinal ischaemia/reperfusion (I/R) injury is unknown. The aim of this study was to determine the consequences of a diet rich in n-3 or n-6 polyunsaturated fatty acids (PUFA) on intestinal I/R-induced damage. Experimental Approach Mice were fed three different isocaloric diets: a balanced diet used as a control and two different PUFA-enriched diets, providing either high levels of n-3 or of n-6 PUFA. Intestinal injury was evaluated after intestinal I/R. PUFA metabolites were quantitated in intestinal tissues by LC-MS/MS. Key Results In control diet-fed mice, intestinal I/R caused inflammation and increased COX and lipoxygenase-derived metabolites compared with sham-operated animals. Lipoxin A4 (LxA4) was significantly and selectively increased after ischaemia. Animals fed a high n-3 diet did not display a different inflammatory profile following intestinal I/R compared with control diet-fed animals. In contrast, intestinal inflammation was decreased in the I/R group fed with high n-6 diet and level of LxA4 was increased post-ischaemia compared with control diet-fed mice. Blockade of the LxA4 receptor (Fpr2), prevented the anti-inflammatory effects associated with the n-6 rich diet. Conclusions and Implications This study indicates that high levels of dietary n-6, but not n-3, PUFAs provides significant protection against intestinal I/R-induced damage and demonstrates that the endogenous production of LxA4 can be influenced by diet. PMID:25296998

Chemoprevention of urothelial cell carcinoma growth and invasion by the dual COX-LOX inhibitor licofelone in UPII-SV40T transgenic mice.

PubMed

Madka, Venkateshwar; Mohammed, Altaf; Li, Qian; Zhang, Yuting; Patlolla, Jagan M R; Biddick, Laura; Lightfoot, Stan; Wu, Xue-Ru; Steele, Vernon; Kopelovich, Levy; Rao, Chinthalapally V

2014-07-01

Epidemiologic and clinical data suggest that use of anti-inflammatory agents is associated with reduced risk for bladder cancer. We determined the chemopreventive efficacy of licofelone, a dual COX-lipoxygenase (LOX) inhibitor, in a transgenic UPII-SV40T mouse model of urothelial transitional cell carcinoma (TCC). After genotyping, six-week-old UPII-SV40T mice (n = 30/group) were fed control (AIN-76A) or experimental diets containing 150 or 300 ppm licofelone for 34 weeks. At 40 weeks of age, all mice were euthanized, and urinary bladders were collected to determine urothelial tumor weights and to evaluate histopathology. Results showed that bladders of the transgenic mice fed control diet weighed 3 to 5-fold more than did those of the wild-type mice due to urothelial tumor growth. However, treatment of transgenic mice with licofelone led to a significant, dose-dependent inhibition of the urothelial tumor growth (by 68.6%-80.2%, P < 0.0001 in males; by 36.9%-55.3%, P < 0.0001 in females) compared with the control group. The licofelone diet led to the development of significantly fewer invasive tumors in these transgenic mice. Urothelial tumor progression to invasive TCC was inhibited in both male (up to 50%; P < 0.01) and female mice (41%-44%; P < 0.003). Urothelial tumors of the licofelone-fed mice showed an increase in apoptosis (p53, p21, Bax, and caspase3) with a decrease in proliferation, inflammation, and angiogenesis markers (proliferating cell nuclear antigen, COX-2, 5-LOX, prostaglandin E synthase 1, FLAP, and VEGF). These results suggest that licofelone can serve as potential chemopreventive for bladder TCC. ©2014 American Association for Cancer Research.

The effects on weight loss and gene expression in adipose and hepatic tissues of very-low carbohydrate and low-fat isoenergetic diets in diet-induced obese mice.

PubMed

Yamazaki, Tomomi; Okawa, Sumire; Takahashi, Mayumi

2016-01-01

Obesity is caused by excessive fat or carbohydrate intake. The improvement of obesity is an important issue, especially in Western societies. Both low-carbohydrate diet (LCD) and low-fat diet (LFD) are used to achieve weight loss in humans. To clarify the mechanisms underlying LCD-induced weight loss, especially in early stage, we compared the gene expression in liver, white adipose tissue (WAT) and brown adipose tissue (BAT) of a very-low carbohydrate diet (VLCD)- and LFD-fed diet-induced obese (DIO) mice. DIO male ddY mice were divided into high-fat diet (HFD), and isoenergetic VLCD and LFD groups. Pair-feeding was performed in the VLCD and LFD groups. Three weeks later, the body, liver, WAT and BAT were weighed and the serum and hepatic lipids, the mRNA expression levels in each tissue, and energy metabolism were analyzed. The caloric intake of the VLCD-fed mice was initially reduced but was subsequently restored. The total energy intake was similar in the VLCD- and LFD-fed mice. There was a similar decrease in the BW of the VLCD- and LFD-fed mice. The VLCD-fed mice had elevated levels of serum fibroblast growth factor 21 (FGF21) and ketone bodies, which are known to increase energy expenditure. The browning of WAT was observed to a greater extent in the VLCD-fed mice. Moreover, in the VLCD-fed mice, BAT activation was observed, the weight of the BAT was decreased, and the expression of G-protein-coupled receptor 120, type 2 iodothyronine deiodinase, and FGF21 in BAT was extremely increased. Although the energy expenditure of the VLCD- and LFD-fed mice did not differ, that of the VLCD-fed mice was sometimes higher during the dark cycle. Hepatic TG accumulation was reduced in LFD-fed mice due to their decreased fatty acid uptake but not in the VLCD-fed mice. The pro-inflammatory macrophage ratio was increased in the WAT of VLCD-fed mice. After 3 weeks, the isoenergetic VLCD- and LFD-fed DIO mice showed similar weight loss. The VLCD-fed mice increased serum concentration of FGF21 and ketone bodies, and marker mRNA levels of browning in WAT, activation in BAT and hepatic lipogenesis.

Enhancement of Muscle Mitochondrial Oxidative Capacity and Alterations in Insulin Action Are Lipid Species Dependent

PubMed Central

Turner, Nigel; Hariharan, Krit; TidAng, Jennifer; Frangioudakis, Georgia; Beale, Susan M.; Wright, Lauren E.; Zeng, Xiao Yi; Leslie, Simon J.; Li, Jing-Ya; Kraegen, Edward W.; Cooney, Gregory J.; Ye, Ji-Ming

2009-01-01

OBJECTIVE Medium-chain fatty acids (MCFAs) have been reported to be less obesogenic than long-chain fatty acids (LCFAs); however, relatively little is known regarding their effect on insulin action. Here, we examined the tissue-specific effects of MCFAs on lipid metabolism and insulin action. RESEARCH DESIGN AND METHODS C57BL6/J mice and Wistar rats were fed either a low-fat control diet or high-fat diets rich in MCFAs or LCFAs for 4–5 weeks, and markers of mitochondrial oxidative capacity, lipid levels, and insulin action were measured. RESULTS Mice fed the MCFA diet displayed reduced adiposity and better glucose tolerance than LCFA-fed animals. In skeletal muscle, triglyceride levels were increased by the LCFA diet (77%, P < 0.01) but remained at low-fat diet control levels in the MCFA-fed animals. The LCFA diet increased (20–50%, P < 0.05) markers of mitochondrial metabolism in muscle compared with low-fat diet–fed controls; however; the increase in oxidative capacity was substantially greater in MCFA-fed animals (50–140% versus low-fat–fed controls, P < 0.01). The MCFA diet induced a greater accumulation of liver triglycerides than the LCFA diet, likely due to an upregulation of several lipogenic enzymes. In rats, isocaloric feeding of MCFA or LCFA high-fat diets induced hepatic insulin resistance to a similar degree; however, insulin action was preserved at the level of low-fat diet–fed controls in muscle and adipose from MCFA-fed animals. CONCLUSIONS MCFAs reduce adiposity and preserve insulin action in muscle and adipose, despite inducing steatosis and insulin resistance in the liver. Dietary supplementation with MCFAs may therefore be beneficial for preventing obesity and peripheral insulin resistance. PMID:19720794

The effect of cannabinoid receptor 1 blockade on hepatic free fatty acid profile in mice with nonalcoholic fatty liver disease.

PubMed

Jorgačević, Bojan; Vučević, Danijela; Đuričić, Ivana; Šobajić, Slađana; Mladenović, Dušan; Vesković, Milena; Vukićević, Rada Ješić; Radosavljević, Tatjana

2017-04-01

We used rimonabant to investigate the role of CB1 receptor on hepatic FFAs profile during NAFLD. Male mice C57BL/6 were divided into: control group fed with control diet 20 weeks (C; n=6); group fed with HFD 20 weeks (HF; n=6); group fed with control diet and treated with rimonabant after 18 weeks (R; n=9); group fed with HFD and treated with rimonabant after 18 weeks (HFR; n=10). Rimonabant (10mg/kg) was administered daily to HFR and R group by oral gavage. Rimonabant decreased liver palmitic acid proportion in HFR group compared to HF group (p<0.05). Liver stearic and oleic acid proportions were decreased in R group compared to control (p<0.01 respectively). Rimonabant increased liver linoleic and arachidonic acid proportions in HFR group compared to HF group (p<0.01 respectively). CB1 blockade may be useful in the treatment of HFD-induced NAFLD due to modulation of plasma lipid and hepatic FFA profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of dietary dairy polar lipids on lipid metabolism of mice fed a high-fat diet.

PubMed

Reis, Mariza G; Roy, Nicole C; Bermingham, Emma N; Ryan, Leigh; Bibiloni, Rodrigo; Young, Wayne; Krause, Lutz; Berger, Bernard; North, Mike; Stelwagen, Kerst; Reis, Marlon M

2013-03-20

The effect of milk polar lipids on lipid metabolism of liver, adipose tissue, and brain and on composition of intestinal microbiota was investigated. C57BL/6J mice were fed a high-fat diet (HFD) for 5 weeks, followed by 5 weeks with HFD without (control) or supplemented with total polar lipids (TPL), phospholipids (PL), or sphingolipids (SPL). Animals fed SPL showed a tendency for lower triglyceride synthesis (P = 0.058) in the liver, but not in adipose tissue. PL and TPL reduced de novo hepatic fatty acid biosynthesis. The ratio of palmitoleic to palmitic acid in the liver was lower for animals fed SPL or TPL compared to control. There was little effect of the supplementation on the cecal microbiota composition. In the brain, DHA (C22:6) content correlated negatively with tetracosanoic acid (C24:0) after TPL supplementation (-0.71, P = 0.02) but not in control (0.26, P = 0.44). Arachidonic acid (C20:4) was negatively correlated with C24:0 in both groups (TPL, -0.77, P = 0.008; control, -0.81, P = 0.003).

Zinc metabolism in genetically obese (ob/ob) mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kennedy, M.L.; Failla, M.L.

1987-05-01

Recent reports indicate that the concentrations and total amounts of several essential trace metals in various tissues of genetically obese rodents differ markedly from those in lean controls. In the present studies the absorption, retention and tissue distribution of zinc and constitutive levels of zinc-metallothionein (Zn-MT) in selected tissues were compared in obese (ob/ob) and lean (+/.) C57BL/6J mice. When 5-, 10- and 22-wk-old mice were administered 1.2 mumol /sup 65/Zn by stomach tube the apparent absorption of /sup 65/Zn by obese mice was 1.5, 2.2 and 3.9 times higher, respectively, than that in age-matched lean mice. Retention of orallymore » administered /sup 65/Zn after 96 h was also substantially higher in obese mice than in lean mice. To assess the possible influences of hyperphagia and intestinal hypertrophy on the enhanced apparent absorption of /sup 65/Zn by obese mice food intake by an additional group of obese mice was restricted to that of age-matched lean controls. When actual absorption of zinc was determined according to the method of Heth and Hoekstra, groups of ad libitum--fed obese, pair-fed obese and lean mice absorbed 38, 32 and 18% of administered /sup 65/Zn, respectively. In contrast, the rate of /sup 65/Zn excretion 2-6 d after oral or subcutaneous administration of the metal was similar for obese and lean mice. Unrestricted and pair-fed obese mice had significantly lower percentages of carcass /sup 65/Zn present in skin, muscle plus bone, spleen and testes and higher percentages present in liver, small intestine and adipose tissue than lean mice.« less

Changes of Tight Junction Protein Claudins in Small Intestine and Kidney Tissues of Mice Fed a DDC Diet.

PubMed

Abiko, Yukie; Kojima, Takashi; Murata, Masaki; Tsujiwaki, Mitsuhiro; Takeuchi, Masaya; Sawada, Norimasa; Mori, Michio

2013-12-01

DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine)-fed mice are widely used as a model for cholestatic liver disease. We examined the expression of tight junction protein claudin subspecies by immunofluorescent histochemistry in small intestine and kidney tissues of mice fed a DDC diet for 12 weeks. In the small intestine, decreases in claudin-3, claudin-7 and claudin-15 were observed in villous epithelial cells corresponding to the severity of histological changes while leaving the abundance of these claudin subspecies unchanged in crypt cells. Nevertheless, the proliferative activity of intestinal crypt cells measured by immunohistochemistry for Ki-67 decreased in the mice fed the DDC diet compared with that of control mice. These results suggest the possibility that DDC feeding affects the barrier function of villous epithelial cells and thus inhibits the proliferative activity of crypt epithelial cells. On the other hand, in the kidney, remarkable changes were found in the subcellular localization of claudin subspecies in a segment-specific manner, although histological changes of renal epithelial cells were quite minimal. These results indicate that immunohistochemistry for claudin subspecies can serve as a useful tool for detecting minute functional alterations of intestinal and renal epithelial cells.

Changes in environmental temperature influence leptin responsiveness in low- and high-fat-fed mice.

PubMed

Harris, Ruth B S; Mitchell, Tiffany D; Kelso, Emily W; Flatt, W P

2007-07-01

Loss of body fat in leptin-treated animals has been attributed to reduced energy intake, increased thermogenesis, and preferential fatty acid oxidation. Leptin does not decrease food intake or body fat in leptin-resistant high-fat (HF)-fed mice, possibly due to a failure of leptin to activate hypothalamic receptors. We measured energy expenditure of male C57BL/6 mice adapted to low-fat (LF) or HF diet and infused them for 13 days with PBS or 10 mug leptin/day from an intraperitoneal mini-osmotic pump to test whether leptin resistance prevented leptin-induced increases in energy expenditure and fatty acid oxidation. There was no effect of low-dose leptin infusions on either of these measures in LF-fed or HF-fed mice, even though LF-fed mice lost body fat. Experiment 2 tested leptin responsiveness in LF-fed and HF-fed mice housed at different temperatures (18 degrees C, 23 degrees C, 27 degrees C), assuming that the cold would increase and the hot environment would inhibit food intake and thermogenesis, which could potentially interfere with leptin action. LF-fed mice housed at 23 degrees C were the only mice that lost body fat during leptin infusion, suggesting that an ability to modify energy expenditure is essential to the maintenance of leptin responsiveness. HF-fed mice in cold or warm environments did not respond to leptin. HF-fed mice in the hot environment were fatter than other HF-fed mice, and, surprisingly, leptin caused a further increase in body fat, demonstrating that the mice were not totally leptin resistant and that partial leptin resistance in a hot environment favors positive energy balance and fat deposition.

Aging and alcohol interact to alter hepatic DNA hydroxymethylation

PubMed Central

Tammen, Stephanie A.; Dolnikowski, Gregory G.; Ausman, Lynne M.; Liu, Zhenhua; Sauer, Julia; SimonettaFriso; Choi, Sang-Woon

2014-01-01

Background Aging and chronic alcohol consumption are both modifiers of DNA methylation but it is not yet known whether chronic alcohol consumption also alters DNA hydroxymethylation, a newly discovered epigenetic mark produced by oxidation of methylcytosine. Furthermore, it has not been tested whether aging and alcohol interact to modify this epigenetic phenomenon, thereby having an independent effect on gene expression. Methods Old (18 months) and young (4 months) male C57BL/6 mice were pair-fed either a Lieber-DeCarli liquid diet with alcohol (18% of energy) or an isocaloricLieber-DeCarli control diet for 5 weeks. Global DNA hydroxymethylation and DNA methylation were analyzed from hepatic DNA using a new LC/MS-MS method. Hepatic mRNA expression of the Tet enzymes and Cyp2e1 were measured via qRTPCR. Results In young mice, mild chronic alcohol exposure significantly reduced global DNA hydroxymethylation compared with control mice (0.22%±0.01% vs 0.29±0.06%, p = 0.004). Alcohol did not significantly alter hydroxymethylcytosine levels in old mice. Old mice fed the control diet showed decreased global DNA hydroxymethylation compared with young mice fed the control diet (0.24±0.02% vs 0.29±0.06%, p = 0.04). This model suggests an interaction between aging and alcohol in determining DNA hydroxymethylation (pinteraction = 0.009). Expression of Tet2 and Tet3 enzymes was decreased in the old mice relative to the young (p < 0.005). Conclusions The observation that alcohol alters DNA hydroxymethylation indicates a new epigenetic effect of alcohol. This is the first study demonstrating the interactive effects of chronic alcohol consumption and aging on DNA hydroxymethylation. PMID:25070523

Energy utilization of a low carbohydrate diet fed genetically obese rats and mice.

PubMed

Thenen, S W; Mayer, J

1977-02-01

Genetically obese Zucker rats, ob/ob mice and non-obese littermates were fed low carbohydrate (2%, 48%, and 50% of energy as carbohydrate, protein, and fat, respectively) and control (60%, 19%, and 21%, as carobhydrate, protein, and fat) diets. The oxidation of the energy components of these diets was measured by adding D-[U-14C]glucose, L-[U-14C]glutamic acid, and glyceryl tri-[1-14C]oleate to test meals given intragastrically and collecting respiratory CO2 for 4 hours. The animals responded to the low carbohydrate diet by oxidizing less glucose and more glutamic acid, but these amounts were proportional to dietary carbohydrate and protein composition, In contrast, the animals oxidized both higher amounts and percentages of glyceryl trioleate when fed the low carbohydrate diet. Obese Zucker rats oxidized less fat than non-obese rats when fed both diets, while obese mice oxidized fat to the same extent as non-obese mice. Feeding the low carbohydrate diet significantly increased body weight in the obese mice, but not in obese rats and non-obese mice and rats. The effect of obesity and the low carbohydrate diet on food intake, serum glucose and lipid values and CO2 production are also reported.

Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet.

PubMed

Waite, Kristin A; Vance, Dennis E

2004-03-22

Mice that lack phosphatidylethanolamine-N-methyltransferase (PEMT) and are fed a choline-deficient (CD) diet suffer severe liver damage and do not survive. Since phosphatidyldimethylethanolamine (PDME) has physical properties similar to those of phosphatidylcholine (PC), we hypothesized that dimethylethanolamine (DME) would be converted into PDME that might substitute for PC, and therefore abrogate the liver damage in the Pemt -/- mice fed a CD diet. We fed Pemt -/- mice either a CD diet, a CD diet supplemented with choline, or a CD diet supplemented with DME (CD + DME). Pemt -/- mice fed the CD diet developed severe liver failure by 4 days while CD + DME-fed mice developed severe liver failure by 5 days. The hepatic PC level in choline-supplemented (CS) mice was 67 +/- 4 nmol/mg protein, whereas the PC content was reduced in CD- and CD + DME-fed mice (49 +/- 3 and 30 +/- 3 nmol/mg protein, respectively). Upon supplementation of the CD diet with DME the amount of hepatic PDME was 81 +/- 9 nmol/mg protein so that the hepatic content of PC + PDME combined was 111 nmol/mg protein. Moreover, plasma apolipoprotein B100 and Al levels were markedly lower in mice fed the CD + DME diet compared to mice fed the CS diet, as was the plasma content of PC. Thus, despite replacement of the deficit in hepatic PC with PDME in Pemt -/- mice fed a CD diet, normal liver function was not restored. We conclude that although PC and PDME exhibit similar physical properties, the three methyl groups of choline are required for hepatic function in mice.

Mixed Tocotrienols Inhibit Prostate Carcinogenesis in TRAMP Mice

PubMed Central

Barve, Avantika; Khor, Tin Oo; Reuhl, Kenneth; Reddy, Bandaru; Newmark, Harold; Kong, Ah-Ng

2015-01-01

The biological activities of tocotrienols are receiving increasing attention. Herein, we report the efficacy of a mixed-tocotrienol diet against prostate tumorigenesis in the transgenic adenocarcinoma mouse prostate (TRAMP) mouse model. Male TRAMP mice, 8 wk old, were fed 0.1%, 0.3%, or 1% mixed tocotrienols in AIN-76A diet up to 24 wk old. Likewise, a positive control group consisting of male TRAMP mice and a negative control group consisting of wild-type nontransgenic mice were fed regular AIN-76A diet up to 24 wk old. Our results show that mixed-tocotrienol-fed groups had a lower incidence of tumor formation along with a significant reduction in the average wet weight of genitourinary apparatus. Furthermore, mixed tocotrienols significantly reduced the levels of high-grade neoplastic lesions as compared to the positive controls. This decrease in levels of high-grade neoplastic lesions was found to be associated with increased expression of proapoptotic proteins BAD (Bcl2 antagonist of cell death) and cleaved caspase-3 and cell cycle regulatory proteins cyclin dependent kinase inhibitors p21 and p27. In contrast, the expression of cyclins A and E were found to be decreased in mixed-tocotrienol groups. Taken together, our results show that by modulating cell cycle regulatory proteins and increasing expression of proapoptotic proteins, mixed tocotrienols suppress prostate tumorigenesis in the TRAMP mice. PMID:20661828

A high fat diet-induced decrease in hippocampal newly-born neurons of male mice is exacerbated by mild psychological stress using a Communication Box.

PubMed

Murata, Yusuke; Narisawa, Yukiyasu; Shimono, Rima; Ohmori, Hiraku; Mori, Masayoshi; Ohe, Kenji; Mine, Kazunori; Enjoji, Munechika

2017-02-01

Obese persons have a higher incidence of depression than healthy-weight persons. Several studies indicated that the exposure to a high fat diet (HFD) results in a decrease in hippocampal neurogenesis, which leads to higher stress response and stress-induced depression. Although stress is a risk factor for obesity and depression, no studies to date have investigated the effect of stress on the hippocampal neurogenesis of HFD-induced obese animals. The aim of this study was to elucidate whether or not obese HFD-fed mice are vulnerable to stress-induced depression by investigating hippocampal neurogenesis. Sixty-four male ICR mice (four weeks of age) were fed a control (N=24) or 45%HFD (N=40) for seven weeks. Of the HFD-fed group, twenty-four mice met the criteria for "diet-induced obesity". The animals were then exposed to three consecutive days of psychological stress using a Communication Box. Half were sacrificed to evaluate the physiological changes, and the other half were perfused to quantify hippocampal neuroblasts/immature neurons by the estimation of doublecortin-immunopositive cells. In the HFD-fed mice, psychological stress resulted in increases in caloric intake and visceral adipose tissue and a significant decrease in doublecortin-positive cells in the dentate gyrus; however, no such differences were found in the control diet-fed group. Limitations Further study using other neurogenic markers to assess the stage-specific changes in hippocampal neurogenesis will be required CONCLUSIONS: Our findings suggest that an HFD-induced decrease in hippocampal newly-born neurons leads to stress vulnerability, which may contribute to a high risk of stress-induced depression for obese persons. Copyright © 2016 Elsevier B.V. All rights reserved.

Inhibitory effects of omega-3 fatty acids on injury-induced epidermal growth factor receptor transactivation contribute to delayed wound healing

PubMed Central

Turk, Harmony F.; Monk, Jennifer M.; Fan, Yang-Yi; Callaway, Evelyn S.; Weeks, Brad

2013-01-01

Epidermal growth factor receptor (EGFR)-mediated signaling is required for optimal intestinal wound healing. Since n-3 polyunsaturated fatty acids (PUFA), specifically docosahexaenoic acid (DHA), alter EGFR signaling and suppress downstream activation of key signaling pathways, we hypothesized that DHA would be detrimental to the process of intestinal wound healing. Using a mouse immortalized colonocyte model, DHA uniquely reduced EGFR ligand-induced receptor activation, whereas DHA and its metabolic precursor eicosapentaenoic acid (EPA) reduced wound-induced EGFR transactivation compared with control (no fatty acid or linoleic acid). Under wounding conditions, the suppression of EGFR activation was associated with a reduction in downstream activation of cytoskeletal remodeling proteins (PLCγ1, Rac1, and Cdc42). Subsequently, DHA and EPA reduced cell migration in response to wounding. Mice were fed a corn oil-, DHA-, or EPA-enriched diet prior to intestinal wounding (2.5% dextran sodium sulfate for 5 days followed by termination after 0, 3, or 6 days of recovery). Mortality was increased in EPA-fed mice and colonic histological injury scores were increased in EPA- and DHA-fed mice compared with corn oil-fed (control) mice. Although kinetics of colonic EGFR activation and downstream signaling (PLCγ1, Rac1, and Cdc42) were delayed by both n-3 PUFA, colonic repair was increased in EPA- relative to DHA-fed mice. These results indicate that, during the early response to intestinal wounding, DHA and EPA uniquely delay the activation of key wound-healing processes in the colon. This effect is mediated, at least in part, via suppression of EGFR-mediated signaling and downstream cytoskeletal remodeling. PMID:23426968

Pomegranate peel extract decreases small intestine lipid peroxidation by enhancing activities of major antioxidant enzymes.

PubMed

Al-Gubory, Kaïs H; Blachier, François; Faure, Patrice; Garrel, Catherine

2016-08-01

Pomegranate peel extract (PPE) contains several compounds with antioxidative properties. PPE added to foods may interact with endogenous antioxidants and promote health. However, little is known about the biochemical mechanisms by which PPE exerts their actions on tissues of biological systems in vivo. The purpose of this study was to determine the effects of PPE on activities of antioxidant enzymes. Mice were used to investigate the effects of PPE on plasma levels of malondialdehyde (MDA), tissue MDA content and activities of superoxide dismutase 1 (SOD1), SOD2 and glutathione peroxidase (GPX) in the small intestine, liver and skeletal muscle - different tissues involved in the digestion, absorption and metabolism of dietary nutrients. Control mice were fed a standard diet, whereas treated mice were fed for 40 days with the standard diet containing 5% or 10% PPE. Mice fed the 10% PPE diet exhibited lower plasma MDA concentrations, reduced content of MDA in the small intestine and liver and higher levels of SOD1 and GPX activities in the small intestine compared to mice fed the control diet. These findings demonstrate that intake of PPE in diet attenuates small intestine lipid peroxidation and strengthens the first line of small intestine antioxidant defense by enhancing enzymatic antioxidative pathways. PPE is worthy of further study as a therapeutic approach to prevent peroxidative stress-induced gut pathogenesis. © 2015 Society of Chemical Industry. © 2015 Society of Chemical Industry.

LXRα Regulates Hepatic ChREBPα Activity and Lipogenesis upon Glucose, but Not Fructose Feeding in Mice

PubMed Central

Nørgaard, Rikke C.; Bindesbøll, Christian; Lucas, Christin; Dalen, Knut Tomas; Itkonen, Harri M.; Matthews, Jason; Nebb, Hilde I.; Grønning-Wang, Line M.

2017-01-01

Liver X receptors (LXRα/β) and carbohydrate response element-binding proteins (ChREBPα/β) are key players in the transcriptional control of hepatic de novo lipogenesis. LXRα/β double knockout (LXRα−/−/β−/−) mice have reduced feeding-induced nuclear O-linked N-acetylglucosamine (O-GlcNAc) signaling, ChREBPα activity, and lipogenic gene expression in livers, suggesting important roles for LXRs in linking hepatic glucose utilization to lipid synthesis. However, the role of LXRs in fructose-induced ChREBP activation and lipogenesis is currently unknown. In this study, we studied the effects of high fructose or high glucose feeding on hepatic carbohydrate metabolism and lipogenic gene expression in livers from fasted (24 h) and fasted-refed (12 h) wild type and LXRα knockout (LXRα−/−) mice. Hepatic lipogenic gene expression was reduced in glucose fed, but not fructose fed LXRα−/− mice. This was associated with lower expression of liver pyruvate-kinase (L-pk) and Chrebpβ, indicating reduced ChREBPα activity in glucose fed, but not fructose fed mice. Interestingly, ChREBP binding to the L-pk promoter was increased in fructose fed LXRα−/− mice, concomitant with increased glucose-6-phosphatase (G6pc) expression and O-GlcNAc modified LXRβ, suggesting a role for LXRβ in regulating ChREBPα activity upon fructose feeding. In conclusion, we propose that LXRα is an important regulator of hepatic lipogenesis and ChREBPα activity upon glucose, but not fructose feeding in mice. PMID:28661453

FKBP12.6-knockout mice display hyperinsulinemia and resistance to high-fat diet-induced hyperglycemia.

PubMed

Chen, Zheng; Li, Zhengzheng; Wei, Bin; Yin, Wenxuan; Xu, Tao; Kotlikoff, Michael I; Ji, Guangju

2010-02-01

FK506 binding protein 12.6 kDa (FKBP12.6), a protein that regulates ryanodine Ca(2+) release channels, may act as an important regulator of insulin secretion. In this study, the role of FKBP12.6 in the control of insulin secretion and blood glucose is clarified using FKBP12.6(-/-) mice. FKBP12.6(-/-) mice showed significant fed hyperinsulinemia but exhibited normoglycemia, fasting normoinsulinemia, and normal body weight compared with wild-type (WT) littermate control mice. Deletion of FKBP12.6 resulted in enhanced glucose-stimulated insulin secretion (GSIS) both in vivo and in vitro, a result that is due to enhanced glucose-induced islet Ca(2+) elevation. After a high-fat dietary challenge (HF diet) for 3 mo, FKBP12.6(-/-) mice displayed higher body weight, hyperinsulinemia, and lower fed blood glucose concentrations compared with WT mice. FKBP12.6(-/-) mice displayed hyperinsulinemia, and resistance to HF diet-induced hyperglycemia, suggesting that FKBP12.6 plays an important role in insulin secretion and blood glucose control, and raising the possibility that it may be a potential therapeutic target for the treatment of type 2 diabetes.

1'-Acetoxychavicol acetate ameliorates age-related spatial memory deterioration by increasing serum ketone body production as a complementary energy source for neuronal cells.

PubMed

Kojima-Yuasa, Akiko; Yamamoto, Tomiya; Yaku, Keisuke; Hirota, Shiori; Takenaka, Shigeo; Kawabe, Kouichi; Matsui-Yuasa, Isao

2016-09-25

1'-Acetoxychavicol acetate (ACA) is naturally obtained from the rhizomes and seeds of Alpinia galangal. Here, we examined the effect of ACA on learning and memory in senescence-accelerated mice prone 8 (SAMP8). In mice that were fed a control diet containing 0.02% ACA for 25 weeks, the learning ability in the Morris water maze test was significantly enhanced in comparison with mice that were fed the control diet alone. In the Y-maze test, SAMP8 mice showed decreased spontaneous alterations in comparison with senescence-accelerated resistant/1 (SAMR1) mice, a homologous control, which was improved by ACA pretreatment. Serum metabolite profiles were obtained by GC-MS analysis, and each metabolic profile was plotted on a 3D score plot. Based upon the diagram, it can be seen that the distribution areas for the three groups were completely separate. Furthermore, the contents of β-hydroxybutyric acid and palmitic acid in the serum of SAMP8-ACA mice were higher than those of SAMP8-control mice and SAMR1-control mice. We also found that SAMR1 mice did not show histological abnormalities, whereas histological damage in the CA1 region of the hippocampus in SAMP8-control mice was observed. However, SAMP8-ACA mice were observed in a similar manner as SAMR1 mice. These findings confirm that ACA increases the serum concentrations of β-hydroxybutyric acid and palmitic acid levels and thus these fuels might contribute to the maintenance of the cognitive performance of SAMP8 mice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yu-Kun Jennifer; Yeager, Ronnie L.; Tanaka, Yuji

Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione andmore » exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gst{alpha}1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities.« less

Enhanced expression of Nrf2 in mice attenuates the fatty liver produced by a methionine- and choline-deficient diet.

PubMed

Zhang, Yu-Kun Jennifer; Yeager, Ronnie L; Tanaka, Yuji; Klaassen, Curtis D

2010-06-15

Oxidative stress has been proposed as an important promoter of the progression of fatty liver diseases. The current study investigates the potential functions of the Nrf2-Keap1 signaling pathway, an important hepatic oxidative stress sensor, in a rodent fatty liver model. Mice with no (Nrf2-null), normal (wild type, WT), and enhanced (Keap1 knockdown, K1-kd) expression of Nrf2 were fed a methionine- and choline-deficient (MCD) diet or a control diet for 5 days. Compared to WT mice, the MCD diet-caused hepatosteatosis was more severe in the Nrf2-null mice and less in the K1-kd mice. The Nrf2-null mice had lower hepatic glutathione and exhibited more lipid peroxidation, whereas the K1-kd mice had the highest amount of glutathione in the liver and developed the least lipid peroxidation among the three genotypes fed the MCD diet. The Nrf2 signaling pathway was activated by the MCD diet, and the Nrf2-targeted cytoprotective genes Nqo1 and Gstalpha1/2 were induced in WT and even more in K1-kd mice. In addition, Nrf2-null mice on both control and MCD diets exhibited altered expression profiles of fatty acid metabolism genes, indicating Nrf2 may influence lipid metabolism in liver. For example, mRNA levels of long chain fatty acid translocase CD36 and the endocrine hormone Fgf21 were higher in livers of Nrf2-null mice and lower in the K1-kd mice than WT mice fed the MCD diet. Taken together, these observations indicate that Nrf2 could decelerate the onset of fatty livers caused by the MCD diet by increasing hepatic antioxidant and detoxification capabilities. Copyright 2010. Published by Elsevier Inc.

Sickness behavior induced by endotoxin can be mitigated by the dietary soluble fiber, pectin, through up-regulation of IL-4 and Th2 polarization

PubMed Central

Sherry, Christina L.; Kim, Stephanie S.; Dilger, Ryan N.; Bauer, Laura L.; Moon, Morgan L.; Tapping, Richard I.; Fahey, George C.; Tappenden, Kelly A.; Freund, Gregory G.

2010-01-01

Peripheral activation of the immune system by infectious agents triggers the brain-cytokine system causing sickness behaviors which profoundly impact well-being. Dietary fiber is a beneficial foodstuff that, from a gastrointestinal tract perspective, exists in both insoluble and soluble forms. We show that a diet rich in soluble fiber protects mice from endotoxin-induced sickness behavior by polarizing mice Th2 when compared to a diet containing only insoluble fiber. Mice fed soluble fiber became less sick and recovered faster from endotoxin-induced sickness behaviors than mice fed insoluble fiber. In response to intraperitoneal endotoxin, mice fed soluble fiber had up-regulated IL-1RA and reduced IL-1βand TNF-αin the brain as compared to mice fed insoluble fiber. Importantly, mice fed soluble fiber had a basal increase in IL-4 in the ileum and spleen which was absent in MyD88 knockout mice. Con A stimulated splenocytes from mice fed soluble fiber showed increased IL-4 and IL-5 and decreased IL-2, IL-12 and IFN-γwhen compared to mice fed insoluble fiber. Likewise, endotoxin-stimulated macrophages from mice fed soluble fiber demonstrated decreased IL-1β, TNF-α, IFN-γ, IL-12 and nitrate and increased IL-1RA, arginase 1 and Ym1 when compared to mice fed insoluble fiber. Finally, the behavioral protection afforded by feeding mice soluble fiber was reduced in IL-4 knockout mice, as was the impact of soluble fiber on Con A stimulated splenocytes and endotoxin activated macrophages. These data show that a diet rich in soluble fiber protects against endotoxin-induced sickness behavior by polarizing mice Th2 and promoting alternative activation of macrophages. PMID:20138982

Differential effects of dietary sodium intake on blood pressure and atherosclerosis in hypercholesterolemic mice.

PubMed

Lu, Hong; Wu, Congqing; Howatt, Deborah A; Balakrishnan, Anju; Charnigo, Richard J; Cassis, Lisa A; Daugherty, Alan

2013-01-01

The amount of dietary sodium intake regulates the renin angiotensin system (RAS) and blood pressure, both of which play critical roles in atherosclerosis. However, there are conflicting findings regarding the effects of dietary sodium intake on atherosclerosis. This study applied a broad range of dietary sodium concentrations to determine the concomitant effects of dietary sodium intake on the RAS, blood pressure, and atherosclerosis in mice. Eight-week-old male low-density lipoprotein receptor -/- mice were fed a saturated fat-enriched diet containing selected sodium concentrations (Na 0.01%, 0.1%, or 2% w/w) for 12 weeks. Mice in these three groups were all hypercholesterolemic, although mice fed Na 0.01% and Na 0.1% had higher plasma cholesterol concentrations than mice fed Na 2%. Mice fed Na 0.01% had greater abundances of renal renin mRNA than those fed Na 0.1% and 2%. Plasma renin concentrations were higher in mice fed Na 0.01% (14.2 ± 1.7 ng/ml/30 min) than those fed Na 0.1% or 2% (6.2 ± 0.6 and 5.8 ± 1.6 ng/ml per 30 min, respectively). However, systolic blood pressure at 12 weeks was higher in mice fed Na 2% (138 ± 3 mm Hg) than those fed Na 0.01% and 0.1% (129 ± 3 and 128 ± 4 mmHg, respectively). In contrast, mice fed Na 0.01% (0.17 ± 0.02 mm(2)) had larger atherosclerotic lesion areas in aortic roots than those fed Na 2% (0.09 ± 0.01 mm(2)), whereas lesion areas in mice fed Na 0.1% (0.12 ± 0.02 mm(2)) were intermediate between and not significantly different from those in Na 0.01% and Na 2% groups. In conclusion, while high dietary sodium intake led to higher systolic blood pressure, low dietary sodium intake augmented atherosclerosis in hypercholesterolemic mice. Copyright © 2013 Elsevier Inc. All rights reserved.

The histamine H3 receptor inverse agonist pitolisant reduces body weight in obese mice.

PubMed

Kotańska, Magdalena; Kuder, Kamil J; Szczepańska, Katarzyna; Sapa, Jacek; Kieć-Kononowicz, Katarzyna

2018-05-25

The pharmacological profile of pitolisant, a histamine H 3 receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum. Glucose tolerance test was performed at the beginning of week 15. Insulin tolerance was tested the day after. At the end of study, plasma levels of triglycerides and cholesterol were determined. Pitolisant at dose of 10 mg/kg bw (ip) was administrated during 14 days, starting from the beginning of week 13. Metformin at dose of 100 mg/kg bw (ip) was used as reference drug. Mice fed with high-fat diet and sucrose solution showed more weight gain throughout the 12-week period of inducing obesity. Animals fed with high-fat diet and treated with pitolisant (for the next 14 days) showed significantly less weight gain than mice from the control group consuming a high-fat feed. In the group treated with pitolisant, glucose levels were significantly lower than glucose levels of control obese mice after glucose load. The plasma triglyceride levels in pitolisant-treated mice were significantly lower compared with those in control obese group. In conclusion, pitolisant has a favorable influence of body weight and improves glucose tolerance and the lipid profile in obese mice.

Aronia melanocarpa (chokeberry) polyphenol-rich extract improves antioxidant function and reduces total plasma cholesterol in apolipoprotein E knockout mice.

PubMed

Kim, Bohkyung; Ku, Chai Siah; Pham, Tho X; Park, Youngki; Martin, Derek A; Xie, Liyang; Taheri, Rod; Lee, Jiyoung; Bolling, Bradley W

2013-05-01

We hypothesized that a polyphenol-rich chokeberry extract (CBE) would modulate hepatic lipid metabolism and improve antioxidant function in apolipoprotein E knockout (apoE(-/-)) mice. ApoE(-/-) mice were fed diets containing 15% fat with 0.2% cholesterol alone or supplemented with 0.005% or 0.05% CBE for 4 weeks. CBE polyphenol content was determined by the total phenols, 4-dimethylaminocinnamaldehyde, and ultra high-performance liquid chromatography-mass spectrometry methods. The 0.05% CBE diet provided mice with mean daily doses of 1.2 mg gallic acid equivalents of total phenols, 0.19 mg anthocyanins, 0.17 mg phenolic acids, 0.06 mg proanthocyanidins (as catechin-equivalents), and 0.02 mg flavonols. The 0.05% CBE group had 12% less plasma total cholesterol concentrations than the control. Despite the hypocholesterolemic effect of CBE, hepatic mRNA levels of low-density lipoprotein receptor, hydroxyl-3-methylglutaryl coenzyme A reductase and cholesterol 7α-hydroxylase in CBE-fed mice were not significantly different from controls. Dietary CBE did not alter hepatic lipid content or the hepatic expression of genes involved in lipogenesis and fatty acid β-oxidation such as fatty acid synthase, carnitine palmitoyltransferase 1 and acyl-CoA oxidase. Plasma paraoxonase and catalase activities were significantly increased in mice fed 0.05% CBE. Both CBE diets increased hepatic glutathione peroxidase (GPx) activity but the 0.05% CBE group had 24% less proximal intestine GPx activity relative to controls. Thus, dietary CBE lowered total cholesterol and improved plasma and hepatic antioxidant function at nutritionally-relevant doses in apoE(-/-) mice. Furthermore, the CBE cholesterol-lowering mechanism in apoE(-/-) mice was independent of hepatic expression of genes involved in cholesterol metabolism. Copyright © 2013 Elsevier Inc. All rights reserved.

Efficacy of Spirulina platensis in improvement of the reproductive performance and easing teratogenicity in hyperglycemic albino mice.

PubMed

Pankaj, Pranay Punj

2015-01-01

The present study evaluates the therapeutic efficacy of cell suspension of Spirulina platensis (SP) on estrous cycle, fetal development and embryopathy in alloxan (AXN) induced hyperglycemic mice. Diabetes was induced by intra-peritoneal administration of AXN. Mice with blood glucose level above 200 mg/dl were divided into Group I (control), Group II (diabetic control), Group III (diabetic control mice fed with SP), and Group IV (control mice fed with SP). Litter counts, estrous cycles, percent survival of litter, and gestation length were recorded. In hyperglycemic mice, a significant (P < 0.05) increase in duration of diestrus (14.48%), estrus (84.21%), and metestrus (164.15%) with concomitant decrease in proestrus phase by 26.13% was recorded when compared with control. Reduction in litter count and survival of litter was 68.67% and 88.38%, respectively, whereas gestation length increased to 14.51% day in diabetic mice, but recovery in these parameters was observed (P < 0.05) when subjected to SP treatment. SP resulted in increased fertility rate from 77.5% to 82.5% and dropped off resorption of the fetus to 33.73% while the survival rate of offspring of diabetic mice went up to 88.89% from 83.61%. These findings suggest that SP is effective in improving the reproductive performance and easing teratogenic effects in diabetic mice and hence warrants further detailed dose-dependent studies to understand its mechanism of action.

Efficacy of Spirulina platensis in improvement of the reproductive performance and easing teratogenicity in hyperglycemic albino mice

PubMed Central

Pankaj, Pranay Punj

2015-01-01

Objectives: The present study evaluates the therapeutic efficacy of cell suspension of Spirulina platensis (SP) on estrous cycle, fetal development and embryopathy in alloxan (AXN) induced hyperglycemic mice. Materials and Methods: Diabetes was induced by intra-peritoneal administration of AXN. Mice with blood glucose level above 200 mg/dl were divided into Group I (control), Group II (diabetic control), Group III (diabetic control mice fed with SP), and Group IV (control mice fed with SP). Litter counts, estrous cycles, percent survival of litter, and gestation length were recorded. Results: In hyperglycemic mice, a significant (P < 0.05) increase in duration of diestrus (14.48%), estrus (84.21%), and metestrus (164.15%) with concomitant decrease in proestrus phase by 26.13% was recorded when compared with control. Reduction in litter count and survival of litter was 68.67% and 88.38%, respectively, whereas gestation length increased to 14.51% day in diabetic mice, but recovery in these parameters was observed (P < 0.05) when subjected to SP treatment. SP resulted in increased fertility rate from 77.5% to 82.5% and dropped off resorption of the fetus to 33.73% while the survival rate of offspring of diabetic mice went up to 88.89% from 83.61%. Conclusions: These findings suggest that SP is effective in improving the reproductive performance and easing teratogenic effects in diabetic mice and hence warrants further detailed dose-dependent studies to understand its mechanism of action. PMID:26285837

Finger millet bran supplementation alleviates obesity-induced oxidative stress, inflammation and gut microbial derangements in high-fat diet-fed mice.

PubMed

Murtaza, Nida; Baboota, Ritesh K; Jagtap, Sneha; Singh, Dhirendra P; Khare, Pragyanshu; Sarma, Siddhartha M; Podili, Koteswaraiah; Alagesan, Subramanian; Chandra, T S; Bhutani, K K; Boparai, Ravneet K; Bishnoi, Mahendra; Kondepudi, Kanthi Kiran

2014-11-14

Several epidemiological studies have shown that the consumption of finger millet (FM) alleviates diabetes-related complications. In the present study, the effect of finger millet whole grain (FM-WG) and bran (FM-BR) supplementation was evaluated in high-fat diet-fed LACA mice for 12 weeks. Mice were divided into four groups: control group fed a normal diet (10 % fat as energy); a group fed a high-fat diet; a group fed the same high-fat diet supplemented with FM-BR; a group fed the same high-fat diet supplemented with FM-WG. The inclusion of FM-BR at 10 % (w/w) in a high-fat diet had more beneficial effects than that of FM-WG. FM-BR supplementation prevented body weight gain, improved lipid profile and anti-inflammatory status, alleviated oxidative stress, regulated the expression levels of several obesity-related genes, increased the abundance of beneficial gut bacteria (Lactobacillus, Bifidobacteria and Roseburia) and suppressed the abundance of Enterobacter in caecal contents (P≤ 0·05). In conclusion, FM-BR supplementation could be an effective strategy for preventing high-fat diet-induced changes and developing FM-BR-enriched functional foods.

Sesame oil mitigates nutritional steatohepatitis via attenuation of oxidative stress and inflammation: a tale of two-hit hypothesis.

PubMed

Periasamy, Srinivasan; Chien, Se-Ping; Chang, Po-Cheng; Hsu, Dur-Zong; Liu, Ming-Yie

2014-02-01

Nonalcoholic fatty liver disease, the most common chronic liver disorder worldwide, comprises conditions from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an increased risk of hepatocellular carcinoma. Sesame oil, a healthful food, increases resistance to oxidative stress, inflammation and protects against multiple organ injury in various animal models. We investigated the protective effect of sesame oil against nutritional steatohepatitis in mice. C57BL/6 J mice were fed with methionine-choline deficient (MCD) diet for 28 days to induce NASH. Sesame oil (1 and 2 ml/kg) was treated from 22nd to 28th day. Body weight, steatosis, triglycerides, aspartate transaminase, alanine transaminase, nitric oxide, malondialdehyde, tumor necrosis factor-α, interlukin-6, interleukin-1β, leptin, and transforming growth factor-β1 (TGF-β1) were assessed after 28 days. All tested parameters were higher in MCD-fed mice than in normal control mice. Mice fed with MCD diet for 4 weeks showed severe liver injury with steatosis, oxidative stress, and necrotic inflammation. In sesame-oil-treated mice, all tested parameters were significantly attenuated compared with MCD-alone mice. Sesame oil inhibited oxidative stress, inflammatory cytokines, leptin, and TGF-β1 in MCD-fed mice. In addition, histological analysis showed that sesame oil provided significant protection against fibrotic collagen. We conclude that sesame oil protects against steatohepatitic fibrosis by decreasing oxidative stress, inflammatory cytokines, leptin and TGF-β1. Copyright © 2014 Elsevier Inc. All rights reserved.

Liver Fatty Acid Binding Protein Gene-ablation Exacerbates Weight Gain in High-Fat Fed Female Mice

PubMed Central

McIntosh, Avery L.; Atshaves, Barbara P.; Landrock, Danilo; Landrock, Kerstin K.; Martin, Gregory G.; Storey, Stephen M.; Kier, Ann B.; Schroeder, Friedhelm

2013-01-01

Loss of liver fatty acid binding protein (L-FABP) decreases long chain fatty acid uptake and oxidation in primary hepatocytes and in vivo. On this basis, L-FABP gene ablation would potentiate high-fat diet-induced weight gain and weight gain/energy intake. While this was indeed the case when L-FABP null (−/−) mice on the C57BL/6NCr background were pair-fed high fat diet, whether this would also be observed under high-fat diet fed ad libitum was not known. Therefore, this possibility was examined in female L-FABP (−/−) mice on the same background. L-FABP (−/−) mice consumed equal amounts of defined high-fat or isocaloric control diets fed ad libitum. However, on the ad libitum fed high-fat diet the L-FABP (−/−) mice exhibited: 1) Decreased hepatic long chain fatty acid (LCFA) β-oxidation as indicated by lower serum β–hydroxybutyrate level; 2) Decreased hepatic protein levels of key enzymes mitochondrial (rate limiting carnitine palmitoyl acyltransferase A1, CPT1A; HMG-CoA synthase) and peroxisomal (acyl CoA oxidase 1, ACOX1) LCFA β-oxidation; 3) Increased fat tissue mass (FTM) and FTM/energy intake to the greatest extent; and 4) Exacerbated body weight gain, weight gain/energy intake, liver weight, and liver weight/body weight to the greatest extent. Taken together, these findings showed that L-FABP gene-ablation exacerbated diet-induced weight gain and fat tissue mass gain in mice fed high-fat diet ad libitum—consistent with the known biochemistry and cell biology of L-FABP. PMID:23539345

Low dietary choline and low dietary riboflavin during pregnancy influence reproductive outcomes and heart development in mice.

PubMed

Chan, Jessica; Deng, Liyuan; Mikael, Leonie G; Yan, Jian; Pickell, Laura; Wu, Qing; Caudill, Marie A; Rozen, Rima

2010-04-01

Embryonic development may be compromised by dietary and genetic disruptions in folate metabolism because of the critical role of folate in homocysteine metabolism, methylation, and nucleotide synthesis. Methylenetetrahydrofolate reductase (MTHFR), choline, and riboflavin play distinct roles in homocysteine detoxification and generation of one-carbon donors for methylation. The effect of low dietary choline and riboflavin on pregnancy complications and heart development has not been adequately addressed. Our goal was to determine whether dietary deficiencies of choline and riboflavin in pregnant mice, with and without mild MTHFR deficiency, affect embryonic development. Female Mthfr(+/+) and Mthfr(+/-) mice were fed a control diet (CD), a choline-deficient diet (ChDD), or a riboflavin-deficient diet (RbDD) and were then mated with male Mthfr(+/-) mice. Embryos were collected 14.5 d postcoitum and examined for reproductive outcomes and cardiac defects. Plasma homocysteine was higher in ChDD- than in CD-fed females. Liver MTHFR enzyme activity was greater in ChDD-fed Mthfr(+/+) than in CD-fed Mthfr(+/+) females. The RbDD resulted in a higher percentage of delayed embryos and smaller embryos than did the CD. There were more heart defects, which were all ventricular septal defects, in embryos from the ChDD- and RbDD-fed females than from the CD-fed females. Dietary riboflavin and MTHFR deficiency resulted in decreased left ventricular wall thickness in embryonic hearts compared with embryos from CD-fed Mthfr(+/+) females. Low dietary choline and riboflavin affect embryonic growth and cardiac development in mice. Adequate choline and riboflavin may also play a role in the prevention of these pregnancy complications in women.

Radiological study of the effect of low calcium diet on the mineral metabolism of bone tissue. With reference to mineralization in callus (in Japanese)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nakamura, K.

1972-01-01

Deficiency of available food material due either to poor diet or to malabsorption may adversely affect the skeleton. To study the affection, DDN mice were fed low calcium diet to induce low calcium state corresponding to malabsorption of calcium from the intestine. The femur was fractured manually. Then, calcium deposition in the callus was observed by microradiography and tracer technics with /sup 47/Ca. Increase of the body weight in mice fed low calcium diet was much slower than in the control. The affection of the low calcium diet on bone tissue appeared as a decrease of precipitation of calcium salt.more » This tendency was also observed in callus, Tracer study with /sup 47/Ca was performed in mice fed the low calcium diet for 24 days. Incorporation activity of calcium was generally high in each organ except the kidney. Callus in the site of the fracture in mice fed a low calcium diet was formed to the same degree as the control, although the amount of precipitated calcium in it was significantly poorer. In summary, insufficient mineralization in relation to osteogenesis occurred when the supply of the requisite electrolytes was insufficient or inappropriate. On the other hand, the uptake rate of calcinm in the callus was elevated even in the calcium deficient state. (auth)« less

Oral Glutamine Supplementation Protects Female Mice from Nonalcoholic Steatohepatitis.

PubMed

Sellmann, Cathrin; Jin, Cheng Jun; Degen, Christian; De Bandt, Jean-Pascal; Bergheim, Ina

2015-10-01

Genetic factors, a diet rich in fat and sugar, and an impaired intestinal barrier function are critical in the development of nonalcoholic steatohepatitis (NASH). The nonessential amino acid glutamine (Gln) has been suggested to have protective effects on intestinal barrier function but also against the development of liver diseases of various etiologies. The effect of oral Gln supplementation on the development of Western-style diet (WSD)-induced NASH in mice was assessed. Female 6- to 8-wk-old C57BL/6J mice were pair-fed a control (C) diet or a WSD alone or supplemented with 2.1 g l-Gln/kg body weight for 6 wk (C+Gln or WSD+Gln). Indexes of liver damage, lipid peroxidation, and glucose metabolism and endotoxin concentrations were measured. Although Gln supplementation had no effect on the loss of the tight junction protein occludin, the increased portal endotoxin and fasting glucose concentrations found in WSD-fed mice, markers of liver damage (e.g., nonalcoholic fatty liver disease activity score and number of neutrophils in the liver) were significantly lower in the WSD+Gln group than in the WSD group (~47% and ~60% less, respectively; P < 0.05). Concentrations of inducible nitric oxide synthase (iNOS) protein and 3-nitrotyrosin protein adducts were significantly higher in livers of WSD-fed mice than in all other groups (~8.6- and ~1.9-fold higher, respectively, compared with the C group; P < 0.05) but did not differ between WSD+Gln-, C-, and C+Gln-fed mice. Hepatic tumor necrosis factor α and plasminogen activator inhibitor 1 concentrations were significantly higher in WSD-fed mice (~1.6- and ~1.8-fold higher, respectively; P < 0.05) but not in WSD+Gln-fed mice compared with C mice. Our data suggest that the protective effects of oral Gln supplementation on the development of WSD-induced NASH in mice are associated with protection against the induction of iNOS and lipid peroxidation in the liver. © 2015 American Society for Nutrition.

Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet-Induced Metabolic Heart Disease.

PubMed

Sverdlov, Aaron L; Elezaby, Aly; Qin, Fuzhong; Behring, Jessica B; Luptak, Ivan; Calamaras, Timothy D; Siwik, Deborah A; Miller, Edward J; Liesa, Marc; Shirihai, Orian S; Pimentel, David R; Cohen, Richard A; Bachschmid, Markus M; Colucci, Wilson S

2016-01-11

Mitochondrial reactive oxygen species (ROS) are associated with metabolic heart disease (MHD). However, the mechanism by which ROS cause MHD is unknown. We tested the hypothesis that mitochondrial ROS are a key mediator of MHD. Mice fed a high-fat high-sucrose (HFHS) diet develop MHD with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild-type mice were fed an HFHS or control diet for 4 months. Cardiac mitochondria from HFHS-fed wild-type mice had a 3-fold greater rate of H2O2 production (P=0.001 versus control diet fed), a 30% decrease in complex II substrate-driven oxygen consumption (P=0.006), 21% to 23% decreases in complex I and II substrate-driven ATP synthesis (P=0.01), and a 62% decrease in complex II activity (P=0.002). In transgenic mice that express catalase in mitochondria, all HFHS diet-induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In HFHS-fed wild-type mice complex II substrate-driven ATP synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site-directed mutation of complex II subunit B Cys100 or Cys103 to redox-insensitive serines prevented complex II dysfunction induced by ROS or high glucose/high palmitate in the medium. Mitochondrial ROS are pathogenic in MHD and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and II proteins including reversible oxidative posttranslational modifications of complex II subunit B Cys100 and Cys103. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Immunotoxicological evaluation of wheat genetically modified with TaDREB4 gene on BALB/c mice.

PubMed

Liang, Chun Lai; Zhang, Xiao Peng; Song, Yan; Jia, Xu Dong

2013-08-01

To evaluate the immunotoxicological effects of genetically modified wheat with TaDREB4 gene in female BALB/c mice. Female mice weighing 18-22 g were divided into five groups (10 mice/group), which were set as negative control group, common wheat group, parental wheat group, genetically modified wheat group and cyclophosphamide positive control group, respectively. Mice in negative control group and positive control group were fed with AIN93G diet, mice in common wheat group, non-genetically modified parental wheat group and genetically modified wheat group were fed with feedstuffs added corresponding wheat (the proportion is 76%) for 30 days, then body weight, absolute and relative weight of spleen and thymus, white blood cell count, histological examination of immune organ, peripheral blood lymphocytes phenotyping, serum cytokine, serum immunoglobulin, antibody plaque-forming cell, serum half hemolysis value, mitogen-induced splenocyte proliferation, delayed-type hypersensitivity reaction and phagocytic activities of phagocytes were detected. No immunotoxicological effects related to the consumption of the genetically modified wheat were observed in BALB/c mice when compared with parental wheat group, common wheat group and negative control group. From the immunotoxicological point of view, results from this study demonstrate that genetically modified wheat with TaDREB4 gene is as safe as the parental wheat. Copyright © 2013 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Three Months of High-Fructose Feeding Fails to Induce Excessive Weight Gain or Leptin Resistance in Mice

PubMed Central

Tillman, Erik J.; Morgan, Donald A.; Rahmouni, Kamal; Swoap, Steven J.

2014-01-01

High-fructose diets have been implicated in obesity via impairment of leptin signaling in humans and rodents. We investigated whether fructose-induced leptin resistance in mice could be used to study the metabolic consequences of fructose consumption in humans, particularly in children and adolescents. Male C57Bl/6 mice were weaned to a randomly assigned diet: high fructose, high sucrose, high fat, or control (sugar-free, low-fat). Mice were maintained on their diets for at least 14 weeks. While fructose-fed mice regularly consumed more kcal and expended more energy, there was no difference in body weight compared to control by the end of the study. Additionally, after 14 weeks, both fructose-fed and control mice displayed similar leptin sensitivity. Fructose-feeding also did not change circulating glucose, triglycerides, or free fatty acids. Though fructose has been linked to obesity in several animal models, our data fail to support a role for fructose intake through food lasting 3 months in altering of body weight and leptin signaling in mice. The lack of impact of fructose in the food of growing mice on either body weight or leptin sensitivity over this time frame was surprising, and important information for researchers interested in fructose and body weight regulation. PMID:25211467

Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother's periconceptional diet

PubMed Central

Gohir, Wajiha; Whelan, Fiona J; Surette, Michael G; Moore, Caroline; Schertzer, Jonathan D; Sloboda, Deborah M

2015-01-01

Shifts in the maternal gut microbiome have been implicated in metabolic adaptations to pregnancy. We investigated how pregnancy and diet interact to influence the composition of the maternal gut microbiota. Female C57BL/6 mice were fed either a control or a high fat diet for 8 weeks prior to mating. After confirmation of pregnancy, maternal weight gain and food intake were recorded. Fecal pellets were collected at 2 timepoints prior to mating (at the beginning of the experiment, and after 6 weeks of the specified diet) and at 4 timepoints during pregnancy (gestation day 0.5, 5.5, 10.5, and 15.5). The microbial composition and predicted metabolic functionality of the non-pregnant and pregnant gut was determined via sequencing of the variable 3 region of the 16S rRNA gene. Upon conception, differences in gut microbial communities were observed in both control and high fat-fed mice, including an increase in mucin-degrading bacteria. Control versus high fat-fed pregnant mice possessed the most profound changes to their maternal gut microbiota as indicated by statistically significant taxonomic differences. High fat-fed pregnant mice, when compared to control-fed animals, were found to be significantly enriched in microbes involved in metabolic pathways favoring fatty acid, ketone, vitamin, and bile synthesis. We show that pregnancy-induced changes in the female gut microbiota occur immediately at the onset of pregnancy, are vulnerable to modulation by diet, but are not dependent upon increases in maternal weight gain during pregnancy. High fat diet intake before and during pregnancy results in distinctive shifts in the pregnant gut microbiota in a gestational-age dependent manner and these shifts predict significant differences in the abundance of genes that favor lipid metabolism, glycolysis and gluconeogenic metabolic pathways over the course of pregnancy. PMID:26322500

Coffee and caffeine improve insulin sensitivity and glucose tolerance in C57BL/6J mice fed a high-fat diet.

PubMed

Matsuda, Yuji; Kobayashi, Misato; Yamauchi, Rie; Ojika, Makoto; Hiramitsu, Masanori; Inoue, Takashi; Katagiri, Takao; Murai, Atsushi; Horio, Fumihiko

2011-01-01

We have previously demonstrated that coffee and caffeine ameliorated hyperglycemia in spontaneously diabetic KK-A(y) mice. This present study evaluates the antidiabetic effects of coffee and caffeine on high-fat-diet-induced impaired glucose tolerance in C57BL/6J mice. C57BL/6J mice fed a high-fat diet were given regular drinking water (control group), or a 2.5-fold-diluted coffee or caffeine solution (200 mg/L) for 17 weeks. The ingestion of coffee or caffeine improved glucose tolerance, insulin sensitivity, and hyperinsulinemia when compared with mice in the control group. The adipose tissue mRNA levels of inflammatory adipocytokines (MCP-1 and IL-6) and the liver mRNA levels of genes related to fatty acid synthesis were lower in the coffee and caffeine groups than those in the control group. These results suggest that coffee and caffeine exerted an ameliorative effect on high-fat-diet-induced impaired glucose tolerance by improving insulin sensitivity. This effect might be attributable in part to the reduction of inflammatory adipocytokine expression.

Differential effects of dietary sodium intake on blood pressure and atherosclerosis in hypercholesterolemic mice☆

PubMed Central

Lu, Hong; Wu, Congqing; Howatt, Deborah A.; Balakrishnan, Anju; Charnigo, Richard J.; Cassis, Lisa A.; Daugherty, Alan

2012-01-01

The amount of dietary sodium intake regulates the renin angiotensin system (RAS) and blood pressure, both of which play critical roles in atherosclerosis. However, there are conflicting findings regarding the effects of dietary sodium intake on atherosclerosis. This study applied a broad range of dietary sodium concentrations to determine the concomitant effects of dietary sodium intake on the RAS, blood pressure, and atherosclerosis in mice. Eight-week-old male low-density lipoprotein receptor −/− mice were fed a saturated fat-enriched diet containing selected sodium concentrations (Na 0.01%, 0.1%, or 2% w/w) for 12 weeks. Mice in these three groups were all hypercholesterolemic, although mice fed Na 0.01% and Na 0.1% had higher plasma cholesterol concentrations than mice fed Na 2%. Mice fed Na 0.01% had greater abundances of renal renin mRNA than those fed Na 0.1% and 2%. Plasma renin concentrations were higher in mice fed Na 0.01% (14.2±1.7 ng/ml/30 min) than those fed Na 0.1% or 2% (6.2±0.6 and 5.8±1.6 ng/ml per 30 min, respectively). However, systolic blood pressure at 12 weeks was higher in mice fed Na 2% (138±3 mm Hg) than those fed Na 0.01% and 0.1% (129±3 and 128±4 mmHg, respectively). In contrast, mice fed Na 0.01% (0.17±0.02 mm2) had larger atherosclerotic lesion areas in aortic roots than those fed Na 2% (0.09±0.01 mm2), whereas lesion areas in mice fed Na 0.1% (0.12±0.02 mm2) were intermediate between and not significantly different from those in Na 0.01% and Na 2% groups. In conclusion, while high dietary sodium intake led to higher systolic blood pressure, low dietary sodium intake augmented atherosclerosis in hypercholesterolemic mice. PMID:22705323

Mitochondrial antioxidative capacity regulates muscle glucose uptake in the conscious mouse: effect of exercise and diet.

PubMed

Kang, Li; Lustig, Mary E; Bonner, Jeffrey S; Lee-Young, Robert S; Mayes, Wesley H; James, Freyja D; Lin, Chien-Te; Perry, Christopher G R; Anderson, Ethan J; Neufer, P Darrell; Wasserman, David H

2012-10-15

The objective of this study was to test the hypothesis that exercise-stimulated muscle glucose uptake (MGU) is augmented by increasing mitochondrial reactive oxygen species (mtROS) scavenging capacity. This hypothesis was tested in genetically altered mice fed chow or a high-fat (HF) diet that accelerates mtROS formation. Mice overexpressing SOD2 (sod2(Tg)), mitochondria-targeted catalase (mcat(Tg)), and combined SOD2 and mCAT (mtAO) were used to increase mtROS scavenging. mtROS was assessed by the H(2)O(2) emitting potential (JH(2)O(2)) in muscle fibers. sod2(Tg) did not decrease JH(2)O(2) in chow-fed mice, but decreased JH(2)O(2) in HF-fed mice. mcat(Tg) and mtAO decreased JH(2)O(2) in both chow- and HF-fed mice. In parallel, the ratio of reduced to oxidized glutathione (GSH/GSSG) was unaltered in sod2(Tg) in chow-fed mice, but was increased in HF-fed sod2(Tg) and both chow- and HF-fed mcat(Tg) and mtAO. Nitrotyrosine, a marker of NO-dependent, reactive nitrogen species (RNS)-induced nitrative stress, was decreased in both chow- and HF-fed sod2(Tg), mcat(Tg), and mtAO mice. This effect was not changed with exercise. Kg, an index of MGU was assessed using 2-[(14)C]-deoxyglucose during exercise. In chow-fed mice, sod2(Tg), mcat(Tg), and mtAO increased exercise Kg compared with wild types. Exercise Kg was also augmented in HF-fed sod2(Tg) and mcat(Tg) mice but unchanged in HF-fed mtAO mice. In conclusion, mtROS scavenging is a key regulator of exercise-mediated MGU and this regulation depends on nutritional state.

Diet-Induced Obesity Modulates Epigenetic Responses to Ionizing Radiation in Mice

PubMed Central

Vares, Guillaume; Wang, Bing; Ishii-Ohba, Hiroko; Nenoi, Mitsuru; Nakajima, Tetsuo

2014-01-01

Both exposure to ionizing radiation and obesity have been associated with various pathologies including cancer. There is a crucial need in better understanding the interactions between ionizing radiation effects (especially at low doses) and other risk factors, such as obesity. In order to evaluate radiation responses in obese animals, C3H and C57BL/6J mice fed a control normal fat or a high fat (HF) diet were exposed to fractionated doses of X-rays (0.75 Gy ×4). Bone marrow micronucleus assays did not suggest a modulation of radiation-induced genotoxicity by HF diet. Using MSP, we observed that the promoters of p16 and Dapk genes were methylated in the livers of C57BL/6J mice fed a HF diet (irradiated and non-irradiated); Mgmt promoter was methylated in irradiated and/or HF diet-fed mice. In addition, methylation PCR arrays identified Ep300 and Socs1 (whose promoters exhibited higher methylation levels in non-irradiated HF diet-fed mice) as potential targets for further studies. We then compared microRNA regulations after radiation exposure in the livers of C57BL/6J mice fed a normal or an HF diet, using microRNA arrays. Interestingly, radiation-triggered microRNA regulations observed in normal mice were not observed in obese mice. miR-466e was upregulated in non-irradiated obese mice. In vitro free fatty acid (palmitic acid, oleic acid) administration sensitized AML12 mouse liver cells to ionizing radiation, but the inhibition of miR-466e counteracted this radio-sensitization, suggesting that the modulation of radiation responses by diet-induced obesity might involve miR-466e expression. All together, our results suggested the existence of dietary effects on radiation responses (especially epigenetic regulations) in mice, possibly in relationship with obesity-induced chronic oxidative stress. PMID:25171162

Interactions Between Nuclear Receptor SHP and FOXA1 Maintain Oscillatory Homocysteine Homeostasis in Mice.

PubMed

Tsuchiya, Hiroyuki; da Costa, Kerry-Ann; Lee, Sangmin; Renga, Barbara; Jaeschke, Hartmut; Yang, Zhihong; Orena, Stephen J; Goedken, Michael J; Zhang, Yuxia; Kong, Bo; Lebofsky, Margitta; Rudraiah, Swetha; Smalling, Rana; Guo, Grace; Fiorucci, Stefano; Zeisel, Steven H; Wang, Li

2015-05-01

Hyperhomocysteinemia is often associated with liver and metabolic diseases. We studied nuclear receptors that mediate oscillatory control of homocysteine homeostasis in mice. We studied mice with disruptions in Nr0b2 (called small heterodimer partner [SHP]-null mice), betaine-homocysteine S-methyltransferase (Bhmt), or both genes (BHMT-null/SHP-null mice), along with mice with wild-type copies of these genes (controls). Hyperhomocysteinemia was induced by feeding mice alcohol (National Institute on Alcohol Abuse and Alcoholism binge model) or chow diets along with water containing 0.18% DL-homocysteine. Some mice were placed on diets containing cholic acid (1%) or cholestyramine (2%) or high-fat diets (60%). Serum and livers were collected during a 24-hour light-dark cycle and analyzed by RNA-seq, metabolomic, and quantitative polymerase chain reaction, immunoblot, and chromatin immunoprecipitation assays. SHP-null mice had altered timing in expression of genes that regulate homocysteine metabolism compared with control mice. Oscillatory production of S-adenosylmethionine, betaine, choline, phosphocholine, glyceophosphocholine, cystathionine, cysteine, hydrogen sulfide, glutathione disulfide, and glutathione, differed between SHP-null mice and control mice. SHP inhibited transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1. Expression of Bhmt and cystathionine γ-lyase was decreased when mice were fed cholic acid but increased when they were placed on diets containing cholestyramine or high-fat content. Diets containing ethanol or homocysteine induced hyperhomocysteinemia and glucose intolerance in control, but not SHP-null, mice. In BHMT-null and BHMT-null/SHP-null mice fed a control liquid, lipid vacuoles were observed in livers. Ethanol feeding induced accumulation of macrovesicular lipid vacuoles to the greatest extent in BHMT-null and BHMT-null/SHP-null mice. Disruption of Shp in mice alters timing of expression of genes that regulate homocysteine metabolism and the liver responses to ethanol and homocysteine. SHP inhibits the transcriptional activation of Bhmt and cystathionine γ-lyase by FOXA1. Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Effect of Saffron on Metabolic Profile and Retina in Apolipoprotein E-Knockout Mice Fed a High-Fat Diet.

PubMed

Doumouchtsis, Evangelos K; Tzani, Aspasia; Doulamis, Ilias P; Konstantopoulos, Panagiotis; Laskarina-Maria, Korou; Agrogiannis, Georgios; Agapitos, Emmanouil; Moschos, Marilita M; Kostakis, Alkiviadis; Perrea, Despina N

2017-09-22

Saffron is a spice that has been traditionally used as a regimen for a variety of diseases due to its potent antioxidant attributes. It is well documented that impaired systemic oxidative status is firmly associated with diverse adverse effects including retinal damage. The aim of this study was to investigate the role of saffron administration against the retinal damage in apoE -/- mice fed a high-fat diet, since they constitute a designated experimental model susceptible to oxidative stress. Twenty-one mice were allocated into three groups: Group A (control, n = 7 c57bl/6 mice) received standard chow diet; Group B (high-fat, n = 7 apoE -/- mice) received a high-fat diet; and Group C (high-fat and saffron, n = 7 apoE -/- mice) received a high-fat diet and saffron (25 mg/kg/d) through their drinking water. The duration of the study was 20 weeks. Lipidemic profile, glucose, C-reactive protein (CRP), and total oxidative capacity (PerOX) were measured in blood serum. Histological analysis of retina was also conducted. Administration of saffron resulted in enhanced glycemic control and preservation of retinal thickness when compared with apoE -/- mice fed a high-fat diet. The outcomes of the study suggest the potential protective role of saffron against retinal damage induced by oxidative stress. Nevertheless, verification of these results in humans is required before any definite conclusions can be drawn.

Changes in liver PPARalpha mRNA expression in response to two levels of high-safflower-oil diets correlate with changes in adiposity and serum leptin in rats and mice.

PubMed

Hsu, Shan-Ching; Huang, Ching-jang

2007-02-01

The ligand-dependent transcription factor peroxisome proliferator-activated receptor alpha (PPARalpha) is known to be activated by common fatty acids and to regulate the expression of genes of various lipid oxidation pathways and transport. High-fat diets provide more fatty acids, which presumably could enhance lipid catabolism through up-regulation of PPARalpha signaling. However, high intake of fat could also lead to obesity. To examine PPARalpha signaling in high-fat feeding and obesity, this study examined the hepatic mRNA expression of PPARalpha and some of its target genes in Wistar rats and C57BL/6J mice fed two levels (20% or 30% wt/wt) of high-safflower-oil (SFO; oleic-acid-rich) diets until animals showed significantly higher body weight (13 weeks for rats and 22 weeks for mice) than those of control groups fed a 5% SFO diet. At the end of these respective feeding periods, only the rats fed 30% SFO and the mice fed 20% SFO among the two groups fed high-fat diets showed significantly higher body weight, white adipose tissue weight, serum leptin and mRNA expression of PPARalpha (P<.05) compared to the respective control groups. Despite elevated acyl-CoA (a PPARalpha target gene) protein and activity in both groups fed high-fat diets, the mRNA expression level of most PPARalpha target genes examined correlated mainly to PPARalpha mRNA levels and not to fat intake or liver lipid levels. The observation that the liver PPARalpha mRNA expression in groups fed high-fat diets was significantly higher only in obese animals with elevated serum leptin implied that obesity and associated hyperleptinemia might have a stronger impact than dietary SFO intake per se on PPARalpha-regulated mRNA expression in the liver.

A Salmon Protein Hydrolysate Exerts Lipid-Independent Anti-Atherosclerotic Activity in ApoE-Deficient Mice

PubMed Central

Busnelli, Marco; Bjørndal, Bodil; Holm, Sverre; Brattelid, Trond; Manzini, Stefano; Ganzetti, Giulia S.; Dellera, Federica; Halvorsen, Bente; Aukrust, Pål; Sirtori, Cesare R.; Nordrehaug, Jan E.; Skorve, Jon; Berge, Rolf K.; Chiesa, Giulia

2014-01-01

Fish consumption is considered health beneficial as it decreases cardiovascular disease (CVD)-risk through effects on plasma lipids and inflammation. We investigated a salmon protein hydrolysate (SPH) that is hypothesized to influence lipid metabolism and to have anti-atherosclerotic and anti-inflammatory properties. 24 female apolipoprotein (apo) E−/− mice were divided into two groups and fed a high-fat diet with or without 5% (w/w) SPH for 12 weeks. The atherosclerotic plaque area in aortic sinus and arch, plasma lipid profile, fatty acid composition, hepatic enzyme activities and gene expression were determined. A significantly reduced atherosclerotic plaque area in the aortic arch and aortic sinus was found in the 12 apoE−/− mice fed 5% SPH for 12 weeks compared to the 12 casein-fed control mice. Immunohistochemical characterization of atherosclerotic lesions in aortic sinus displayed no differences in plaque composition between mice fed SPH compared to controls. However, reduced mRNA level of Icam1 in the aortic arch was found. The plasma content of arachidonic acid (C20∶4n-6) and oleic acid (C18∶1n-9) were increased and decreased, respectively. SPH-feeding decreased the plasma concentration of IL-1β, IL-6, TNF-α and GM-CSF, whereas plasma cholesterol and triacylglycerols (TAG) were unchanged, accompanied by unchanged mitochondrial fatty acid oxidation and acyl-CoA:cholesterol acyltransferase (ACAT)-activity. These data show that a 5% (w/w) SPH diet reduces atherosclerosis in apoE−/− mice and attenuate risk factors related to atherosclerotic disorders by acting both at vascular and systemic levels, and not directly related to changes in plasma lipids or fatty acids. PMID:24840793

A fish protein hydrolysate alters fatty acid composition in liver and adipose tissue and increases plasma carnitine levels in a mouse model of chronic inflammation.

PubMed

Bjørndal, Bodil; Berge, Christ; Ramsvik, Marie Sannes; Svardal, Asbjørn; Bohov, Pavol; Skorve, Jon; Berge, Rolf K

2013-10-07

There is growing evidence that fish protein hydrolysate (FPH) diets affect mitochondrial fatty acid metabolism in animals. The aim of the study was to determine if FPH could influence fatty acid metabolism and inflammation in transgene mice expressing human tumor necrosis factor alpha (hTNFα). hTNFα mice (C57BL/6 hTNFα) were given a high-fat (23%, w/w) diet containing 20% casein (control group) or 15% FPH and 5% casein (FPH group) for two weeks. After an overnight fast, blood, adipose tissue, and liver samples were collected. Gene expression and enzyme activity was analysed in liver, fatty acid composition was analyzed in liver and ovarian white adipose tissue, and inflammatory parameters, carnitine, and acylcarnitines were analyzed in plasma. The n-3/n-6 fatty acid ratio was higher in mice fed the FPH diet than in mice fed the control diet in both adipose tissue and liver, and the FPH diet affected the gene expression of ∆6 and ∆9 desaturases. Mice fed this diet also demonstrated lower hepatic activity of fatty acid synthase. Concomitantly, a lower plasma INF-γ level was observed. Plasma carnitine and the carnitine precursor γ-butyrobetaine was higher in the FPH-group compared to control, as was plasma short-chained and medium-chained acylcarnitine esters. The higher level of plasma acetylcarnitine may reflect a stimulated mitochondrial and peroxisomal β-oxidation of fatty acids, as the hepatic activities of peroxisomal acyl-CoA oxidase 1 and mitochondrial carnitine palmitoyltransferase-II were higher in the FPH-fed mice. The FPH diet was shown to influence hepatic fatty acid metabolism and fatty acid composition. This indicates that effects on fatty acid metabolism are important for the bioactivity of protein hydrolysates of marine origin.

Brazilian Green Propolis Promotes Weight Loss and Reduces Fat Accumulation in C57BL/6 Mice Fed A High-Fat Diet.

PubMed

Sakai, Tohru; Ohhata, Miyuki; Fujii, Misaki; Oda, Sayaka; Kusaka, Yasuna; Matsumoto, Miki; Nakamoto, Akiko; Taki, Tomoyo; Nakamoto, Mariko; Shuto, Emi

2017-01-01

Propolis is a bee product with various biological properties. C57BL/6 mice were fed a high-fat diet and treated with propolis for 14 weeks. Body weight in mice treated with 2% propolis was less than that in control mice from 3 weeks after the start of treatment until 14 weeks except for the 7th week. Mice treated with propolis showed significantly lower epididymal fat weight and subcutaneous fat weight. Infiltration of epididymal fat by macrophages and T cells was reduced in the propolis group. Supplementation of propolis increased feces weight and fat content in feces, suggesting that mechanisms of weight reduction by propolis partly include a laxative effect and inhibition of fat absorption.

Expression and role of the genes involved in the transport of bile acids in the liver and kidneys in mice.

PubMed

Attakpa, Eugène S; Djibril, Naguibou M; Baba-Moussa, Farid; Yessoufou, Ganiou; Sezan, Alphonse

2013-01-01

Bile acids are synthesized in the liver from cholesterol. This study investigated the impact and expression of different carriers of bile acid in the liver and kidneys. Eight-week-old male mice were used, which were fed for 15 days and divided into two groups: 15 mice fed with standard diet (control group) and another 15 mice fed with a rich diet of 5% cholesterol (second group). Bile acid dosage was based on their oxidation by 7α hydroxyl-steroid dehydrogenize. The mRNA expression was quantitatively analyzed by the real time of polymerase chain reaction (RT-PCR), and the expression of the renal carrier bile acid protein was analyzed by Western blot. The expression of bile salt export pump involved in the uptake of bile acids in the basolateral membrane of hepatocytes revealed no differences between the two groups of mice. However, the expression of multidrug resistance-associated protein 2 was reduced in mice of the second group. Moreover, the expressions of organic anion transporting polypeptide 4, organic anion transporting polypeptide 1, and sodium taurocholate co-transporting polypeptide (Ntcp) involved in the uptake of bile acids in the apical pole of hepatocytes are suppressed in mice of the second group. The expression of multidrug resistance-associated protein 3 involved in the secretion of bile acids in the apical membrane of hepatocytes revealed no significant differences between the two groups. In mice of the second group, blood concentration of bile acids on the last day was increased. In those mice, the expression of intestinal bile acid transporter was reduced in the kidneys compared with the control mice.

A compromised liver alters polychlorinated biphenyl-mediated toxicity.

PubMed

Wahlang, Banrida; Perkins, Jordan T; Petriello, Michael C; Hoffman, Jessie B; Stromberg, Arnold J; Hennig, Bernhard

2017-04-01

Exposure to environmental toxicants namely polychlorinated biphenyls (PCBs) is correlated with multiple health disorders including liver and cardiovascular diseases. The liver is important for both xenobiotic and endobiotic metabolism. However, the responses of an injured liver to subsequent environmental insults has not been investigated. The current study aims to evaluate the role of a compromised liver in PCB-induced toxicity and define the implications on overall body homeostasis. Male C57Bl/6 mice were fed either an amino acid control diet (CD) or a methionine-choline deficient diet (MCD) during the 12-week study. Mice were subsequently exposed to either PCB126 (4.9mg/kg) or the PCB mixture, Arcolor1260 (20mg/kg) and analyzed for inflammatory, calorimetry and metabolic parameters. Consistent with the literature, MCD diet-fed mice demonstrated steatosis, indicative of a compromised liver. Mice fed the MCD-diet and subsequently exposed to PCB126 showed observable wasting syndrome leading to mortality. PCB126 and Aroclor1260 exposure worsened hepatic fibrosis exhibited by the MCD groups. Interestingly, PCB126 but not Aroclor1260 induced steatosis and inflammation in CD-fed mice. Mice with liver injury and subsequently exposed to PCBs also manifested metabolic disturbances due to alterations in hepatic gene expression. Furthermore, PCB exposure in MCD-fed mice led to extra-hepatic toxicity such as upregulated circulating inflammatory biomarkers, implicating endothelial cell dysfunction. Taken together, these results indicate that environmental pollution can exacerbate toxicity caused by diet-induced liver injury which may be partially due to dysfunctional energy homeostasis. This is relevant to PCB-exposed human cohorts who suffer from alcohol or diet-induced fatty liver diseases. Copyright © 2017 Elsevier B.V. All rights reserved.

Farnesoid X receptor deficiency induces nonalcoholic steatohepatitis in low-density lipoprotein receptor-knockout mice fed a high-fat diet.

PubMed

Kong, Bo; Luyendyk, James P; Tawfik, Ossama; Guo, Grace L

2009-01-01

Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr(-/-)) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr(-/-) mice. In contrast, in the livers of LDLr(-/-)/FXR(-/-) mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor alpha and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr(-/-)/FXR(-/-) mice. In agreement with elevated levels of procollagen 1 alpha 1 and TGF-beta mRNA, type 1 collagen protein levels were increased in livers of LDLr(-/-)/FXR(-/-) mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.

The α-Tocopherol Form of Vitamin E Reverses Age-Associated Susceptibility to Streptococcus pneumoniae Lung Infection by Modulating Pulmonary Neutrophil Recruitment

PubMed Central

Ghanem, Elsa N. Bou; Clark, Stacie; Du, Xiaogang; Wu, Dayong; Camilli, Andrew; Leong, John M.; Meydani, Simin N.

2016-01-01

Streptococcus pneumoniae infections are an important cause of morbidity and mortality in older patients. Uncontrolled neutrophil-driven pulmonary inflammation exacerbates this disease. To test whether the α-tocopherol (α-Toc) form of vitamin E, a regulator of immunity, can modulate neutrophil responses as a preventive strategy to mitigate the age-associated decline in resistance to S. pneumoniae, young (4 mo) and old (22–24 mo) C57BL/6 mice were fed a diet containing 30-PPM (control) or 500-PPM (supplemented) α-Toc for 4 wk and intratracheally infected with S. pneumoniae. Aged mice fed a control diet were exquisitely more susceptible to S. pneumoniae than young mice. At 2 d postinfection, aged mice suffered 1000-fold higher pulmonary bacterial burden, 2.2-fold higher levels of neutrophil recruitment to the lung, and a 2.25-fold higher rate of lethal septicemia. Strikingly, α-Toc supplementation of aged mice resulted in a 1000-fold lower bacterial lung burden and full control of infection. This α-Toc–induced resistance to pneumococcal challenge was associated with a 2-fold fewer pulmonary neutrophils, a level comparable to S. pneumoniae–challenged, conventionally fed young mice. α-Toc directly inhibited neutrophil egress across epithelial cell monolayers in vitro in response to pneumococci or hepoxilin-A3, an eicosanoid required for pneumococcus-elicited neutrophil trans-epithelial migration. α-Toc altered expression of multiple epithelial and neutrophil adhesion molecules involved in migration, including CD55, CD47, CD18/CD11b, and ICAM-1. These findings suggest that α-Toc enhances resistance of aged mice to bacterial pneumonia by modulating the innate immune response, a finding that has potential clinical significance in combating infection in aged individuals through nutritional intervention. PMID:25512603

Ketogenic diet exposure during the juvenile period increases social behaviors and forebrain neural activation in adult Engrailed 2 null mice.

PubMed

Verpeut, Jessica L; DiCicco-Bloom, Emanuel; Bello, Nicholas T

2016-07-01

Prolonged consumption of ketogenic diets (KD) has reported neuroprotective benefits. Several studies suggest KD interventions could be useful in the management of neurological and developmental disorders. Alterations in the Engrailed (En) genes, specifically Engrailed 2 (En2), have neurodevelopmental consequences and produce autism-related behaviors. The following studies used En2 knockout (KO; En2(-/-)), and wild-type (WT; En2(+/+)), male mice fed either KD (80% fat, 0.1% carbohydrates) or control diet (CD; 10% fat, 70% carbohydrates). The objective was to determine whether a KD fed from weaning at postnatal day (PND) 21 to adulthood (PND 60) would alter brain monoamines concentrations, previously found dysregulated, and improve social outcomes. In WT animals, there was an increase in hypothalamic norepinephrine content in the KD-fed group. However, regional monoamines were not altered in KO mice in KD-fed compared with CD-fed group. In order to determine the effects of juvenile exposure to KD in mice with normal blood ketone levels, separate experiments were conducted in mice removed from the KD or CD and fed standard chow for 2days (PND 62). In a three-chamber social test with a novel mouse, KO mice previously exposed to the KD displayed similar social and self-grooming behaviors compared with the WT group. Groups previously exposed to a KD, regardless of genotype, had more c-Fos-positive cells in the cingulate cortex, lateral septal nuclei, and anterior bed nucleus of the stria terminalis. In the novel object condition, KO mice previously exposed to KD had similar behavioral responses and pattern of c-Fos immunoreactivity compared with the WT group. Thus, juvenile exposure to KD resulted in short-term consequences of improving social interactions and appropriate exploratory behaviors in a mouse model that displays autism-related behaviors. Such findings further our understanding of metabolic-based therapies for neurological and developmental disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of Taurine Supplementation on Neuronal Excitability and Glucose Homeostasis.

PubMed

El Idrissi, Abdeslem; El Hilali, Fatiha; Rotondo, Salvatore; Sidime, Francoise

2017-01-01

In this study we examined the role of chronic taurine supplementation on plasma glucose homeostasis and brain excitability through activation of the insulin receptor. FVB/NJ male mice were supplemented with taurine in drinking water (0.05% w/v) for 4 weeks and subjected to a glucose tolerance test (7.5 mg/kg BW) after 12 h fasting. We found that taurine-fed mice were slightly hypoglycemic prior to glucose injection and showed significantly reduced plasma glucose at 30 and 60 min post-glucose injection when compared to control mice. Previously, we reported that taurine supplementation induces biochemical changes that target the GABAergic system. Those studies show that taurine-fed mice are hyperexcitable, have reduced GABA A receptors expression and increased GAD and somatostatin expression in the brain. In this study, we found that taurine-fed mice had a significant increase in insulin receptor (IR) immuno-reactivity in the pancreas and all brain regions examined. At the mRNA level, we found that the IR showed differential regional expression. Surprisingly, we found that neurons express the gene for insulin and that taurine had a significant role in regulating insulin gene expression. We propose that increased insulin production and secretion in taurine-fed mice cause an increase activation of the central IR and may be partially responsible for the increased neuronal excitability observed in taurine supplemented mice. Furthermore, the high levels of neuronal insulin expression and its regulation by taurine implicates taurine in the regulation of metabolic homeostasis.

Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity

PubMed Central

Argueta, Donovan A.; DiPatrizio, Nicholas V.

2017-01-01

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60 days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB1Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60 days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB1Rs with the peripherally-restricted neutral cannabinoid CB1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6 h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB1Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB1Rs. PMID:28065722

Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity.

PubMed

Argueta, Donovan A; DiPatrizio, Nicholas V

2017-03-15

The endocannabinoid system in the brain and periphery plays a major role in controlling food intake and energy balance. We reported that tasting dietary fats was met with increased levels of the endocannabinoids, 2-arachidonoyl-sn-glycerol (2-AG) and anandamide, in the rat upper small intestine, and pharmacological inhibition of this local signaling event dose-dependently blocked sham feeding of fats. We now investigated the contribution of peripheral endocannabinoid signaling in hyperphagia associated with chronic consumption of a western-style diet in mice ([WD] i.e., high fat and sucrose). Feeding patterns were assessed in male C57BL/6Tac mice maintained for 60days on WD or a standard rodent chow (SD), and the role for peripheral endocannabinoid signaling at CB 1 Rs in controlling food intake was investigated via pharmacological interventions. In addition, levels of the endocannabinoids, 2-AG and anandamide, in the upper small intestine and circulation of mice were analyzed via liquid chromatography coupled to tandem mass spectrometry to evaluate diet-related changes in endocannabinoid signaling and the potential impact on food intake. Mice fed WD for 60days exhibited large increases in body weight, daily caloric intake, average meal size, and rate of feeding when compared to control mice fed SD. Inhibiting peripheral CB 1 Rs with the peripherally-restricted neutral cannabinoid CB 1 receptor antagonist, AM6545 (10mg/kg), significantly reduced intake of WD during a 6h test, but failed to modify intake of SD in mice. AM6545 normalized intake of WD, average meal size, and rate of feeding to levels found in SD control mice. These results suggest that endogenous activity at peripheral CB 1 Rs in WD mice is critical for driving hyperphagia. In support of this hypothesis, levels of 2-AG and anandamide in both, jejunum mucosa and plasma, of ad-libitum fed WD mice increased when compared to SC mice. Furthermore, expression of genes for primary components of the endocannabinoid system (i.e., cannabinoid receptors, and endocannabinoid biosynthetic and degradative enzymes) was dysregulated in WD mice when compared to SC mice. Our results suggest that hyperphagia associated with WD-induced obesity is driven by enhanced endocannabinoid signaling at peripheral CB 1 Rs. Copyright © 2017 Elsevier Inc. All rights reserved.

Dietary eicosapentaenoic acid prevents systemic immunosuppression in mice induced by UVB radiation.

PubMed

Moison, R M; Beijersbergen Van Henegouwen, G M

2001-07-01

Moison, R. M. W. and Beijersbergen van Henegouwen, G. M. J. Dietary Eicosapentaenoic Acid Prevents Systemic Immunosuppression in Mice Induced by UVB Radiation. Radiat. Res. 156, 36-44 (2001). Reactive oxygen species (ROS) contribute to the immunosuppression induced by UVB radiation. Omega-3 fatty acids in fish oil, e.g. eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can modulate immunoresponsiveness, but because of their susceptibility to ROS-induced damage, they can also challenge the epidermal antioxidant defense system. The influence of dietary supplementation with different omega-3 fatty acids on systemic immunosuppression induced in mice by UVB radiation was studied using the contact hypersensitivity response to trinitrochlorobenzene. In an attempt to study the mechanisms involved, UVB-radiation-induced changes in epidermal antioxidant status were also studied. Mice received high-fat (25% w/w) diets enriched with either oleic acid (control diet), EPA, DHA, or EPA + DHA (MaxEPA). Immunosuppression induced by UVB radiation was 53% in mice fed the oleic acid diet and 69% in mice fed the DHA diet. In contrast, immunosuppression was only 4% and 24% in mice fed the EPA and MaxEPA diets, respectively. Increased lipid peroxidation and decreased vitamin E levels (P < 0.05) were found in unirradiated mice fed the MaxEPA and DHA diets. For all diets, exposure to UVB radiation increased lipid peroxidation (P < 0.05), but levels of glutathione (P < 0.05) and vitamin C (P > 0.05) decreased only in the mice given fish oil. UVB irradiation did not influence vitamin E levels. In conclusion, dietary EPA, but not DHA, protects against UVB-radiation-induced immunosuppression in mice. The degree of protection appears to be related to the amount of EPA incorporated and the ability of the epidermis to maintain an adequate antioxidant level after irradiation.

Differential effects of EPA, DPA and DHA on cardio-metabolic risk factors in high-fat diet fed mice.

PubMed

Guo, Xiao-Fei; Sinclair, Andrew J; Kaur, Gunveen; Li, Duo

2017-09-22

The aim of the present study was to assess and compare the effects of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) supplementation on lipid metabolism in 4 month-old male C57BL/6J mice fed a high-fat diet. The high-fat fed mice showed evidence of fatty liver, obesity and insulin resistance after being on the high-fat diet for 6 weeks compared with the control low-fat diet fed mice. Supplementation of the high-fat diet with either EPA, DPA or DHA prevented the fatty liver, prevented high serum cholesterol and serum glucose and prevented high liver cholesterol levels. DPA (but not EPA or DHA) was associated with a significantly improved homeostasis model assessment of insulin resistance (HOMA-IR) compared with the high-fat fed mice. Supplementation with DPA and DHA both prevented the decreased serum adiponectin levels, compared with EPA and the high-fat diet. In addition, supplementation with DPA and DHA both prevented the increased serum alanine aminotransferase (ALT) levels compared with EPA and the high-fat group, which can be attributed to down-regulation of TLR-4/NF-κB signaling pathway and decreasing lipogenesis in the liver. Therefore, DPA and DHA seem to exert similar effects in cardio-metabolic protection against the high-fat diet and these effects seem to be different to those of EPA. Copyright © 2017 Elsevier Ltd. All rights reserved.

Dietary supplementation with curcumin enhances metastatic growth of Lewis lung carcinoma in mice

USDA-ARS?s Scientific Manuscript database

The present study investigated the effects of dietary supplementation with curcumin (the principal curcuminoid of the popular Indian spice turmeric) on spontaneous metastasis of Lewis lung carcinoma (LLC) in female C57/BL6 mice. Mice were fed the AIN93G control diet or that diet supplemented with 2...

Failure to ferment dietary resistant starch in specific mouse models of obesity results in no body fat loss

PubMed Central

Zhou, June; Martin, Roy J; Tulley, Richard T; Raggio, Anne M; Shen, Li; Lissy, Elizabeth; McCutcheon, Kathleen; Keenan, Michael J

2009-01-01

Resistant starch (RS) is a fermentable fiber that decreases dietary energy density and results in fermentation in the lower gut. The current studies examined the effect of RS on body fat loss in mice. In a 12 week study (study 1), the effect of two different types of RS on body fat was compared with two control diets (0% RS) in C57Bl/6J mice: regular control diet or the control diet that had equal energy density as the RS diet (EC). All testing diets had 7% (wt/wt) dietary fat. In a 16 week study (study 2), the effect of RS on body fat was compared with EC in C57BL/6J mice and two obese mouse models (NONcNZO10/LtJ or Non/ShiLtJ). All mice were fed control (0% RS) or 30% RS diet for 6 weeks with 7% dietary fat. On the 7th week, the dietary fat was increased to 11% for half of the mice, and remained the same for the rest. Body weight, body fat, energy intake, energy expenditure, and oral glucose tolerance were measured during the study. At the end of the studies, the pH of cecal contents was measured as an indicator of RS fermentation. Results: Compared with EC, dietary RS decreased body fat and improved glucose tolerance in C57BL/6J mice, but not in obese mice. For other metabolic characteristics measured, the alterations by RS diet were similar for all three types of mice. The difference in dietary fat did not interfere with these results. The pH of cecal contents in RS fed mice was decreased for C57BL/6J mice but not for obese mice, implying the impaired RS fermentation in obese mice. Conclusion: 1) decreased body fat by RS is not simply due to dietary energy dilution in C57Bl/6J mice, and 2) along with their inability to ferment RS; RS fed obese mice did not lose body fat. Thus, colonic fermentation of RS might play an important role in the effect of RS on fat loss. PMID:19739641

Chronic subordination stress selectively downregulates the insulin signaling pathway in liver and skeletal muscle but not in adipose tissue of male mice

PubMed Central

Sanghez, Valentina; Cubuk, Cankut; Sebastián-Leon, Patricia; Carobbio, Stefania; Dopazo, Joaquin; Vidal-Puig, Antonio; Bartolomucci, Alessandro

2016-01-01

Abstract Chronic stress has been associated with obesity, glucose intolerance, and insulin resistance. We developed a model of chronic psychosocial stress (CPS) in which subordinate mice are vulnerable to obesity and the metabolic-like syndrome while dominant mice exhibit a healthy metabolic phenotype. Here we tested the hypothesis that the metabolic difference between subordinate and dominant mice is associated with changes in functional pathways relevant for insulin sensitivity, glucose and lipid homeostasis. Male mice were exposed to CPS for four weeks and fed either a standard diet or a high-fat diet (HFD). We first measured, by real-time PCR candidate genes, in the liver, skeletal muscle, and the perigonadal white adipose tissue (pWAT). Subsequently, we used a probabilistic analysis approach to analyze different ways in which signals can be transmitted across the pathways in each tissue. Results showed that subordinate mice displayed a drastic downregulation of the insulin pathway in liver and muscle, indicative of insulin resistance, already on standard diet. Conversely, pWAT showed molecular changes suggestive of facilitated fat deposition in an otherwise insulin-sensitive tissue. The molecular changes in subordinate mice fed a standard diet were greater compared to HFD-fed controls. Finally, dominant mice maintained a substantially normal metabolic and molecular phenotype even when fed a HFD. Overall, our data demonstrate that subordination stress is a potent stimulus for the downregulation of the insulin signaling pathway in liver and muscle and a major risk factor for the development of obesity, insulin resistance, and type 2 diabetes mellitus. PMID:26946982

Dietary flaxseed administered post thoracic radiation treatment improves survival and mitigates radiation-induced pneumonopathy in mice

PubMed Central

2011-01-01

Background Flaxseed (FS) is a dietary supplement known for its antioxidant and anti-inflammatory properties. Radiation exposure of lung tissues occurs either when given therapeutically to treat intrathoracic malignancies or incidentally, such as in the case of exposure from inhaled radioisotopes released after the detonation of a radiological dispersion devise (RDD). Such exposure is associated with pulmonary inflammation, oxidative tissue damage and irreversible lung fibrosis. We previously reported that dietary FS prevents pneumonopathy in a rodent model of thoracic X-ray radiation therapy (XRT). However, flaxseed's therapeutic usefulness in mitigating radiation effects post-exposure has never been evaluated. Methods We evaluated the effects of a 10%FS or isocaloric control diet given to mice (C57/BL6) in 2 separate experiments (n = 15-25 mice/group) on 0, 2, 4, 6 weeks post a single dose 13.5 Gy thoracic XRT and compared it to an established radiation-protective diet given preventively, starting at 3 weeks prior to XRT. Lungs were evaluated four months post-XRT for blood oxygenation levels, inflammation and fibrosis. Results Irradiated mice fed a 0%FS diet had a 4-month survival rate of 40% as compared to 70-88% survival in irradiated FS-fed mouse groups. Additionally, all irradiated FS-fed mice had decreased fibrosis compared to those fed 0%FS. Lung OH-Proline content ranged from 96.5 ± 7.1 to 110.2 ± 7.7 μg/ml (Mean ± SEM) in all irradiated FS-fed mouse groups, as compared to 138 ± 10.8 μg/ml for mice on 0%FS. Concomitantly, bronchoalveolar lavage (BAL) protein and weight loss associated with radiation cachexia was significantly decreased in all FS-fed groups. Inflammatory cell influx to lungs also decreased significantly except when FS diet was delayed by 4 and 6 weeks post XRT. All FS-fed mice (irradiated or not), maintained a higher blood oxygenation level as compared to mice on 0%FS. Similarly, multiplex cytokine analysis in the BAL fluid revealed a significant decrease of specific inflammatory cytokines in FS-fed mice. Conclusions Dietary FS given post-XRT mitigates radiation effects by decreasing pulmonary fibrosis, inflammation, cytokine secretion and lung damage while enhancing mouse survival. Dietary supplementation of FS may be a useful adjuvant treatment mitigating adverse effects of radiation in individuals exposed to inhaled radioisotopes or incidental radiation. PMID:21702963

Aneuploidy assessed by DNA index influences the effect of iron status on plasma and/or supernatant cytokine levels and progression of cells through the cell cycle in a mouse model.

PubMed

Kuvibidila, Solo; Porretta, Connie; Baliga, Surendra

2014-02-01

Aneuploidy, a condition associated with altered chromosome number, hence DNA index, is frequently seen in many diseases including cancers and affects immunity. Iron, an essential nutrient for humans, modulates the immune function and the proliferation of normal and cancer cells. To determine whether impaired immunity seen in iron-deficient subjects may be related to aneuploidy, we measured spleen cell DNA index, percent of cells in different phases of the cell cycle, plasma and/or supernatant IL-2, IL-10, IL-12, and interferon-gamma in control, pair-fed, iron-deficient, and iron-replete mice (N=20-22/group). The test and control diets differed only in iron content (0.09mmol/kg versus 0.9mmol/kg) and were fed for 68days. Mean levels of hemoglobin and liver iron stores of iron-deficient and iron-replete mice were 40-60% lower than those of control and pair-fed mice (P<0.05). Mean plasma levels of IL-10, interferon-gamma and percent of cells in S+G2/M phases were lower in mice with than in those without aneuploidy (P<0.05). Lowest plasma IL-12 and interferon-gamma concentrations were observed in iron-deficient mice with aneuploidy. Mean percents of cultures with aneuploidy and DNA indexes were higher in iron-deficient and iron-replete than in control and pair-fed mice likely due to delayed cell division (P<0.05). Aneuploidy decreased the concentration of IL-2 and interferon-gamma in baseline cultures while it increased that of interferon-gamma in anti-CD3 treated cultures. Aneuploidic indexes negatively correlated with cytokine levels, percents of cells in S+G2/M phases and indicators of iron status (P<0.05). Although chromosome cytogenetics was not performed, for the first time, we report that increased aneuploidy rate may modulate the immune function during iron-deficiency. Copyright © 2014. Published by Elsevier Ltd.

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin administration and high-fat diet on the body weight and hepatic estrogen metabolism in female C3H/HeN mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhu Baoting; Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers-State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ 08854; Gallo, Michael A.

We studied the effect of administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by i.p. injection once every 2 weeks in combination with a high-fat (HF) diet for 8 or 16 weeks on the body and organ weight changes as well as on the hepatic enzyme activity for estrogen metabolism in C3H/HeN female mice. Administration of TCDD at 100 {mu}g/kg b.w. once every 2 weeks for 8 weeks increased the body weight by 46% in the HF diet-fed animals, but not in the regular diet-fed animals. This is the first observation suggesting that TCDD at a high dose (100 {mu}g/kg b.w.), but not atmore » lower doses (1 or 10 {mu}g/kg b.w.), may have a strong obesity-inducing effect in C3H/HeN mice fed an HF diet. While TCDD increased liver weight and decreased thymus weight in animals, these effects were enhanced by feeding animals an HF diet. Metabolism studies showed that TCDD administration for 8 or 16 weeks increased the liver microsomal activity for the 2- and 4-hydroxylation of 17{beta}-estradiol in animals fed a control diet, but surprisingly not in animals fed an HF diet. Treatment with TCDD dose-dependently increased the hepatic activity for the O-methylation of catechol estrogens in both control and HF diet-fed animals, and it also decreased the levels of liver microsomal sulfatase activity for hydrolysis of estrone-3-sulfate. TCDD did not significantly affect the hepatic enzyme activity for the glucuronidation or esterification of endogenous estrogens. It is suggested that enhanced metabolic inactivation of endogenous estrogens by hepatic estrogen-metabolizing enzymes in TCDD-treated, control diet-fed animals contributes importantly to the reduced incidence of estrogen-associated tumors in animals treated with TCDD.« less

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.

PubMed

Coccurello, Roberto; Romano, Adele; Giacovazzo, Giacomo; Tempesta, Bianca; Fiore, Marco; Giudetti, Anna Maria; Marrocco, Ilaria; Altieri, Fabio; Moles, Anna; Gaetani, Silvana

2018-06-01

Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress. In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression. CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFD-fed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD. CPD appears to uncouple the intake of HFD from energy homeostasis causing higher HFD intake, larger iBAT accumulation, increased energy expenditure and lipid oxidation, and lower body weight. Overall, the present study confirms the notion that the chronic activation of the stress response can be associated with metabolic disorders, altered energy homeostasis, and changes of orexigenic and anorexigenic signaling. These changes might be relevant to better understand the etiology of stress-induced obesity and eating disorders and might represent a valid therapeutic approach for the development of new therapies in this field.

Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

PubMed Central

2011-01-01

Background We and others have demonstrated previously that ghrelin receptor (GhrR) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Results Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. Conclusions These results indicate that improved glucose homeostasis of GhrR KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. GhrR KO mice have an intact 1st phase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of GhrR KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the GhrR KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge. PMID:21211044

Body composition and hormonal effects following exposure to mycotoxin deoxynivalenol in the high-fat diet-induced obese mouse.

PubMed

Kobayashi-Hattori, Kazuo; Amuzie, Chidozie J; Flannery, Brenna M; Pestka, James J

2011-07-01

To characterize the effects of ingesting the common foodborne mycotoxin deoxynivalenol (DON) on body weight and composition in the high-fat (HF) diet-induced obese mice, a model of human obesity. Female B6C3F1 mice were initially fed HF diets containing 45% kcal (HF45) or 60% kcal (HF60) as fat for 94 days to induce obesity. Half of each group was either continued on unamended HF diets or fed HF diets containing 10 mg/kg DON (DON-HF45 or DON-HF60) for another 54 days. Additional control mice were fed a low-fat (LF) diet containing 10%  kcal as fat for the entire 148-day period. DON induced rapid decreases in body weights and fat mass, which stabilized to those of the LF control within 11 days. These effects corresponded closely to a robust transient decrease in food consumption. While lean body mass did not decline in DON-fed groups, further increases were suppressed. DON exposure reduced plasma insulin, leptin, insulin-like growth factor 1, and insulin-like growth factor acid labile subunit as well as increased hypothalamic mRNA level of the orexigenic agouti-related protein. DON-mediated effects on body weight, fat mass, food intake, and hormonal levels in obese mice were consistent with a state of chronic energy restriction. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Biotin-deficient diet induces chromosome misalignment and spindle defects in mouse oocytes.

PubMed

Tsuji, Ai; Nakamura, Toshinobu; Shibata, Katsumi

2015-01-01

Increased abnormal oocytes due to meiotic chromosome misalignment and spindle defects lead to elevated rates of infertility, miscarriage, and trisomic conceptions. Here, we investigated the effect of biotin deficiency on oocyte quality. Three-week-old female ICR mice were fed a biotin-deficient or control diet (0, 0.004 g biotin/kg diet) for 21 days. On day 22, these mouse oocytes were analyzed by immunofluorescence. Due to biotin, undernutrition increased the frequency of abnormal oocytes (the biotin deficient vs. control: 40 vs. 16%). Next, the remaining mice in the biotin-deficient group were fed a control or biotin-deficient diet from day 22 to 42. Although biotin nutritional status in the recovery group was restored, the frequency of abnormal oocytes in the recovery group was still higher than that in the control group (48 vs. 18%). Our results indicate that steady, sufficient biotin intake is required for the production of high-quality oocytes in mice.

Anti-inflammatory effects of sucrose-derived oligosaccharides produced by a constitutive mutant L. mesenteroides B-512FMCM dextransucrase in high fat diet-fed mice.

PubMed

Kang, Min-Gyung; Lee, Hee Jae; Cho, Jae-Young; Kim, Kanghwa; Yang, Soo Jin; Kim, Doman

2016-08-26

Oligosaccharide (OS) is used as a sugar replacement as well as an ingredient in functional foods because of its beneficial effects, mainly on reducing calorie content and promoting intestinal health. By contrast, the effects of OS on inflammation are less well investigated. The purpose of this study was to investigate the effects of sucrose-derived OS on glucose control and inflammation in high fat (HF) diet-fed mice. Male C57BL6 mice were randomly assigned to six treatment groups (n = 10-14 mice per group): 1) lean control (CON), 2) HF control, 3) HF-low sucrose (LS, 100 mg/kg/day), 4) HF-high sucrose (HS, 1000 mg/kg/day), 5) HF-low OS (LOS, 100 mg/kg/day), and 6) HF-high OS (HOS, 1000 mg/kg/day). PBS (vehicle), sucrose, and OS were administered by stomach gavage. Body weight, food intake, and markers of liver function (activities of aspartate aminotransferase and alanine aminotransferase) were not affected by the treatments. HOS treatment decreased levels of serum glucose, insulin, and homeostasis model assessment-insulin resistance compared with sucrose treatment. However, serum adiponectin levels of the HOS group were higher than those of the sucrose groups. Serum levels of the pro-inflammatory cytokines interleukin-6 (IL-6) and fetuin-A were lower in the HOS group than in the sucrose groups. Hepatic gene expression levels of pro-inflammatory cytokines and related factors (fetuin-A, NF-κB, TLR4, TNF-alpha, and IL-6) were decreased and the levels of insulin signaling-related molecules (sirtuin 1, insulin receptor, and Akt) were increased in HOS-treated mice as compared with sucrose-treated mice. These results demonstrate that OS treatment is effective in improving glucose control and inflammation in high fat diet-fed mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Supplementation with chromium picolinate recovers renal Cr concentration and improves carbohydrate metabolism and renal function in type 2 diabetic mice.

PubMed

Mita, Yukiko; Ishihara, Kengo; Fukuchi, Yoshiko; Fukuya, Yoko; Yasumoto, Kyoden

2005-01-01

To study the preventive effect of supplemented chromium picolinate (CrPic) on the development of diabetic nephropathy in mice, we analyzed the effects of CrPic supplementation on renal function and concentrations of serum glucose and tissue chromium (Cr). In experiment 1, male KK-Ay obese diabetic mice were fed either a control diet (control) or a diet supplemented with 2 mg/kg diet (Cr2) or 10 mg/kg diet (Cr10) of Cr for 12 wk. Cr10 significantly ameliorated hyperglycemia after a glucose load, creatinine clearance rates, and urinary microalbumin levels (p<0.05). In experiment 2, the Cr10 diet was fed to male KK-Ay obese diabetic mice and C57BL nondiabetic mice for 4 wk. The CrPic diet reduced urinary albumin excretion in the diabetic mice (p<0.05). Inductively coupled plasma-mass spectrometry analysis revealed that the renal Cr content and the recovery of renal Cr concentration after Cr supplementation were significantly lower in the diabetic mice than in the nondiabetic mice (p<0.01). These observations suggest that Cr supplementation of type 2 diabetic mice reduces the symptoms of hyperglycemia and improves the renal function by recovering renal Cr concentration.

Dietary ribonucleic acid suppresses inflammation of adipose tissue and improves glucose intolerance that is mediated by immune cells in C57BL/6 mice fed a high-fat diet.

PubMed

Sakai, Tohru; Taki, Tomoyo; Nakamoto, Akiko; Tazaki, Shiho; Arakawa, Mai; Nakamoto, Mariko; Tsutsumi, Rie; Shuto, Emi

2015-01-01

Recent evidence suggests that immune cells play an important role in differentiation of inflammatory macrophages in adipose tissue, which contributes to systemic chronic inflammation. Dietary ribonucleic acid (RNA) has been shown to modulate immune function. We hypothesized that RNA affects immune cell function in adipose tissue and then improves inflammatory response in adipose tissue. C57/BL6 mice and recombination activating gene-1 (RAG-1) knockout mice on a C57BL/6 mice background were fed a high-fat diet containing 1% RNA for 12 wk. An oral glucose tolerance test was performed. Supplementation of dietary RNA in C57BL/6 mice fed a high-fat diet resulted in a smaller area under the curve (AUC) after oral glucose administration than that for control mice. The mRNA expression levels of inflammation-related cytokines in adipose tissue and serum interleukin-6 levels were reduced by dietary RNA supplementation. Interestingly, reduction of the AUC value by RNA supplementation was abolished in T and B cell-deficient RAG-1 knockout mice. These results indicate that RNA improves inflammation in adipose tissue and reduces the AUC value following oral glucose administration in a T and B cell-dependent manner.

Partial deficiency of CTRP12 alters hepatic lipid metabolism

PubMed Central

Tan, Stefanie Y.; Little, Hannah C.; Lei, Xia; Li, Shuoyang; Rodriguez, Susana

2016-01-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/−) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/−) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/−) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/−) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/−) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. PMID:27815536

Partial deficiency of CTRP12 alters hepatic lipid metabolism.

PubMed

Tan, Stefanie Y; Little, Hannah C; Lei, Xia; Li, Shuoyang; Rodriguez, Susana; Wong, G William

2016-12-01

Secreted hormones play pivotal roles in tissue cross talk to maintain physiologic blood glucose and lipid levels. We previously showed that C1q/TNF-related protein 12 (CTRP12) is a novel secreted protein involved in regulating glucose metabolism whose circulating levels are reduced in obese and insulin-resistant mouse models. Its role in lipid metabolism, however, is unknown. Using a novel heterozygous mouse model, we show that the loss of a single copy of the Ctrp12 gene (also known as Fam132a and adipolin) affects whole body lipid metabolism. In Ctrp12 (+/-) male mice fed a control low-fat diet, hepatic fat oxidation was upregulated while hepatic VLDL-triglyceride secretion was reduced relative to wild-type (WT) littermates. When challenged with a high-fat diet, Ctrp12 (+/-) male mice had impaired lipid clearance in response to acute lipid gavage, reduced hepatic triglyceride secretion, and greater steatosis with higher liver triglyceride and cholesterol levels. Unlike male mice, Ctrp12 (+/-) female mice fed a control low-fat diet were indistinguishable from WT littermates. When obesity was induced by high-fat feeding, Ctrp12 (+/-) female mice developed mild insulin resistance with impaired insulin tolerance. In contrast to male mice, hepatic triglyceride secretion was increased in Ctrp12 (+/-) female mice fed a high-fat diet. Thus, in different dietary and metabolic contexts, loss of a single Ctrp12 allele affects glucose and lipid metabolism in a sex-dependent manner, highlighting the importance of genetic and environmental determinants of metabolic phenotypes. Copyright © 2016 the American Physiological Society.

The cis-9,trans-11 isomer of conjugated linoleic acid (CLA) lowers plasma triglyceride and raises HDL cholesterol concentrations but does not suppress aortic atherosclerosis in diabetic apoE-deficient mice.

PubMed

Nestel, Paul; Fujii, Akihiko; Allen, Terri

2006-12-01

Reduction in atherosclerosis has been reported in experimental animals fed mixtures of conjugated linoleic acid (CLA). In this study, the major naturally occurring CLA isomer (cis-9,trans-11) was tested in an atherosclerosis-prone mouse model. In a model of insulin deficient apoE deficient mice, 16 animals were fed for 20 weeks with supplemental CLA (09.%, w/w) and compared with a similar number of mice of this phenotype. A control comparison was made of metabolic changes in non-diabetic apoE deficient mice that develop little atherosclerosis over 20 weeks. At 20 weeks, plasma lipids were measured and aortic atherosclerosis quantified by Sudan staining in the arch, thoracic and abdominal segments. The diabetic apoE deficient mice developed marked dyslipidemia, primarily as cholesterol-enriched chylomicron and VLDL-sized lipoproteins and atherosclerosis in the aortic arch. However, there were no significant differences between CLA fed and non-CLA fed mice in either phenotype in plasma cholesterol concentration (in diabetic: 29.4+/-7.7 and 29.5+/-5.9 mmol/L, respectively) or in the area of aortic arch atherosclerosis (in diabetic: 24.8+/-10.3 and 27.6+/-7.7%, respectively). However, among diabetic mice the triglyceride concentration in triglyceride-rich lipoproteins was significantly lower in those fed CLA (for plasma 2.2+/-0.8 to 1.1+/-0.3 mmol/L; P<0.001), a significant difference that was seen also in the non-diabetic mice in which HDL cholesterol increased significantly with CLA (0.35+/-0.12-0.56+/-0.15 mmol/L). In this atherosclerosis-prone model, the diabetic apoE deficient mouse, supplemental 0.9% CLA (cis-9,trans-11) failed to reduce the severity of aortic atherosclerosis, although plasma triglyceride concentration was substantially lowered and HDL cholesterol raised.

Neuronal Suppressor of Cytokine Signaling 3: Role in Modulating Chronic Metabolic and Cardiovascular Effects of Leptin.

PubMed

do Carmo, Jussara M; da Silva, Alexandre A; Freeman, John Nathan; Wang, Zhen; Moak, Sydney P; Hankins, Michael W; Drummond, Heather A; Hall, John E

2018-06-01

We determined whether deficiency of neuronal SOCS3 (suppressor of cytokine signaling 3)-a potential negative regulator of leptin signaling-amplifies the chronic effects of leptin on food intake, energy expenditure, glucose, and blood pressure (BP) and protects against adverse cardiometabolic effects of obesity. BP and heart rate were recorded by telemetry, and oxygen consumption (VO 2 ) was monitored in 22-week-old mice with nervous system SOCS3 deficiency (SOCS3-Nestin-Cre) and control mice (SOCS3 flox/flox ) fed normal or high-fat-high-fructose diet from 6 to 22 weeks of age. Compared with controls, SOCS3-Nestin-Cre mice had lower plasma glucose (124±7 versus 146±10 mg/dL), consumed less food (3.0±0.4 versus 3.6±0.2 g/d), and had similar VO 2 (77±6 versus 73±3 mL/kg per minute) and BP (103±3 versus 107±3 mm Hg) but higher heart rate (666±15 versus 602±17 bpm). In mice fed the normal diet, leptin infusion for 7 days caused similar reductions in food intake (2.3±0.1 versus 2.4±0.2 g) but greater increases in BP (15±3 versus 7±2 mm Hg) in SOCS3-Nestin-Cre compared with controls. Leptin reduced blood glucose concentrations in both groups. Male or female SOCS3-Nestin-Cre fed high-fat-high-fructose diet exhibited less weight gain, body fat, and liver steatosis and greater energy expenditure and heart rate compared with controls. Female SOCS3-Nestin-Cre mice fed high-fat-high-fructose diet had higher BP compared with controls. Thus, neuronal SOCS3 seems to play an important role in cardiometabolic regulation because neuronal SOCS3 deficiency reduced body weight and food intake while amplifying leptin's effects on appetite and BP and attenuating the adverse metabolic effects of high-fat-high-fructose diet. © 2018 American Heart Association, Inc.

The effect of isorhamnetin glycosides extracted from Opuntia ficus-indica in a mouse model of diet induced obesity.

PubMed

Rodríguez-Rodríguez, César; Torres, Nimbe; Gutiérrez-Uribe, Janet A; Noriega, Lilia G; Torre-Villalvazo, Iván; Leal-Díaz, Ana M; Antunes-Ricardo, Marilena; Márquez-Mota, Claudia; Ordaz, Guillermo; Chavez-Santoscoy, Rocío A; Serna-Saldivar, Sergio O; Tovar, Armando R

2015-03-01

A diet rich in polyphenols can ameliorate some metabolic alterations associated with obesity and type 2 diabetes. Opuntia ficus-indica (OFI) is a plant rich in isorhamnetin glycosides and is highly consumed in Mexico. The purpose of this research was to determine the metabolic effect of an OFI extract on a mouse model of diet-induced obesity and in isolated pancreatic islets. OFI extract was added to a high fat (HF) diet at a low (0.3%) or high (0.6%) dose and administered to C57BL/6 mice for 12 weeks. Mice fed the HF diet supplemented with the OFI extract gained less body weight and exhibited significantly lower circulating total cholesterol, LDL cholesterol and HDL cholesterol compared to those fed the HF diet alone. The HF-OFI diet fed mice presented lower glucose and insulin concentration than the HF diet fed mice. However, the HF-OFI diet fed mice tended to have higher insulin concentration than control mice. The OFI extract stimulated insulin secretion in vitro, associated with increased glucose transporter 2 (GLUT2) and peroxisome proliferator-activated receptor gamma (PPARγ) mRNA content. Furthermore, the OFI extract improved glucose tolerance, and additionally increased energy expenditure. These metabolic improvements were associated with reduced adipocyte size, increased hepatic IRS1 tyr-608 and S6 K thr-389 phosphorylation. OFI isorhamnetin glycosides also diminished the hepatic lipid content associated with reduced mRNA expression of the endoplasmic reticulum stress markers and lipogenic enzymes and increased mRNA expression of genes related to fatty acid oxidation. Overall, the OFI extract prevented the development of metabolic abnormalities associated with diet-induced obesity.

Susceptibility of Nrf2-Null Mice to Steatohepatitis and Cirrhosis upon Consumption of a High-Fat Diet Is Associated with Oxidative Stress, Perturbation of the Unfolded Protein Response, and Disturbance in the Expression of Metabolic Enzymes but Not with Insulin Resistance

PubMed Central

Meakin, Paul J.; Chowdhry, Sudhir; Sharma, Ritu S.; Ashford, Fiona B.; Walsh, Shaun V.; McCrimmon, Rory J.; Dinkova-Kostova, Albena T.; Dillon, John F.

2014-01-01

Mice lacking the transcription factor NF-E2 p45-related factor 2 (Nrf2) develop more severe nonalcoholic steatohepatitis (NASH), with cirrhosis, than wild-type (Nrf2+/+) mice when fed a high-fat (HF) diet for 24 weeks. Although NASH is usually associated with insulin resistance, HF-fed Nrf2−/− mice exhibited better insulin sensitivity than HF-fed Nrf2+/+ mice. In livers of HF-fed mice, loss of Nrf2 resulted in greater induction of lipogenic genes, lower expression of β-oxidation genes, greater reduction in AMP-activated protein kinase (AMPK) levels, and diminished acetyl coenzyme A (CoA) carboxylase phosphorylation than in the wild-type livers, which is consistent with greater fatty acid (FA) synthesis in Nrf2−/− livers. Moreover, primary Nrf2−/− hepatocytes displayed lower glucose and FA oxidation than Nrf2+/+ hepatocytes, with FA oxidation partially rescued by treatment with AMPK activators. The unfolded protein response (UPR) was perturbed in control regular-chow (RC)-fed Nrf2−/− mouse livers, and this was associated with constitutive activation of NF-κB and JNK, along with upregulation of inflammatory genes. The HF diet elicited an antioxidant response in Nrf2+/+ livers, and as this was compromised in Nrf2−/− livers, they suffered oxidative stress. Therefore, Nrf2 protects against NASH by suppressing lipogenesis, supporting mitochondrial function, increasing the threshold for the UPR and inflammation, and enabling adaptation to HF-diet-induced oxidative stress. PMID:24958099

Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes but not with insulin resistance.

PubMed

Meakin, Paul J; Chowdhry, Sudhir; Sharma, Ritu S; Ashford, Fiona B; Walsh, Shaun V; McCrimmon, Rory J; Dinkova-Kostova, Albena T; Dillon, John F; Hayes, John D; Ashford, Michael L J

2014-09-01

Mice lacking the transcription factor NF-E2 p45-related factor 2 (Nrf2) develop more severe nonalcoholic steatohepatitis (NASH), with cirrhosis, than wild-type (Nrf2(+/+)) mice when fed a high-fat (HF) diet for 24 weeks. Although NASH is usually associated with insulin resistance, HF-fed Nrf2(-/-) mice exhibited better insulin sensitivity than HF-fed Nrf2(+/+) mice. In livers of HF-fed mice, loss of Nrf2 resulted in greater induction of lipogenic genes, lower expression of β-oxidation genes, greater reduction in AMP-activated protein kinase (AMPK) levels, and diminished acetyl coenzyme A (CoA) carboxylase phosphorylation than in the wild-type livers, which is consistent with greater fatty acid (FA) synthesis in Nrf2(-/-) livers. Moreover, primary Nrf2(-/-) hepatocytes displayed lower glucose and FA oxidation than Nrf2(+/+) hepatocytes, with FA oxidation partially rescued by treatment with AMPK activators. The unfolded protein response (UPR) was perturbed in control regular-chow (RC)-fed Nrf2(-/-) mouse livers, and this was associated with constitutive activation of NF-κB and JNK, along with upregulation of inflammatory genes. The HF diet elicited an antioxidant response in Nrf2(+/+) livers, and as this was compromised in Nrf2(-/-) livers, they suffered oxidative stress. Therefore, Nrf2 protects against NASH by suppressing lipogenesis, supporting mitochondrial function, increasing the threshold for the UPR and inflammation, and enabling adaptation to HF-diet-induced oxidative stress. Copyright © 2014 Meakin et al.

GPA protects the nigrostriatal dopamine system by enhancing mitochondrial function.

PubMed

Horvath, Tamas L; Erion, Derek M; Elsworth, John D; Roth, Robert H; Shulman, Gerald I; Andrews, Zane B

2011-07-01

Guanidinopropionic acid (GPA) increases AMPK activity, mitochondrial function and biogenesis in muscle and improves physiological function, for example during aging. Mitochondrial dysfunction is a major contributor to the pathogenesis of Parkinson's disease. Here we tested whether GPA prevents neurodegeneration of the nigrostriatal dopamine system in MPTP-treated mice. Mice were fed a diet of 1% GPA or normal chow for 4 weeks and then treated with either MPTP or saline. Indices of nigrostriatal function were examined by HPLC, immunohistochemistry, stereology, electron microscopy and mitochondrial respiration. MPTP intoxication decreased TH neurons in the SNpc of normal chow-fed mice; however GPA-fed mice remarkably exhibited no loss of TH neurons in the SNpc. MPTP caused a decrease in striatal dopamine of both normal chow- and GPA-fed mice, although this effect was significantly attenuated in GPA-fed mice. GPA-fed mice showed increased AMPK activity, mitochondrial respiration and mitochondrial number in nigrostriatal TH neurons, suggesting that the neuroprotective effects of GPA involved AMPK-dependent increases in mitochondrial function and biogenesis. MPTP treatment produced a decrease in mitochondrial number and volume in normal chow-fed mice but not GPA-fed mice. Our results show the neuroprotective properties of GPA in a mouse model of Parkinson's disease are partially mediated by AMPK and mitochondrial function. Mitochondrial dysfunction is a common problem in neurodegeneration and thus GPA may slow disease progression in other models of neurodegeneration. Copyright © 2011 Elsevier Inc. All rights reserved.

Chromium (d-Phenylalanine)3 Alleviates High Fat-Induced Insulin Resistance and Lipid Abnormalities

PubMed Central

Kandadi, Machender Reddy; Unnikrishnan, MK; Warrier, Ajaya Kumar Sankara; Du, Min; Ren, Jun; Sreejayan, Nair

2010-01-01

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (d-phenylalanine)3 [Cr(d-Phe)3] on -glucose and -insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(d-Phe)3 (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body -glucose and- insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up- take in the gastrocnemius muscles, assessed as 2-[3H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-32P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)3. These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling. PMID:21134603

Effect of brown seaweed lipids on fatty acid composition and lipid hydroperoxide levels of mouse liver.

PubMed

Airanthi, M K Widjaja-Adhi; Sasaki, Naoya; Iwasaki, Sayaka; Baba, Nobuko; Abe, Masayuki; Hosokawa, Masashi; Miyashita, Kazuo

2011-04-27

Brown seaweed lipids from Undaria pinnatifida (Wakame), Sargassum horneri (Akamoku), and Cystoseira hakodatensis (Uganomoku) contained several bioactive compounds, namely, fucoxanthin, polyphenols, and omega-3 polyunsaturated fatty acids (PUFA). Fucoxanthin and polyphenol contents of Akamoku and Uganomoku lipids were higher than those of Wakame lipids, while Wakame lipids showed higher total omega-3 PUFA content than Akamoku and Uganomoku lipids. The levels of docosahexaenoic acid (DHA) and arachidonic acid (AA) in liver lipids of KK-A(y) mouse significantly increased by Akamoku and Uganomoku lipid feeding as compared with the control, but not by Wakame lipid feeding. Fucoxanthin has been reported to accelerate the bioconversion of omega-3 PUFA and omega-6 PUFA to DHA and AA, respectively. The higher hepatic DHA and AA level of mice fed Akamoku and Uganomoku lipids would be attributed to the higher content of fucoxanthin of Akamoku and Uganomoku lipids. The lipid hydroperoxide levels of the liver of mice fed brown seaweed lipids were significantly lower than those of control mice, even though total PUFA content was higher in the liver of mice fed brown seaweed lipids. This would be, at least in part, due to the antioxidant activity of fucoxanthin metabolites in the liver.

Gelidium elegans Regulates the AMPK-PRDM16-UCP-1 Pathway and Has a Synergistic Effect with Orlistat on Obesity-Associated Features in Mice Fed a High-Fat Diet.

PubMed

Choi, Jia; Kim, Kui-Jin; Koh, Eun-Jeong; Lee, Boo-Yong

2017-03-30

The incidence of obesity is rising at an alarming rate throughout the world and is becoming a major public health concern with incalculable social and economic costs. Gelidium elegans (GENS), also previously known as Gelidium amansii , has been shown to exhibit anti-obesity effects. Nevertheless, the mechanism by which GENS is able to do this remains unclear. In the present study, our results showed that GENS prevents high-fat diet (HFD)-induced weight gain through modulation of the adenosine monophosphate-activated protein kinase (AMPK)-PR domain-containing16 (PRDM16)-uncoupling protein-1 (UCP-1) pathway in a mice model. We also found that GENS decreased hyperglycemia in mice that had been fed a HFD compared to corresponding controls. We also assessed the beneficial effect of the combined treatment with GENS and orlistat (a Food and Drug Administration-approved obesity drug) on obesity characteristics in HFD-fed mice. We found that in HFD-fed mice, the combination of GENS and orlistat is associated with more significant weight loss than orlistat treatment alone. Moreover, our results demonstrated a positive synergistic effect of GENS and orlistat on hyperglycemia and plasma triglyceride level in these animals. Thus, we suggest that a combination therapy of GENS and orlistat may positively influence obesity-related health outcomes in a diet-induced obese population.

Gelidium elegans Regulates the AMPK-PRDM16-UCP-1 Pathway and Has a Synergistic Effect with Orlistat on Obesity-Associated Features in Mice Fed a High-Fat Diet

PubMed Central

Choi, Jia; Kim, Kui-Jin; Koh, Eun-Jeong; Lee, Boo-Yong

2017-01-01

The incidence of obesity is rising at an alarming rate throughout the world and is becoming a major public health concern with incalculable social and economic costs. Gelidium elegans (GENS), also previously known as Gelidium amansii, has been shown to exhibit anti-obesity effects. Nevertheless, the mechanism by which GENS is able to do this remains unclear. In the present study, our results showed that GENS prevents high-fat diet (HFD)-induced weight gain through modulation of the adenosine monophosphate-activated protein kinase (AMPK)-PR domain-containing16 (PRDM16)-uncoupling protein-1 (UCP-1) pathway in a mice model. We also found that GENS decreased hyperglycemia in mice that had been fed a HFD compared to corresponding controls. We also assessed the beneficial effect of the combined treatment with GENS and orlistat (a Food and Drug Administration-approved obesity drug) on obesity characteristics in HFD-fed mice. We found that in HFD-fed mice, the combination of GENS and orlistat is associated with more significant weight loss than orlistat treatment alone. Moreover, our results demonstrated a positive synergistic effect of GENS and orlistat on hyperglycemia and plasma triglyceride level in these animals. Thus, we suggest that a combination therapy of GENS and orlistat may positively influence obesity-related health outcomes in a diet-induced obese population. PMID:28358328

Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice.

PubMed

Li, B; Nolte, L A; Ju, J S; Han, D H; Coleman, T; Holloszy, J O; Semenkovich, C F

2000-10-01

To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling protein (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% higher in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and triglycerides and better glucose tolerance than did control mice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin, and had enhanced glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.

The Effects of Diet Composition on Body Fat and Hepatic Steatosis in an Animal (Peromyscus californicus) Model of the Metabolic Syndrome

PubMed Central

Krugner-Higby, Lisa; Caldwell, Stephen; Coyle, Kathryn; Bush, Eugene; Atkinson, Richard; Joers, Valerie

2011-01-01

The objective of this research was to determine body composition, total fat content, fat distribution, and serum leptin concentration in hyperlipidemic (high responder, HR) and normolipidemic (low responder, LR) California mice (Peromyscus californicus). In our initial experiments, we sought to determine whether differences in regional fat storage were associated with hyperlipidemia in this species. To further characterize the hepatic steatosis in the mice, we performed 2 additional experiments by using a diet containing 45% of energy as fat. The body fat content of mice fed a low fat-diet (12.3% energy as fat) was higher than that of mice fed a moderate-fat diet (25.8% energy as fat). Total body fat did not differ between HR and LR mice. There was no significant difference between intraabdominal, gonadal, or inguinal fat pad weights. Liver weights of HR mice fed the moderate-fat diet were higher than those of LR mice fed the same diet, and the moderate-fat diet was associated with nonalcoholic fatty liver (NAFL). Mice fed the 45% diet had higher histologic score for steatosis but very little inflammatory response. Chemical analysis indicated increased lipid in the livers of mice fed the high-fat diet compared with those fed the low-fat diet. HR and LR mice had similar serum leptin concentrations. California mice develop NAFL without excess fat accumulation elsewhere. NAFL was influenced by genetic and dietary factors. These mice may be a naturally occuring model of partial lipodystrophy. PMID:21819679

Mammalian Toxicity of Munitions Compounds. Phase III. Effects of Life-Time Exposure. Part III. Nitrocellulose.

DTIC Science & Technology

1980-01-01

male No. 52-25 injured his left hind leg on the metal bench in the run. High dose female No. 54-38 had a rectal prolapse in Month 24. These dogs ...studied in dogs , rats and mice. A cotton control (fed 10% cotton linters) was included with each species. Ancillary studies included cyto- genetic...increase in feed consumption. No other effects were seen in dogs . In rats and mice, those fed 10% fiber (NC or linters) had decreased DO , 1473 EoTIOM OF’ t

Lipolysis-Stimulating Peptide from Soybean Protects Against High Fat Diet-Induced Apoptosis in Skeletal Muscles.

PubMed

Marthandam Asokan, Shibu; Hung, Tsu-Han; Chiang, Wen-Dee; Lin, Wan-Teng

2018-03-01

Obesity is generally associated with low-grade chronic inflammation that involves the recruitment of macrophages and other inflammation factors to the adipocytes of obese individuals. Tumor necrosis factor-alpha (TNF-α), a cytokine associated with systemic inflammation, is elevated in conditions of obesity. TNF-α is an important factor that plays an important role in skeletal muscle wasting. Apoptosis of myonuclei contributes to the loss of muscle mass and therefore plays an important role in skeletal muscle atrophy. In mouse models that were fed a high fat diet (HFD), a lipolysis-stimulating peptide-VHVV (purified from hydrolysate resulting from flavourzyme treatment of soy protein) was found to reduce HFD-related apoptotic effects in mice skeletal muscle and potentially control atrophy. HFD fed mice had heavier body weight than those fed with normal chow, and VHVV administration restricted lipid accumulation in muscle tissues of mice fed with HFD but increased nutrient uptake. Moreover, specific concentrations of VHVV regulated TNF-α expression that was elevated by HFD, suppressed apoptosis-related proteins and regulated the proteins of lipid metabolism.

Choline Diet and Its Gut Microbe-Derived Metabolite, Trimethylamine N-Oxide, Exacerbate Pressure Overload-Induced Heart Failure.

PubMed

Organ, Chelsea L; Otsuka, Hiroyuki; Bhushan, Shashi; Wang, Zeneng; Bradley, Jessica; Trivedi, Rishi; Polhemus, David J; Tang, W H Wilson; Wu, Yuping; Hazen, Stanley L; Lefer, David J

2016-01-01

Trimethylamine N-oxide (TMAO), a gut microbe-dependent metabolite of dietary choline and other trimethylamine-containing nutrients, is both elevated in the circulation of patients having heart failure and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerates atherosclerotic lesion development in ApoE-deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the low-density lipoprotein receptor knockout mouse. C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks before surgical transverse aortic constriction. Mice were studied for 12 weeks after transverse aortic constriction. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post transverse aortic constriction, myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac brain natriuretic peptide, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction were significantly (P<0.05, each) worse in mice fed either TMAO- or choline-supplemented diets when compared with the control diet. In addition, myocardial fibrosis was also significantly greater (P<0.01, each) in the TMAO and choline groups relative to controls. Heart failure severity is significantly enhanced in mice fed diets supplemented with either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that additional studies are warranted examining whether gut microbiota and the dietary choline → TMAO pathway contribute to increased heart failure susceptibility. © 2015 American Heart Association, Inc.

Choline Diet and Its Gut Microbe Derived Metabolite, Trimethylamine N-Oxide (TMAO), Exacerbate Pressure Overload-Induced Heart Failure

PubMed Central

Organ, Chelsea L.; Otsuka, Hiroyuki; Bhushan, Shashi; Wang, Zeneng; Bradley, Jessica; Trivedi, Rishi; Polhemus, David J.; Tang, W. H. Wilson; Wu, Yuping; Hazen, Stanley L.; Lefer, David J.

2015-01-01

Background Trimethylamine N-oxide (TMAO), a gut microbe dependent metabolite of dietary choline and other trimethylamine containing nutrients, is both elevated in the circulation of patients suffering from heart failure (HF) and heralds worse overall prognosis. In animal studies, dietary choline or TMAO significantly accelerate atherosclerotic lesion development in ApoE deficient mice, and reduction in TMAO levels inhibits atherosclerosis development in the LDL receptor knockout mouse. Methods and Results C57BL6/J mice were fed either a control diet, a diet containing choline (1.2%) or a diet containing TMAO (0.12%) starting 3 weeks prior to surgical TAC. Mice were studied for 12 weeks following TAC. Cardiac function and left ventricular structure were monitored at 3-week intervals using echocardiography. Twelve weeks post-TAC myocardial tissues were collected to evaluate cardiac and vascular fibrosis, and blood samples were evaluated for cardiac BNP, choline, and TMAO levels. Pulmonary edema, cardiac enlargement, and left ventricular ejection fraction (LVEF) were significantly (p < 0.05, each) worse in mice fed either TMAO or choline supplemented diets compared to the control diet. In addition, myocardial fibrosis was also significantly greater (p < 0.01, each) in the TMAO and choline groups relative to controls. Conclusions Heart failure severity is significantly enhanced in mice fed diets supplemented in either choline or the gut microbe-dependent metabolite TMAO. The present results suggest that further studies are warranted examining whether gut microbiota and the dietary choline -> TMAO pathway contribute to increased heart failure susceptibility. PMID:26699388

Effects of Yangtze River source water on genomic polymorphisms of male mice detected by RAPD.

PubMed

Zhang, Xiaolin; Zhang, Zongyao; Zhang, Xuxiang; Wu, Bing; Zhang, Yan; Yang, Liuyan; Cheng, Shupei

2010-02-01

In order to evaluate the environmental health risk of drinking water from Yangtze River source, randomly amplified polymorphic DNA (RAPD) markers were used to detect the effects of the source water on genomic polymorphisms of hepatic cell of male mice (Mus musculus, ICR). After the mice were fed with source water for 90 days, RAPD-polymerase chain reactions (PCRs) were performed on hepatic genomic DNA using 20 arbitrary primers. Totally, 189 loci were generated, including 151 polymorphic loci. On average, one PCR primer produced 5.3, 4.9 and 4.8 bands for each mouse in the control, the groups fed with source water and BaP solution, respectively. Compared with the control, feeding mice with Yangtze River source water caused 33 new loci to appear and 19 to disappear. Statistical analysis of RAPD printfingers revealed that Yangtze River source water exerted a significant influence on the hepatic genomic polymorphisms of male mice. This study suggests that RAPD is a reliable and sensitive method for the environmental health risk of Yangtze River source water.

Lipid Metabolism, Oxidative Stress and Cell Death Are Regulated by PKC Delta in a Dietary Model of Nonalcoholic Steatohepatitis

PubMed Central

Greene, Michael W.; Burrington, Christine M.; Lynch, Darin T.; Davenport, Samantha K.; Johnson, Andrew K.; Horsman, Melissa J.; Chowdhry, Saleem; Zhang, Jian; Sparks, Janet D.; Tirrell, Paul C.

2014-01-01

Steatosis, oxidative stress, and apoptosis underlie the development of nonalcoholic steatohepatitis (NASH). Protein kinase C delta (PKCδ) has been implicated in fatty liver disease and is activated in the methionine and choline-deficient (MCD) diet model of NASH, yet its pathophysiological importance towards steatohepatitis progression is uncertain. We therefore addressed the role of PKCδ in the development of steatosis, inflammation, oxidative stress, apoptosis, and fibrosis in an animal model of NASH. We fed PKCδ−/− mice and wildtype littermates a control or MCD diet. PKCδ−/− primary hepatocytes were used to evaluate the direct effects of fatty acids on hepatocyte lipid metabolism gene expression. A reduction in hepatic steatosis and triglyceride levels were observed between wildtype and PKCδ−/− mice fed the MCD diet. The hepatic expression of key regulators of β-oxidation and plasma triglyceride metabolism was significantly reduced in PKCδ−/− mice and changes in serum triglyceride were blocked in PKCδ−/− mice. MCD diet-induced hepatic oxidative stress and hepatocyte apoptosis were reduced in PKCδ−/− mice. MCD diet-induced NADPH oxidase activity and p47phox membrane translocation were blunted and blocked, respectively, in PKCδ−/− mice. Expression of pro-apoptotic genes and caspase 3 and 9 cleavage in the liver of MCD diet fed PKCδ−/− mice were blunted and blocked, respectively. Surprisingly, no differences in MCD diet-induced fibrosis or pro-fibrotic gene expression were observed in 8 week MCD diet fed PKCδ−/− mice. Our results suggest that PKCδ plays a role in key pathological features of fatty liver disease but not ultimately in fibrosis in the MCD diet model of NASH. PMID:24454937

Short term supplementation of dietary antioxidants selectively regulates the inflammatory responses during early cutaneous wound healing in diabetic mice

PubMed Central

2011-01-01

Background Diabetic foot ulcers are serious complications for diabetic patients, yet the precise mechanism that underlines the treatment of these diabetic complications remains unclear. We hypothesized that dietary antioxidant supplementation with vitamin C, combined either with vitamin E or with vitamin E and NAC, improves delayed wound healing through modulation of blood glucose levels, oxidative stress, and inflammatory response. Methods Diabetes was induced by administration of alloxan monohydrate. Mice were divided into 4 groups; CON (non-diabetic control mice fed AIN 93 G purified rodent diet), DM (diabetic mice fed AIN 93 G purified rodent diet), VCE (diabetic mice fed 0.5% vitamin C and 0.5% vitamin E supplemented diet), and Comb (diabetic mice fed 0.5% vitamin C, 0.5% vitamin E, and 2.5% NAC supplemented diet). After 10 days of dietary antioxidant supplementation, cutaneous full-thickness excisional wounds were performed, and the rate of wound closure was examined. TBARS as lipid peroxidation products and vitamin E levels were measured in the liver. Expression levels of oxidative stress and inflammatory response related proteins were measured in the cutaneous wound site. Results Dietary antioxidant supplementation improved blood glucose levels and wound closure rate and increased liver vitamin E, but not liver TBARS levels in the diabetic mice as compared to those of the CON. In addition, dietary antioxidant supplementation modulated the expression levels of pIκBα, HO-1, CuZnSOD, iNOS and COX-2 proteins in the diabetic mice. Conclusions These findings demonstrated that delayed wound healing is associated with an inflammatory response induced by hyperglycaemia, and suggests that dietary antioxidant supplementation may have beneficial effects on wound healing through selective modulation of blood glucose levels, oxidative stress, and inflammatory response. PMID:22088091

Cortistatin Is a Key Factor Regulating the Sex-Dependent Response of the GH and Stress Axes to Fasting in Mice.

PubMed

Cordoba-Chacón, José; Gahete, Manuel D; Pozo-Salas, Ana I; de Lecea, Luis; Castaño, Justo P; Luque, Raúl M

2016-07-01

Cortistatin (CORT) shares high structural and functional similarities with somatostatin (SST) but displays unique sex-dependent pituitary actions. Indeed, although female CORT-knockout (CORT-KO) mice exhibit enhanced GH expression/secretion, Proopiomelanocortin expression, and circulating ACTH/corticosterone/ghrelin levels, male CORT-KO mice only display increased plasma GH/corticosterone levels. Changes in peripheral ghrelin and SST (rather than hypothalamic levels) seem to regulate GH/ACTH axes in CORT-KOs under fed conditions. Because changes in GH/ACTH axes during fasting provide important adaptive mechanisms, we sought to determine whether CORT absence influences GH/ACTH axes during fasting. Accordingly, fed and fasted male/female CORT-KO were compared with littermate controls. Fasting increased circulating GH levels in male/female controls but not in CORT-KO, suggesting that CORT can be a relevant regulator of GH secretion during fasting. However, GH levels were already higher in CORT-KO than in controls in fed state, which might preclude a further elevation in GH levels. Interestingly, although fasting-induced pituitary GH expression was elevated in both male/female controls, GH expression only increased in fasted female CORT-KOs, likely owing to specific changes observed in key factors controlling somatotrope responsiveness (ie, circulating ghrelin and IGF-1, and pituitary GHRH and ghrelin receptor expression). Fasting increased corticosterone levels in control and, most prominently, in CORT-KO mice, which might be associated with a desensitization to SST signaling and to an augmentation in CRH and ghrelin-signaling regulating corticotrope function. Altogether, these results provide compelling evidence that CORT plays a key, sex-dependent role in the regulation of the GH/ACTH axes in response to fasting.

Mitochondrial Protein Profile in Mice with Low or Excessive Selenium Diets

PubMed Central

Hu, Lianmei; Wang, Congcong; Zhang, Qin; Yan, Hao; Li, Ying; Pan, Jiaqiang; Tang, Zhaoxin

2016-01-01

Dietary selenium putatively prevents oxidative damage, whereas excessive selenium may lead to animal disorder. In this study, we investigated the effects of low and excessive levels of dietary selenium on oxidative stress and mitochondrial proteins in mouse liver. Six to eight week old mice were fed a diet with low, excessive, or moderate (control) levels of selenium (sodium selenite). The selenium concentration and oxidative stress-related parameters in hepatic mitochondria were evaluated. Two-dimensional electrophoresis and mass spectrometry were applied to identify the differentially-expressed proteins associated with dietary selenium. The selenium content of the livers in mice with the low selenium diet was significantly lower than that of the control, while that of mice fed excessive levels was significantly higher. In both groups oxidative stress in hepatic mitochondria was found; accompanied by lower superoxide dismutase (SOD) and glutathione peroxidase (GPX) levels and higher malondialdehyde (MDA) content, compared with the control group. Furthermore, ten proteins in the hepatic mitochondria of the selenium-low or -excessive groups with more than two-fold differences in abundance compared with the control group were identified. The differentially-expressed proteins in hepatic mitochondria may be associated with dietary (low or excessive) selenium-induced oxidative stress. PMID:27428959

CYP2E1 Potentiates Ethanol-induction of Hypoxia and HIF-1α in vivo

PubMed Central

Wang, Xiaodong; Wu, Defeng; Yang, Lili; Gan, Lixia; Cederbaum, Arthur I

2013-01-01

Ethanol induces hypoxia and elevates HIF-1α in the liver. CYP2E1 plays a role in the mechanisms by which ethanol generates oxidative stress, fatty liver and liver injury. The current study evaluated whether CYP2E1 contributes to ethanol-induced hypoxia and activation of HIF-1α in vivo and whether HIF-1α protects against or promotes CYP2E1-dependent toxicity in vitro. Wild type (WT), CYP2E1-knockin (KI) and CYP2E1 knockout (KO) mice were fed ethanol chronically; pair fed controls received isocaloric dextrose. Ethanol produced liver injury in the KI mice to a much greater extent than in the WT and KO mice. Protein levels of HIF-1α and downstream targets of HIF-1α activation were elevated in the ethanol-fed KI mice compared to the WT and KO mice. Levels of HIF prolylhydroxlase 2 which promotes HIF-1α degradation were decreased in the ethanol-fed KI mice in association with the increases in HIF-1α. Hypoxia occurred in the ethanol-fed CYP2E1 KI mice as shown by an increased area of staining using the hypoxia-specific marker pimonidazole. Hypoxia was lower in the ethanol-fed WT mice and lowest in the ethanol fed KO mice and all the dextrose-fed mice. In situ double staining showed that pimonidazole and CYP2E1 were co-localized to the same area of injury in the hepatic centrilobule. Increased protein levels of HIF-1α were also found after acute ethanol treatment of KI mice. Treatment of HepG2 E47 cells which express CYP2E1 with ethanol plus arachidonic (AA) acid or ethanol plus buthionine sulfoximine (BSO) which depletes GSH caused loss of cell viability to greater extent than in HepG2 C34 cells which do not express CYP2E1. These treatments elevated protein levels of HIF-1α to a greater extent in E47 cells than C34 cells. 2-Methoxyestradiol, an inhibitor of HIF-1α, blunted the toxic effects of ethanol plus AA and ethanol plus BSO in the E47 cells in association with inhibition of HIF-1α. The HIF-1α inhibitor also blocked the elevated oxidative stress produced by ethanol/AA or ethanol/BSO in the E47 cells. These results suggest that CYP2E1 plays a role in ethanol-induced hypoxia, oxidative stress and activation of HIF-1α and that HIF-1α contributes to CYP2E1-dependent ethanol-induced toxicity. Blocking HIF-1α activation and actions may have therapeutic implications for protection against ethanol/CYP2E1-induced oxidative stress, steatosis and liver injury. PMID:23669278

The effect of perioperative insulin treatment on cardiodepression in mild adiposity in mice.

PubMed

Boly, Chantal A; Eringa, Etto C; Bouwman, R Arthur; van den Akker, Rob F P; de Man, Frances S; Schalij, Ingrid; Loer, Stephan A; Boer, Christa; van den Brom, Charissa E

2016-09-20

While most studies focus on cardiovascular morbidity following anesthesia and surgery in excessive obesity, it is unknown whether these intraoperative cardiovascular alterations also occur in milder forms of adiposity without type 2 diabetes and if insulin is a possible treatment to improve intraoperative myocardial performance. In this experimental study we investigated whether mild adiposity without metabolic alterations is already associated with cardiometabolic dysfunction during anesthesia, mechanical ventilation and surgery and whether these myocardial alterations can be neutralized by intraoperative insulin treatment. Mice were fed a western (WD) or control diet (CD) for 4 weeks. After metabolic profiling, mice underwent general anesthesia, mechanical ventilation and surgery. Cardiac function was determined with echocardiography and left-ventricular pressure-volume analysis. Myocardial perfusion was determined with contrast-enhanced echocardiography. WD-fed mice were subsequently treated with insulin by hyperinsulinemic euglycemic clamping followed by the same measurements of cardiac function and perfusion. Western-type diet feeding led to a 13 % increase in bodyweight, (p < 0.0001) and increased adipose tissue mass, without metabolic alterations. Despite this mild phenotype, WD-fed mice had decreased systolic and diastolic function (end-systolic elastance was 2.0 ± 0.5 versus 4.1 ± 2.4 mmHg/μL, p = 0.01 and diastolic beta was 0.07 ± 0.03 versus 0.04 ± 0.01 mmHg/μL, p = 0.02) compared to CD-fed mice. Ventriculo-arterial coupling and myocardial perfusion were decreased by 48 % (p = 0.003) and 43 % (p = 0.03) respectively. Insulin treatment in WD-fed mice improved echo-derived systolic function (fractional shortening 42 ± 5 % to 46 ± 3, p = 0.05), likely due to decreased afterload, but there was no effect on load-independent measures of systolic function or myocardial perfusion. However, there was a trend towards improved diastolic function after insulin treatment (43 % improvement, p = 0.05) in WD-fed mice. Mild adiposity without metabolic alterations already affected cardiac function and perfusion during anesthesia, mechanical ventilation and surgery in mice. Intraoperative insulin may be beneficial to reduce afterload and enhance intraoperative ventricular relaxation, but not to improve ventricular contractility or myocardial perfusion.

Feeding mice with diets containing mercury-contaminated fish flesh from French Guiana: a model for the mercurial intoxication of the Wayana Amerindians

PubMed Central

Bourdineaud, Jean-Paul; Bellance, Nadège; Bénard, Giovani; Brèthes, Daniel; Fujimura, Masatake; Gonzalez, Patrice; Marighetto, Aline; Maury-Brachet, Régine; Mormède, Cécile; Pédron, Vanessa; Philippin, Jean-Nicolas; Rossignol, Rodrigue; Rostène, William; Sawada, Masumi; Laclau, Muriel

2008-01-01

Background In 2005, 84% of Wayana Amerindians living in the upper marshes of the Maroni River in French Guiana presented a hair mercury concentration exceeding the limit set up by the World Health Organization (10 μg/g). To determine whether this mercurial contamination was harmful, mice have been fed diets prepared by incorporation of mercury-polluted fish from French Guiana. Methods Four diets containing 0, 0.1, 1, and 7.5% fish flesh, representing 0, 5, 62, and 520 ng methylmercury per g, respectively, were given to four groups of mice for a month. The lowest fish regimen led to a mercurial contamination pressure of 1 ng mercury per day per g of body weight, which is precisely that affecting the Wayana Amerindians. Results The expression of several genes was modified with mercury intoxication in liver, kidneys, and hippocampus, even at the lowest tested fish regimen. A net genetic response could be observed for mercury concentrations accumulated within tissues as weak as 0.15 ppm in the liver, 1.4 ppm in the kidneys, and 0.4 ppm in the hippocampus. This last value is in the range of the mercury concentrations found in the brains of chronically exposed patients in the Minamata region or in brains from heavy fish consumers. Mitochondrial respiratory rates showed a 35–40% decrease in respiration for the three contaminated mice groups. In the muscles of mice fed the lightest fish-containing diet, cytochrome c oxidase activity was decreased to 45% of that of the control muscles. When mice behavior was assessed in a cross maze, those fed the lowest and mid-level fish-containing diets developed higher anxiety state behaviors compared to mice fed with control diet. Conclusion We conclude that a vegetarian diet containing as little as 0.1% of mercury-contaminated fish is able to trigger in mice, after only one month of exposure, disorders presenting all the hallmarks of mercurial contamination. PMID:18959803

Murine Norovirus Increases Atherosclerotic Lesion Size and Macrophages in Ldlr−/− Mice

PubMed Central

Paik, Jisun; Fierce, Yvette; Mai, Phuong-Oanh; Phelps, Susan R; McDonald, Thomas; Treuting, Piper; Drivdahl, Rolf; Brabb, Thea; LeBoeuf, Renee; O'Brien, Kevin D

2011-01-01

Murine norovirus (MNV) is prevalent in rodent facilities in the United States. Because MNV has a tropism for macrophages and dendritic cells, we hypothesized that it may alter phenotypes of murine models of inflammatory diseases, such as obesity and atherosclerosis. We examined whether MNV infection influences phenotypes associated with diet-induced obesity and atherosclerosis by using Ldlr−/− mice. Male Ldlr−/− mice were maintained on either a diabetogenic or high-fat diet for 16 wk, inoculated with either MNV or vehicle, and monitored for changes in body weight, blood glucose, glucose tolerance, and insulin sensitivity. Influence of MNV on atherosclerosis was analyzed by determining aortic sinus lesion area. Under both dietary regimens, MNV-infected and control mice gained similar amounts of weight and developed similar degrees of insulin resistance. However, MNV infection was associated with significant increases in aortic sinus lesion area and macrophage content in Ldlr−/− mice fed a high-fat diet but not those fed a diabetogenic diet. In conclusion, MNV infection exacerbates atherosclerosis in Ldlr−/− mice fed a high-fat diet but does not influence obesity- and diabetes-related phenotypes. Increased lesion size was associated with increased macrophages, suggesting that MNV may influence macrophage activation or accumulation in the lesion area. PMID:22330248

Probiotics modify tight-junction proteins in an animal model of nonalcoholic fatty liver disease

PubMed Central

Briskey, David; Heritage, Mandy; Jaskowski, Lesley-Anne; Peake, Jonathan; Gobe, Glenda; Subramaniam, V. Nathan; Crawford, Darrell; Campbell, Catherine; Vitetta, Luis

2016-01-01

Background: We have investigated the effects of a multispecies probiotic preparation containing a combination of probiotic bacterial genera that included Bifidobacteria, Lactobacilli and a Streptococcus in a mouse model of high-fat diet or obesity-induced liver steatosis. Methods: Three groups of C57B1/6J mice were fed either a standard chow or a high-fat diet for 20 weeks, while a third group was fed a high-fat diet for 10 weeks and then concomitantly administered probiotics for a further 10 weeks. Serum, liver and large bowel samples were collected for analysis. Results: The expression of the tight-junction proteins ZO-1 and ZO-2 was reduced (p < 0.05) in high-fat diet-fed mice compared to chow-fed mice. Probiotic supplementation helped to maintain tight ZO-1 and ZO-2 expression compared with the high-fat diet group (p < 0.05), but did not restore ZO-1 or ZO-2 expression compared with chow-fed mice. Mice fed a high-fat diet ± probiotics had significant steatosis development compared with chow-fed mice (p < 0.05); steatosis was less severe in the probiotics group compared with the high-fat diet group. Hepatic triglyceride concentration was higher in mice fed a high-fat diet ± probiotics compared with the chow group (p < 0.05), and was lower in the probiotics group compared with the high-fat diet group (p < 0.05). Compared with chow-fed mice, serum glucose, cholesterol concentration and the activity of alanine transaminase were higher (p < 0.05), whereas serum triglyceride concentration was lower (p < 0.05) in mice fed a high-fat diet ± probiotics. Conclusions: Supplementation with a multispecies probiotic formulation helped to maintain tight-junction proteins ZO-1 and ZO-2, and reduced hepatic triglyceride concentration compared with a high-fat diet alone. PMID:27366215

Effects of ambient temperature on glucose tolerance and insulin sensitivity test outcomes in normal and obese C57 male mice.

PubMed

Dudele, Anete; Rasmussen, Gitte Marie; Mayntz, David; Malte, Hans; Lund, Sten; Wang, Tobias

2015-05-01

Mice are commonly used as animal models to study human metabolic diseases, but experiments are typically performed at room temperature, which is far below their thermoneutral zone and is associated with elevated heart rate, food intake, and energy expenditure. We set out to study how ambient temperature affects glucose tolerance and insulin sensitivity in control and obese male mice. Adult male C57BL/6J mice were housed at room temperature (23°C) for 6 weeks and fed either control or high fat diet. They were then fasted for 6 h before glucose or insulin tolerance tests were performed at 15, 20, 25, or 30°C. To ensure that behavioral thermoregulation did not counterbalance the afflicted ambient temperatures, oxygen consumption was determined on mice with the same thermoregulatory opportunities as during the tests. Decreasing ambient temperatures increased oxygen consumption and body mass loss during fasting in both groups. Mice fed high fat diet had improved glucose tolerance at 30°C and increased levels of fasting insulin followed by successive decrease of fasting glucose. However, differences between control and high-fat diet mice were present at all temperatures. Ambient temperature did not affect glucose tolerance in control group and insulin tolerance in either of the groups. Ambient temperature affects glucose metabolism in mice and this effect is phenotype specific. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Effects of propolis and gamma-cyclodextrin on intestinal neoplasia in normal weight and obese mice.

PubMed

Cho, Youngjin; Gutierrez, Linda; Bordonaro, Michael; Russo, Daniel; Anzelmi, Frank; Hooven, Jayde T; Cerra, Carmine; Lazarova, Darina L

2016-09-01

Obesity is associated with colorectal cancer (CRC). This effect might be attributed to adipokine-supported signaling. We have established that propolis suppresses survival signaling in CRC cells in vitro; therefore, we ascertained the ability of a propolis supplement to modulate intestinal neoplastic development in C57BL/6J-ApcMin/+/J mice in the lean and obese state. To induce obesity, mice were fed with a Western diet containing 40% fat. Since the propolis supplement includes gamma-cyclodextrin, the interventions included diets supplemented with or without gamma-cyclodextrin. The animals were administered the following diets: (1) control diet, (2) control diet/gamma-cyclodextrin, (3) control diet/propolis, (4) Western diet, (5) Western diet/gamma-cyclodextrin, and (6) Western diet/propolis. Western diet, resulting in obesity, accelerated neoplastic progression, as evidenced by the larger size and higher grade dysplasia of the neoplasms. In the context of normal weight, gamma-cyclodextrin and propolis affected neoplastic progression, as determined by the size of the lesions and their grade of dysplasia. A statistically significant decrease in the number of adenomas was detected in mice fed a control diet with the propolis supplement (61.8 ± 10.6 vs. 35.3 ± 7.6, P = 0.008). Although there was no significant difference in the polyp numbers between the six groups, the mice with the lowest number and size of adenomas were those fed a Western diet with gamma-cyclodextrin. This unexpected outcome might be explained by the increased levels of apoptosis detected in the intestinal tissues of these obese mice. We posit that butyrate derived from the metabolism of gamma-cyclodextrin may contribute to the decreased neoplastic burden in the context of obesity; however, future studies are required to address this possibility. © 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Isoflavones in soy flour diet have different effects on whole-genome expression patterns than purified isoflavone mix in human MCF-7 breast tumors in ovariectomized athymic nude mice.

PubMed

Liu, Yunxian; Hilakivi-Clarke, Leena; Zhang, Yukun; Wang, Xiao; Pan, Yuan-Xiang; Xuan, Jianhua; Fleck, Stefanie C; Doerge, Daniel R; Helferich, William G

2015-08-01

Soy flour diet (MS) prevented isoflavones from stimulating MCF-7 tumor growth in athymic nude mice, indicating that other bioactive compounds in soy can negate the estrogenic properties of isoflavones. The underlying signal transduction pathways to explain the protective effects of soy flour consumption were studied here. Ovariectomized athymic nude mice inoculated with MCF-7 human breast cancer cells were fed either Soy flour diet (MS) or purified isoflavone mix diet (MI), both with equivalent amounts of genistein. Positive controls received estradiol pellets and negative controls received sham pellets. GeneChip Human Genome U133 Plus 2.0 Array platform was used to evaluate gene expressions, and results were analyzed using bioinformatics approaches. Tumors in MS-fed mice exhibited higher expression of tumor growth suppressing genes ATP2A3 and BLNK and lower expression of oncogene MYC. Tumors in MI-fed mice expressed a higher level of oncogene MYB and a lower level of MHC-I and MHC-II, allowing tumor cells to escape immunosurveillance. MS-induced gene expression alterations were predictive of prolonged survival among estrogen-receptor-positive breast cancer patients, whilst MI-induced gene changes were predictive of shortened survival. Our findings suggest that dietary soy flour affects gene expression differently than purified isoflavones, which may explain why soy foods prevent isoflavones-induced stimulation of MCF-7 tumor growth in athymic nude mice. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Effects of chocolate supplementation on metabolic and cardiovascular parameters in ApoE3L mice fed a high-cholesterol atherogenic diet.

PubMed

Yakala, Gopala K; Wielinga, Peter Y; Suarez, Manuel; Bunschoten, Annelies; van Golde, Jolanda M; Arola, Lluis; Keijer, Jaap; Kleemann, Robert; Kooistra, Teake; Heeringa, Peter

2013-11-01

Dietary intake of cocoa and/or chocolate has been suggested to exhibit protective cardiovascular effects although this is still controversial. The aim of this study was to investigate the effects of chocolate supplementation on metabolic and cardiovascular parameters. Four groups of ApoE*3Leiden mice were exposed to the following diet regimens. Group 1: cholesterol-free control diet (CO). Group 2: high-dose (1.0% w/w) control cholesterol (CC). Group 3: CC supplemented chocolate A (CCA) and Group 4: CC supplemented chocolate B (CCB). Both chocolates differed in polyphenol and fiber content, CCA had a relatively high-polyphenol and low-fiber content compared to CCB. Mice fed a high-cholesterol diet showed increased plasma-cholesterol and developed atherosclerosis. Both chocolate treatments, particularly CCA, further increased plasma-cholesterol and increased atherosclerotic plaque formation. Moreover, compared to mice fed a high-cholesterol diet, both chocolate-treated groups displayed increased liver injury. Mice on high-cholesterol diet had elevated plasma levels of sVCAM-1, sE-selectin and SAA, which was further increased in the CCB group. Similar effects were observed for renal inflammation markers. The two chocolate preparations showed unfavorable, but different effects on cardiometabolic health in E3L mice, which dissimilarities may be related to differences in chocolate composition. We conclude that discrepancies reported on the effects of chocolate on cardiometabolic health may at least partly be due to differences in chocolate composition. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Role of 5-HT3 Receptor on Food Intake in Fed and Fasted Mice

PubMed Central

Li, Bingjin; Shao, Dongyuan; Luo, Yungang; Wang, Pu; Liu, Changhong; Zhang, Xingyi; Cui, Ranji

2015-01-01

Background Many studies have shown that 5-hydroxytryptamine (5-HT) receptor subtypes are involved in the regulation of feeding behavior. However, the relative contribution of 5-HT3 receptor remains unclear. The present study was aimed to investigate the role of 5-HT3 receptor in control of feeding behavior in fed and fasted mice. Methodology/Principal Findings Food intake and expression of c-Fos, tyrosine hydroxylase (TH), proopiomelanocortin (POMC) and 5-HT in the brain were examined after acute treatment with 5-HT3 receptor agonist SR-57227 alone or in combination with 5-HT3 receptor antagonist ondansetron. Food intake was significantly inhibited within 3 h after acute treatment with SR 57227 in fasted mice but not fed mice, and this inhibition was blocked by ondansetron. Immunohistochemical study revealed that fasting-induced c-Fos expression was further enhanced by SR 57227 in the brainstem and the hypothalamus, and this enhancement was also blocked by ondansetron. Furthermore, the fasting-induced downregulation of POMC expression in the hypothalamus and the TH expression in the brain stem was blocked by SR 57227 in the fasted mice, and this effect of SR 57227 was also antagonized by ondansetron. Conclusion/Significance Taken together, our findings suggest that the effect of SR 57227 on the control of feeding behavior in fasted mice may be, at least partially, related to the c-Fos expression in hypothalamus and brain stem, as well as POMC system in the hypothalamus and the TH system in the brain stem. PMID:25789930

Isoproterenol exacerbates hyperglycemia and modulates chromium distribution in mice fed with a high fat diet.

PubMed

Chang, Geng-Ruei; Chen, Wen-Kai; Hou, Po-Hsun; Mao, Frank Chiahung

2017-12-01

Isoproterenol (ISO), a nonselective β-adrenoceptor agonist for treating bradycardia and asthma, has been proposed to raise blood glucose level. Little is known regarding the relationship between ISO treatment, the induced chromium (Cr) redistribution, and changes in glucose metabolism. We aimed to characterize the effects of a single dose of ISO on glucose homeostasis and Cr level changes in an obesity mouse model. Mice (C57BL6/j strain) were first fed for a continuous period of 12 weeks with either a high fat diet (HFD), to develop an obesity animal model, or a standard diet (SD), to develop a lean animal model as controls. These groups were each separated into two subgroups to receive either a single dose of ISO or saline (control). We measured in vivo their metabolic parameters, fasting glucose level, area under the curve (AUC) for glucose level time profile, insulin level time profile, insulin sensitivity index, and chromium distribution. After a single dose of ISO, the SD-fed mice had slightly higher blood glucose levels compared with the SD controls, when the level was measured 30 and 60min after injection. By contrast, the ISO-treated HFD-fed mice had significantly higher blood glucose levels and AUC during the entire 120min following one administration compared with the HFD control group. Additionally, they had a substantially lower HOMA-IR index, whereas insulin levels remained unchanged. The Cr level in their bones and liver was decreased, and loss of Cr through urinary excretion was elevated. The results demonstrated that ISO exacerbated hyperglycemic syndrome in the obesity animal model. ISO induced a net negative Cr balance as a result of increased urinary excretion, leading to Cr mobilization that was not desirable to overcome the hyperglycemia. Copyright © 2017 Elsevier GmbH. All rights reserved.

Mice Orally Immunized with a Transgenic Plant Expressing the Glycoprotein of Crimean-Congo Hemorrhagic Fever Virus ▿

PubMed Central

Ghiasi, S. M.; Salmanian, A. H.; Chinikar, S.; Zakeri, S.

2011-01-01

While Crimean-Congo hemorrhagic fever (CCHF) has a high mortality rate in humans, the associated virus (CCHFV) does not induce clinical symptoms in animals, but animals play an important role in disease transmission to humans. Our aim in this study was to examine the immunogenicity of the CCHFV glycoprotein when expressed in the root and leaf of transgenic plants via hairy roots and stable transformation of tobacco plants, respectively. After confirmatory analyses of transgenic plant lines and quantification of the expressed glycoprotein, mice were either fed with the transgenic leaves or roots, fed the transgenic plant material and injected subcutaneously with the plant-made CCHFV glycoprotein (fed/boosted), vaccinated with an attenuated CCHF vaccine (positive control), or received no treatment (negative control). All immunized groups had a consistent rise in anti-glycoprotein IgG and IgA antibodies in their serum and feces, respectively. The mice in the fed/boosted group showed a significant rise in specific IgG antibodies after a single boost. Our results imply that oral immunization of animals with edible materials from transgenic plants is feasible, and further assessments are under way. In addition, while the study of CCHF is challenging, our protocol should be further used to study CCHFV infection in the knockout mouse model and virus neutralization assays in biosafety level 4 laboratories. PMID:22012978

Mice orally immunized with a transgenic plant expressing the glycoprotein of Crimean-Congo hemorrhagic fever virus.

PubMed

Ghiasi, S M; Salmanian, A H; Chinikar, S; Zakeri, S

2011-12-01

While Crimean-Congo hemorrhagic fever (CCHF) has a high mortality rate in humans, the associated virus (CCHFV) does not induce clinical symptoms in animals, but animals play an important role in disease transmission to humans. Our aim in this study was to examine the immunogenicity of the CCHFV glycoprotein when expressed in the root and leaf of transgenic plants via hairy roots and stable transformation of tobacco plants, respectively. After confirmatory analyses of transgenic plant lines and quantification of the expressed glycoprotein, mice were either fed with the transgenic leaves or roots, fed the transgenic plant material and injected subcutaneously with the plant-made CCHFV glycoprotein (fed/boosted), vaccinated with an attenuated CCHF vaccine (positive control), or received no treatment (negative control). All immunized groups had a consistent rise in anti-glycoprotein IgG and IgA antibodies in their serum and feces, respectively. The mice in the fed/boosted group showed a significant rise in specific IgG antibodies after a single boost. Our results imply that oral immunization of animals with edible materials from transgenic plants is feasible, and further assessments are under way. In addition, while the study of CCHF is challenging, our protocol should be further used to study CCHFV infection in the knockout mouse model and virus neutralization assays in biosafety level 4 laboratories.

Effects of nutrition on disease and life span. I. Immune responses, cardiovascular pathology, and life span in MRL mice.

PubMed Central

Mark, D. A.; Alonso, D. R.; Quimby, F.; Thaler, H. T.; Kim, Y. T.; Fernandes, G.; Good, R. A.; Weksler, M. E.

1984-01-01

Mice of the autoimmune, lymphoproliferative strain MRL/lpr and the congenic, nonlymphoproliferative strain MRL/n were fed one of six diets from weaning on-ward. These mice were sacrificed at 3 or 5 months of age. Low fat diets resulted in lower cholesterol and higher triglyceride levels than did cholesterol-containing high-fat diets. Caloric restriction of MRL/lpr mice was associated with an increased plaque-forming cell response to trinitrophenylated polyacrylamide beads, less lymphoproliferation, and less severe glomerulonephritis. Diet did not affect the incidence of autoimmune vasculitis in MRL/lpr mice sacrificed at 5 months. MRL/lpr mice fed a low-fat, calorically restricted diet from 5 months of age to death lived longer than mice which were fed ad libitum a cholesterol-containing, high-fat diet. At death, MRL/lpr mice fed the former diet had the autoimmune vasculitis which had been evident in mice killed at 5 months, whereas mice fed the latter diet, in addition to the vasculitis, had a high incidence of atherosclerotic lesions of intrarenal and aortic branch arteries. Images Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 PMID:6333184

Transcriptome analysis of the effects of chitosan on the hyperlipidemia and oxidative stress in high-fat diet fed mice.

PubMed

Wang, Bin; Zhang, Sicong; Wang, Xiaoya; Yang, Shuo; Jiang, Qixing; Xu, Yanshun; Xia, Wenshui

2017-09-01

Transcriptome analysis was performed to investigate the alterations in gene expression after chitosan (CS) treatment on the liver of mice fed with high-fat diet (HFD). The results showed that the body weight, the liver weight and the epididymal fat mass of HFD mice, which were 62.98%, 46.51% and 239.37%, respectively, higher than those of control mice, could be significantly decreased by chitosan supplementation. Also, high-fat diet increased both plasma lipid and liver lipid as compared with the control mice. Chitosan supplementation decreased the plasma lipid and liver lipid, increased the lipoprotein lipase (LPL) and hepatic lipase (HL) activity, increased T-AOC and decreased MDA in the liver and the epididymis adipose as compared with the HFD mice. Transcriptome analysis indicated that increased Mups, Lcn2, Gstm3 and CYP2E1 expressions clearly indicated HFD induced lipid metabolism disorder and oxidative damage. Especially, chitosan treatment decreased the Mup17 and Lcn2 expressions by 64.32% and 82.43% respectively as compared with those of HFD mice. These results indicated that chitosan possess the ability to improve the impairment of lipid metabolism as strongly associated with increased Mups expressions and gene expressions related to oxidative stress. Copyright © 2017 Elsevier B.V. All rights reserved.

Chromium (D-phenylalanine)3 alleviates high fat-induced insulin resistance and lipid abnormalities.

PubMed

Kandadi, Machender Reddy; Unnikrishnan, M K; Warrier, Ajaya Kumar Sankara; Du, Min; Ren, Jun; Sreejayan, Nair

2011-01-01

High-fat diet has been implicated as a major cause of insulin resistance and dyslipidemia. The objective of this study was to evaluate the impact of dietary-supplementation of chromium (D-phenylalanine)(3) [Cr(D-Phe)(3)] on glucose and insulin tolerance in high-fat diet fed mice. C57BL/6-mice were randomly assigned to orally receive vehicle or Cr(D-Phe)(3) (45 μg of elemental chromium/kg/day) for 8-weeks. High-fat-fed mice exhibited impaired whole-body-glucose and -insulin tolerance and elevated serum triglyceride levels compared to normal chow-fed mice. Insulin-stimulated glucose up-take in the gastrocnemius muscles, assessed as 2-[(3)H-deoxyglucose] incorporation was markedly diminished in high-fat fed mice compared to control mice. Treatment with chromium reconciled the high-fat diet-induced alterations in carbohydrate and lipid metabolism. Treatment of cultured, differentiated myotubes with palmitic acid evoked insulin resistance as evidenced by lower levels of insulin-stimulated Akt-phosphorylation, elevated JNK-phosphorylation, (assessed by Western blotting), attenuation of phosphoinositol-3-kinase activity (determined in the insulin-receptor substrate-1-immunoprecipitates by measuring the extent of phosphorylation of phosphatidylinositol by γ-(32)P-ATP), and impairment in cellular glucose up-take, all of which were inhibited by Cr(d-Phe)(3). These results suggest a beneficial effect of chromium-supplementation in insulin resistant conditions. It is likely that these effects of chromium may be mediated by augmenting downstream insulin signaling. Copyright © 2010 Elsevier Inc. All rights reserved.

Lack of hepcidin ameliorates anemia and improves growth in an adenine-induced mouse model of chronic kidney disease

PubMed Central

Sureshbabu, Angara; Doty, Steve B.; Zhu, Yuan-Shan; Patino, Edwin; Cunningham-Rundles, Susanna; Choi, Mary E.; Boskey, Adele; Rivella, Stefano

2016-01-01

Growth delay is common in children with chronic kidney disease (CKD), often associated with poor quality of life. The role of anemia in uremic growth delay is poorly understood. Here we describe an induction of uremic growth retardation by a 0.2% adenine diet in wild-type (WT) and hepcidin gene (Hamp) knockout (KO) mice, compared with their respective littermates fed a regular diet. Experiments were started at weaning (3 wk). After 8 wk, blood was collected and mice were euthanized. Adenine-fed WT mice developed CKD (blood urea nitrogen 82.8 ± 11.6 mg/dl and creatinine 0.57 ± 0.07 mg/dl) and were 2.1 cm shorter compared with WT controls. WT adenine-fed mice were anemic and had low serum iron, elevated Hamp, and elevated IL6 and TNF-α. WT adenine-fed mice had advanced mineral bone disease (serum phosphorus 16.9 ± 3.1 mg/dl and FGF23 204.0 ± 115.0 ng/ml) with loss of cortical and trabecular bone volume seen on microcomputed tomography. Hamp disruption rescued the anemia phenotype resulting in improved growth rate in mice with CKD, thus providing direct experimental evidence of the relationship between Hamp pathway and growth impairment in CKD. Hamp disruption ameliorated CKD-induced growth hormone-insulin-like growth factor 1 axis derangements and growth plate alterations. Disruption of Hamp did not mitigate the development of uremia, inflammation, and mineral and bone disease in this model. Taken together, these results indicate that an adenine diet can be successfully used to study growth in mice with CKD. Hepcidin appears to be related to pathways of growth retardation in CKD suggesting that investigation of hepcidin-lowering therapies in juvenile CKD is warranted. PMID:27440777

Green tea polyphenol treatment attenuates atherosclerosis in high-fat diet-fed apolipoprotein E-knockout mice via alleviating dyslipidemia and up-regulating autophagy

PubMed Central

Jiang, Jinjin; Yu, Pengxin; Zhang, Guofu; Zhang, Guanghui; Liu, Xiaoting

2017-01-01

Background: Green tea polyphenol (GTP) is a polyphenol source from green tea that has drawn wide attention owing to epidemiological evidence of its beneficial effects in the prevention of cardiovascular disease; the underlying molecular mechanisms of these effects are not well understood. This study aimed to investigate the effects of GTP treatment on autophagy regulation in the vessel wall and lipid metabolism of HFD-fed male ApoE-knockout mice. Methods: Adult male ApoE-knockout mice (n = 30) fed with a high-fat diet (HFD) were treated with either vehicle or GTP (3.2 or 6.4 g/L) administered via drinking water for 15 weeks, and C57BL/6J mice fed with standard chow diet (STD) were used as the control group. Metabolic parameters, expression of key mRNAs and proteins of hepatic lipid metabolism and autophagy in the vessel wall of mice were determined after the 15-week treatment. Results: A HFD induced atherosclerosis formation and lipid metabolism disorders as well as reduced autophagy expression in the vessel wall of ApoE-knockout mice, but GTP treatment alleviated the lipid metabolism disorders, decreased the oxLDL levels in serum, and increased the mRNA and protein expressions of hepatic PPARα and autophagy markers (LC3, Beclin1 and p62) in the vessel wall of ApoE-knockout mice. Conclusions: Our findings suggest that GTP supplementation showed marked suppression of atherogenesis through improved lipid metabolism as well as through a direct impact on oxLDL and autophagy flux in the vessel wall. PMID:28777810

Characterization of the Impaired Glucose Homeostasis Produced in C57BL/6 Mice by Chronic Exposure to Arsenic and High-Fat Diet

PubMed Central

Paul, David S.; Walton, Felecia S.; Saunders, R. Jesse

2011-01-01

Background: Type 2 diabetes is characterized by glucose intolerance and insulin resistance. Obesity is the leading cause of type 2 diabetes. Growing evidence suggests that chronic exposure to inorganic arsenic (iAs) also produces symptoms consistent with diabetes. Thus, iAs exposure may further increase the risk of diabetes in obese individuals. Objectives: Our goal was to characterize diabetogenic effects of iAs exposure and high-fat diet (HFD) in weaned C57BL/6 mice. Methods: Mice were fed HFD or low-fat diet (LFD) while exposed to iAs in drinking water (25 or 50 ppm As) for 20 weeks; control HFD and LFD mice drank deionized water. Body mass and adiposity were monitored throughout the study. We measured glucose and insulin levels in fasting blood and in blood collected during oral glucose tolerance tests (OGTT) to evaluate the diabetogenic effects of the treatment. Results: Control mice fed HFD accumulated more fat, had higher fasting blood glucose, and were more insulin resistant than were control LFD mice. However, these diabetes indicators decreased with iAs intake in a dose-dependent manner. OGTT showed impaired glucose tolerance for both control and iAs-treated HFD mice compared with respective LFD mice. Notably, glucose intolerance was more pronounced in HFD mice treated with iAs despite a significant decrease in adiposity, fasting blood glucose, and insulin resistance. Conclusions: Our data suggest that iAs exposure acts synergistically with HFD-induced obesity in producing glucose intolerance. However, mechanisms of the diabetogenic effects of iAs exposure may differ from the mechanisms associated with the obesity-induced type 2 diabetes. PMID:21592922

Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Xiaoyu; Zhao, Shiqi; Su, Mengqi

Endothelial dysfunction occurs in obese patients and high-fat diet (HFD) fed experimental animals. While geraniol has been reported to ameliorate inflammation and oxidative stress, inhibit tumor cell proliferation, and improve atherosclerosis, its direct effect on endothelial function remains uncharacterized. The present study therefore investigated the effect of geraniol on endothelial function in HFD mice and its underlying mechanisms. C57 BL/6 mice were fed an HFD (n = 40) or a normal diet (n = 20) for 8 weeks. HFD fed mice then were randomized to intraperitoneal treatment with geraniol (n = 20) or vehicle (n = 20) for another 6 weeks. Acetylcholine (Ach)-induced endothelial dependent vasorelaxation was measuredmore » on wire myography; reactive oxygen species (ROS) generation was assessed by fluorescence imaging, and NADPH oxidases (NOXs) and adhesive molecules VCAM-1 and ICAM-1 protein expression by western blotting. Geraniol improved endothelial function in HFD fed mice, as evidenced by its: 1. restoring endothelial dependent vasorelaxation induced by Ach, and reversing increased VCAM-1 and ICAM-1 expression; 2. attenuating HFD induced increased serum TBARS and aortic ROS generation; and 3. downregulating aortic NOX-2 expression in both HFD fed mice and in palmitic acid treated endothelial cells. Geraniol therefore protects against endothelial dysfunction induced by HFD through reducing NOX-2 associated ROS generation. -- Highlights: •Geraniol improved endothelial dependent relaxation in high fat diet fed mice. •Geraniol alleviated vascular injury in high fat diet fed mice. •Geraniol inhibited ROS generation through downregulating NOX-2 expression.« less

Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.

PubMed

Xu, Bing; Jiang, Mingzuo; Chu, Yi; Wang, Weijie; Chen, Di; Li, Xiaowei; Zhang, Zhao; Zhang, Di; Fan, Daiming; Nie, Yongzhan; Shao, Feng; Wu, Kaichun; Liang, Jie

2017-12-20

Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd -/- ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd -/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd -/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd -/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis. Non-alcoholic fatty liver disease has become one of the most feared chronic liver diseases, because it is the most rapidly growing indication for adult liver transplantation and a major cause of hepatocellular carcinoma. However, the mechanisms involved in the transformation of simple steatosis to steatohepatitis remain unclear. Herein, we show that gasdermin D driven pyroptosis is prominent in patients with non-alcoholic steatohepatitis (NASH), and gasdermin-N domain remains a potential biomarker for the diagnosis of NASH. Gasdermin D plays a key role in the pathogenesis of NASH by regulating lipogenesis, the inflammatory response, and the NF-ĸB signaling pathway, revealing potential treatment targets for NASH in humans. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and Cd8+ T Cell Function after Pseudomonas Aeruginosa Pneumonia-Induced Sepsis.

PubMed

Klingensmith, Nathan J; Fay, Katherine T; Lyons, John D; Chen, Ching-Wen; Otani, Shunsuke; Liang, Zhe; Chihade, Deena B; Burd, Eileen M; Ford, Mandy L; Coopersmith, Craig M

2018-04-16

Mortality is higher in septic patients with a history of alcohol use disorder than in septic patients without a history of chronic alcohol usage. We have previously described a model of chronic alcohol ingestion followed by sepsis from cecal ligation and puncture in which alcohol-fed septic mice have higher mortality than water-fed septic mice, associated with altered gut integrity and increased production of TNF and IFNγ by splenic CD4 T cells without alterations in CD8 T cell function. The purpose of this study was to determine whether this represents a common host response to the combination of alcohol and sepsis by creating a new model in which mice with chronic alcohol ingestion were subjected to a different model of sepsis. C57Bl/6 mice were randomized to receive either alcohol or water for 12 weeks and then subjected to Pseudomonas aeruginosa pneumonia. Mice were sacrificed either 24 hours after the onset of sepsis or followed for survival. Alcohol-fed septic mice had significantly higher 7-day mortality than water-fed septic mice (96% vs 58%). This was associated with a 5-fold increase in intestinal apoptosis in alcohol-fed septic animals, accompanied by an increase in the pro-apoptotic protein Bax. Serum IL-6 levels were higher and IL-2 levels were lower in alcohol-fed septic mice. In contrast, CD8 T cell frequency was lower in alcohol-fed mice than water-fed septic mice, associated with increased production of IFNγ and TNF in stimulated splenocytes. No significant differences were noted in CD4 T cells, lung injury or bacteremia. Mice with chronic alcohol ingestion thus have increased mortality regardless of their septic insult, associated with changes in both the gut and the immune system.

Low dose dietary nitrate improves endothelial dysfunction and plaque stability in the ApoE-/- mouse fed a high fat diet.

PubMed

Bakker, J R; Bondonno, N P; Gaspari, T A; Kemp-Harper, B K; McCashney, A J; Hodgson, J M; Croft, K D; Ward, N C

2016-10-01

Nitric oxide (NO) is an important vascular signalling molecule. NO is synthesised endogenously by endothelial nitric oxide synthase (eNOS). An alternate pathway is exogenous dietary nitrate, which can be converted to nitrite and then stored or further converted to NO and used immediately. Atherosclerosis is associated with endothelial dysfunction and subsequent lesion formation. This is thought to arise due to a reduction in the bioavailability and/or bioactivity of endogenous NO. To determine if dietary nitrate can protect against endothelial dysfunction and lesion formation in the ApoE -/- mouse fed a high fat diet (HFD). ApoE -/- fed a HFD were randomized to receive (i) high nitrate (10mmol/kg/day, n=12), (ii) moderate nitrate (1mmol/kg/day, n=8), (iii) low nitrate (0.1mmol/kg/day, n=8), or (iv) sodium chloride supplemented drinking water (control, n=10) for 10 weeks. A group of C57BL6 mice (n=6) received regular water and served as a healthy reference group. At 10 weeks, ACh-induced vessel relaxation was significantly impaired in ApoE -/- mice versus C57BL6. Mice supplemented with low or moderate nitrate showed significant improvements in ACh-induced vessel relaxation compared to ApoE -/- mice given the high nitrate or sodium chloride. Plaque collagen expression was increased and lipid deposition reduced following supplementation with low or moderate nitrate compared to sodium chloride, reflecting increased plaque stability with nitrate supplementation. Plasma nitrate and nitrite levels were significantly increased in all three groups fed the nitrate-supplemented water. Low and moderate dose nitrate significantly improved endothelial function and atherosclerotic plaque composition in ApoE -/- mice fed a HFD. Copyright © 2016 Elsevier Inc. All rights reserved.

Hepatic inflammation caused by dysregulated bile acid synthesis is reversible by butyrate supplementation.

PubMed

Sheng, Lili; Jena, Prasant Kumar; Hu, Ying; Liu, Hui-Xin; Nagar, Nidhi; Kalanetra, Karen M; French, Samuel William; French, Samuel Wheeler; Mills, David A; Wan, Yu-Jui Yvonne

2017-12-01

Dysregulated bile acid (BA) synthesis or reduced farnesoid X receptor (FXR) levels are found in patients having metabolic diseases, autoimmune hepatitis, and liver cirrhosis or cancer. The objective of this study was to establish the relationship between butyrate and dysregulated BA synthesis-induced hepatitis as well as the effect of butyrate in reversing the liver pathology. Wild-type (WT) and FXR knockout (KO) male mice were placed on a control (CD) or western diet (WD) for 15 months. In the presence or absence of butyrate supplementation, feces obtained from 15-month-old WD-fed FXR KO mice, which had severe hepatitis and liver tumors, were transplanted to 7-month-old WD-fed FXR KO for 3 months. Hepatic phenotypes, microbiota profile, and BA composition were analyzed. Butyrate-generating bacteria and colonic butyrate concentration were reduced due to FXR inactivation and further reduced by WD intake. In addition, WD-fed FXR KO male mice had the highest concentration of hepatic β-muricholic acid (β-MCA) and bacteria-generated deoxycholic acid (DCA) accompanied by serious hepatitis. Moreover, dysregulated BA and reduced SCFA signaling co-existed in both human liver cancers and WD-fed FXR KO mice. Microbiota transplantation using butyrate-deficient feces derived from 15-month-old WD-fed FXR KO mice increased hepatic lymphocyte numbers as well as hepatic β-MCA and DCA concentrations. Furthermore, butyrate supplementation reduced hepatic β-MCA as well as DCA and eliminated hepatic lymphocyte infiltration. In conclusion, reduced butyrate contributes to the development of hepatitis in the FXR KO mouse model. In addition, butyrate reverses dysregulated BA synthesis and its associated hepatitis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Impact of Korean pine nut oil on weight gain and immune responses in high-fat diet-induced obese mice

PubMed Central

Park, Soyoung; Lim, Yeseo; Shin, Sunhye

2013-01-01

Korean pine nut oil (PNO) has been reported to have favorable effects on lipid metabolism and appetite control. We investigated whether PNO consumption could influence weight gain, and whether the PNO-induced effect would result in an improvement of immune function in high-fat diet (HFD)-induced obese mice. C57BL/6 mice were fed control diets with 10% energy fat from either PNO or soybean oil (SBO), or HFDs with 45% energy fat from 10% PNO or SBO and 35% lard, 20% PNO or SBO and 25% lard, or 30% PNO or SBO and 15% lard for 12 weeks. The proliferative responses of splenocytes upon stimulation with concanavalin A (Con A) or lipopolysaccharide (LPS), Con A-stimulated production of interleukin (IL)-2 and interferon (IFN)-γ, and LPS-stimulated production of IL-6, IL-1β, and prostaglandin E2 (PGE2) by splenocytes were determined. Consumption of HFDs containing PNO resulted in significantly less weight gain (17% less, P < 0.001), and lower weight gain was mainly due to less white adipose tissue (18% less, P = 0.001). The reduction in weight gain did not result in the overall enhancement in splenocyte proliferation. Overall, PNO consumption resulted in a higher production of IL-1β (P = 0.04). Replacement of SBO with PNO had no effect on the production of IL-2, IFN-γ, IL-6, or PGE2 in mice fed with either the control diets or HFDs. In conclusion, consumption of PNO reduced weight gain in mice fed with HFD, but this effect did not result in the overall improvement in immune responses. PMID:24133613

The prebiotics 3′Sialyllactose and 6′Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut-brain axis

PubMed Central

Tarr, Andrew J.; Galley, Jeffrey D.; Fisher, Sydney; Chichlowski, Maciej; Berg, Brian M.; Bailey, Michael T.

2015-01-01

There are extensive bidirectional interactions between the gut microbiota and the central nervous system (CNS), and studies demonstrate that stressor exposure significantly alters gut microbiota community structure. We tested whether oligosaccharides naturally found in high levels in human milk, which have been reported to impact brain development and enhance the growth of beneficial commensal microbes, would prevent stressor-induced alterations in gut microbial community composition and attenuate stressor-induced anxiety-like behavior. Mice were fed standard laboratory diet, or laboratory diet containing the human milk oligosaccharides 3′Sialyllactose (3′SL) or 6′Sialyllactose (6′SL) for two weeks prior to being exposed to either a social disruption stressor or a non-stressed control condition. Stressor exposure significantly changed the structure of the colonic mucosa-associated microbiota in control mice, as indicated by changes in beta diversity. The stressor resulted in anxiety-like behavior in both the light/dark preference and open field tests in control mice. This effect was associated with a reduction in immature neurons in the dentate gyrus as indicated by doublecortin (DCX) immunostaining. These effects were not evident in mice fed milk oligosaccharides; stressor exposure did not significantly change microbial community structure in mice fed 3′SL or 6′SL. In addition, 3′SL and 6′SL helped maintain normal behavior on tests of anxiety-like behavior and normal numbers of DCX+ immature neurons. These studies indicate that milk oligosaccharides support normal microbial communities and behavioral responses during stressor exposure, potentially through effects on the gut microbiota-brain axis. PMID:26144888

Mitochondrial-related proteomic changes during obesity and fasting in mice are greater in the liver than skeletal muscles.

PubMed

Nesteruk, Monika; Hennig, Ewa E; Mikula, Michal; Karczmarski, Jakub; Dzwonek, Artur; Goryca, Krzysztof; Rubel, Tymon; Paziewska, Agnieszka; Woszczynski, Marek; Ledwon, Joanna; Dabrowska, Michalina; Dadlez, Michal; Ostrowski, Jerzy

2014-03-01

Although mitochondrial dysfunction is implicated in the pathogenesis of obesity, the molecular mechanisms underlying obesity-related metabolic abnormalities are not well established. We performed mitochondrial quantitative proteomic and whole transcriptome analysis followed by functional annotations within liver and skeletal muscles, using fasted and non-fasted 16- and 48-week-old high-fat diet (HFD)-fed and normal diet-fed (control group) wild-type C56BL/6J mice, and hyperphagic ob/ob and db/db obese mice. Our study identified 1,675 and 704 mitochondria-associated proteins with at least two peptides in liver and muscle, respectively. Of these, 221 liver and 44 muscle proteins were differentially expressed (adjusted p values ≤ 0.05) between control and all obese mice, while overnight fasting altered expression of 107 liver and 35 muscle proteins. In the liver, we distinguished a network of 27 proteins exhibiting opposite direction of expression changes in HFD-fed and hyperphagic mice when compared to control. The network centered on cytochromes P450 3a11 (Cyp3a11) and 4a14 (Cyp4a14), and fructose-bisphosphate aldolase B (Aldob) proteins which bridged proteins cluster involved in Metabolism of xenobiotics with proteins engaged in Fatty acid metabolism and PPAR signaling pathways. Functional annotations revealed that most of the hepatic molecular alterations, which characterized both obesity and fasting, related to different aspects of energy metabolism (such as Fatty acid metabolism, Peroxisome, and PPAR signaling); however, only a limited number of functional annotations could be selected from skeletal muscle data sets. Thus, our comprehensive molecular overview revealed that both obesity and fasting states induce more pronounced mitochondrial proteome changes in the liver than in the muscles.

Impaired compensatory beta-cell function and growth in response to high-fat diet in LDL receptor knockout mice

PubMed Central

Oliveira, Ricardo B d; Carvalho, Carolina P d F; Polo, Carla C; Dorighello, Gabriel d G; Boschero, Antônio C; Oliveira, Helena C F d; Collares-Buzato, Carla B

2014-01-01

In this study, we investigated the effect of low density lipoprotein receptor (LDLr) deficiency on gap junctional connexin 36 (Cx36) islet content and on the functional and growth response of pancreatic beta-cells in C57BL/6 mice fed a high-fat (HF) diet. After 60 days on regular or HF diet, the metabolic state and morphometric islet parameters of wild-type (WT) and LDLr−/− mice were assessed. HF diet-fed WT animals became obese and hypercholesterolaemic as well as hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, characterizing them as prediabetic. Also they showed a significant decrease in beta-cell secretory response to glucose. Overall, LDLr−/− mice displayed greater susceptibility to HF diet as judged by their marked cholesterolaemia, intolerance to glucose and pronounced decrease in glucose-stimulated insulin secretion. HF diet induced similarly in WT and LDLr−/− mice, a significant decrease in Cx36 beta-cell content as revealed by immunoblotting. Prediabetic WT mice displayed marked increase in beta-cell mass mainly due to beta-cell hypertrophy/replication. Nevertheless, HF diet-fed LDLr−/− mice showed no significant changes in beta-cell mass, but lower islet–duct association (neogenesis) and higher beta-cell apoptosis index were seen as compared to controls. The higher metabolic susceptibility to HF diet of LDLr−/− mice may be explained by a deficiency in insulin secretory response to glucose associated with lack of compensatory beta-cell expansion. PMID:24853046

Germinated Brown Rice Attenuates Atherosclerosis and Vascular Inflammation in Low-Density Lipoprotein Receptor-Knockout Mice.

PubMed

Zhao, Ruozhi; Ghazzawi, Nora; Wu, Jiansu; Le, Khuong; Li, Chunyang; Moghadasian, Mohammed H; Siow, Yaw L; Apea-Bah, Franklin B; Beta, Trust; Yin, Zhengfeng; Shen, Garry X

2018-05-02

The present study investigates the impact of germinated brown rice (GBR) on atherosclerosis and the underlying mechanism in low-density lipoprotein receptor-knockout (LDLr-KO) mice. The intensity of atherosclerosis in aortas of LDLr-KO mice receiving diet supplemented with 60% GBR (weight/weight) was significantly less than that in mice fed with 60% white rice (WR) or control diet ( p < 0.05); all diets contained 0.06% cholesterol. WR or GBR diet did not significantly alter plasma total or LDL-cholesterol, fecal sterols, or glucose, or the activities of antioxidant enzymes, compared to the control diet. The adhesion of monocytes to aortas from LDLr-KO mice fed with WR diet was significantly more than that from mice receiving the control diet ( p < 0.01). GBR diet decreased monocyte adhesion to aortas compared to WR diet ( p < 0.01). GBR diet also reduced the levels of plasminogen activator inhibitor-1 (PAI-1), monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-α (TNF-α) in plasma, and the abundances of MCP-1, PAI-1, TNF-α, intracellular cell adhesion molecule-1, toll-like receptor-4, PAI-1, LDLr-like protein, and urokinase plasminogen activator and its receptor in aortas or hearts from LDLr-KO mice in comparison to the WR diet ( p < 0.05, 0.01, respectively). The findings suggest that GBR administration attenuated atherosclerosis and vascular inflammation in LDLr-KO mice compared to WR. The anti-atherosclerotic effect of GBR in LDLr-KO mice at least in part results from its anti-inflammatory activity.

Tomatoes protect against development of UV-induced keratinocyte carcinoma via metabolomic alterations.

PubMed

Cooperstone, Jessica L; Tober, Kathleen L; Riedl, Ken M; Teegarden, Matthew D; Cichon, Morgan J; Francis, David M; Schwartz, Steven J; Oberyszyn, Tatiana M

2017-07-11

Prolonged tomato consumption can mitigate ultraviolet (UV) light induced sunburn via unknown mechanisms. Dietary carotenoids distributed to skin are hypothesized to protect skin against UV-induced damage, although other phytochemicals may play a role. We hypothesize that tomato consumption would protect against skin cancer. SKH-1 hairless and immunocompetent mice (n = 180) were fed AIN-93G or AIN-93G + 10% tangerine or red tomato powder for 35 weeks. From weeks 11-20, mice (n = 120) were exposed to 2240 J/m 2 UV-B light, 3x/week, and tumors were tracked weekly. Control mice were fed the same diets but not exposed to UV. Tumor number was significantly lower in male mice consuming red tomato diets (1.73 ± 0.50, P = 0.015) or pooled tomato diets (2.03 ± 0.45, P = 0.017) compared to controls (4.04 ± 0.65). Carotenoid levels in plasma and skin were quantitated, with total lycopene higher in skin of tangerine fed animals despite a lower dose. Metabolomic analyses elucidated compounds derived from tomato glycoalkaloids (including tomatidine and hydroxylated-tomatidine) as significantly different metabolites in skin after tomato exposure. Here, we describe that tomato consumption can modulate risk for keratinocyte carcinomas; however, the role of the newly identified specific phytochemicals possibly responsible for this action require further investigation.

A Possible Link between Food and Mood: Dietary Impact on Gut Microbiota and Behavior in BALB/c Mice

PubMed Central

Pyndt Jørgensen, Bettina; Hansen, Julie Torpe; Krych, Lukasz; Larsen, Christian; Klein, Anders Bue; Nielsen, Dennis Sandris; Josefsen, Knud; Hansen, Axel Kornerup; Sørensen, Dorte Bratbo

2014-01-01

Major depressive disorder is a debilitating disease in the Western World. A western diet high in saturated fat and refined sugar seems to play an important part in disease development. Therefore, this study is aimed at investigating whether saturated fat or sucrose predisposes mice to develop behavioral symptoms which can be interpreted as depression-like, and the possible influence of the gut microbiota (GM) in this. Fourty-two mice were randomly assigned to one of three experimental diets, a high-fat, a high-sucrose or a control diet for thirteen weeks. Mice on high-fat diet gained more weight (p = 0.00009), displayed significantly less burrowing behavior than the control mice (p = 0.034), and showed decreased memory in the Morris water maze test compared to mice on high-sucrose diet (p = 0.031). Mice on high-sucrose diet burrowed less goal-oriented, showed greater latency to first bout of immobility in the forced swim test when compared to control mice (p = 0.039) and high-fat fed mice (p = 0.013), and displayed less anxiety than mice on high-fat diet in the triple test (p = 0.009). Behavioral changes were accompanied by a significant change in GM composition of mice fed a high-fat diet, while no difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. A series of correlations was found between GM, behavior, BDNF and inflammatory mediators. In conclusion, the study shows that dietary fat and sucrose affect behavior, sometimes in opposite directions, and suggests a possible association between GM and behavior. PMID:25133574

A possible link between food and mood: dietary impact on gut microbiota and behavior in BALB/c mice.

PubMed

Pyndt Jørgensen, Bettina; Hansen, Julie Torpe; Krych, Lukasz; Larsen, Christian; Klein, Anders Bue; Nielsen, Dennis Sandris; Josefsen, Knud; Hansen, Axel Kornerup; Sørensen, Dorte Bratbo

2014-01-01

Major depressive disorder is a debilitating disease in the Western World. A western diet high in saturated fat and refined sugar seems to play an important part in disease development. Therefore, this study is aimed at investigating whether saturated fat or sucrose predisposes mice to develop behavioral symptoms which can be interpreted as depression-like, and the possible influence of the gut microbiota (GM) in this. Fourty-two mice were randomly assigned to one of three experimental diets, a high-fat, a high-sucrose or a control diet for thirteen weeks. Mice on high-fat diet gained more weight (p = 0.00009), displayed significantly less burrowing behavior than the control mice (p = 0.034), and showed decreased memory in the Morris water maze test compared to mice on high-sucrose diet (p = 0.031). Mice on high-sucrose diet burrowed less goal-oriented, showed greater latency to first bout of immobility in the forced swim test when compared to control mice (p = 0.039) and high-fat fed mice (p = 0.013), and displayed less anxiety than mice on high-fat diet in the triple test (p = 0.009). Behavioral changes were accompanied by a significant change in GM composition of mice fed a high-fat diet, while no difference between diet groups was observed for sucrose preferences, LPS, cholesterol, HbA1c, BDNF and the cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12(p70), IL-17 and TNF-α. A series of correlations was found between GM, behavior, BDNF and inflammatory mediators. In conclusion, the study shows that dietary fat and sucrose affect behavior, sometimes in opposite directions, and suggests a possible association between GM and behavior.

Role of insulin signaling impairment, adiponectin and dyslipidemia in peripheral and central neuropathy in mice.

PubMed

Anderson, Nicholas J; King, Matthew R; Delbruck, Lina; Jolivalt, Corinne G

2014-06-01

One of the tissues or organs affected by diabetes is the nervous system, predominantly the peripheral system (peripheral polyneuropathy and/or painful peripheral neuropathy) but also the central system with impaired learning, memory and mental flexibility. The aim of this study was to test the hypothesis that the pre-diabetic or diabetic condition caused by a high-fat diet (HFD) can damage both the peripheral and central nervous systems. Groups of C57BL6 and Swiss Webster mice were fed a diet containing 60% fat for 8 months and compared to control and streptozotocin (STZ)-induced diabetic groups that were fed a standard diet containing 10% fat. Aspects of peripheral nerve function (conduction velocity, thermal sensitivity) and central nervous system function (learning ability, memory) were measured at assorted times during the study. Both strains of mice on HFD developed impaired glucose tolerance, indicative of insulin resistance, but only the C57BL6 mice showed statistically significant hyperglycemia. STZ-diabetic C57BL6 mice developed learning deficits in the Barnes maze after 8 weeks of diabetes, whereas neither C57BL6 nor Swiss Webster mice fed a HFD showed signs of defects at that time point. By 6 months on HFD, Swiss Webster mice developed learning and memory deficits in the Barnes maze test, whereas their peripheral nervous system remained normal. In contrast, C57BL6 mice fed the HFD developed peripheral nerve dysfunction, as indicated by nerve conduction slowing and thermal hyperalgesia, but showed normal learning and memory functions. Our data indicate that STZ-induced diabetes or a HFD can damage both peripheral and central nervous systems, but learning deficits develop more rapidly in insulin-deficient than in insulin-resistant conditions and only in Swiss Webster mice. In addition to insulin impairment, dyslipidemia or adiponectinemia might determine the neuropathy phenotype. © 2014. Published by The Company of Biologists Ltd.

Activation of Kupffer Cells Is Associated with a Specific Dysbiosis Induced by Fructose or High Fat Diet in Mice

PubMed Central

Ferrere, Gladys; Leroux, Anne; Wrzosek, Laura; Puchois, Virginie; Gaudin, Françoise; Ciocan, Dragos; Renoud, Marie-Laure; Naveau, Sylvie; Perlemuter, Gabriel; Cassard, Anne-Marie

2016-01-01

The increase consumption of fructose in diet is associated with liver inflammation. As a specific fructan substrate, fructose may modify the gut microbiota which is involved in obesity-induced liver disease. Here, we aimed to assess whether fructose-induced liver damage was associated with a specific dysbiosis, especially in mice fed a high fat diet (HFD). To this end, four groups of mice were fed with normal and HFD added or not with fructose. Body weight and glucose sensitivity, liver inflammation, dysbiosis and the phenotype of Kupffer cells were determined after 16 weeks of diet. Food intake was increased in the two groups of mice fed with the HFD. Mice fed with HFD and fructose showed a higher infiltration of lymphocytes into the liver and a lower inflammatory profile of Kupffer cells than mice fed with the HFD without fructose. The dysbiosis associated with diets showed that fructose specifically prevented the decrease of Mouse intestinal bacteria in HFD fed mice and increased Erysipelotrichi in mice fed with fructose, independently of the amount of fat. In conclusion, fructose, used as a sweetener, induced a dysbiosis which is different in presence of fat in the diet. Consequently, the activation of Kupffer cells involved in mice model of HFD-induced liver inflammation was not observed in an HFD/fructose combined diet. These data highlight that the complexity of diet composition could highly impact the development of liver lesions during obesity. Specific dysbiosis associated with the diet could explain that the progressions of liver damage are different. PMID:26731543

The Zinc Transporter Zip5 (Slc39a5) Regulates Intestinal Zinc Excretion and Protects the Pancreas against Zinc Toxicity

PubMed Central

Geiser, Jim; De Lisle, Robert C.; Andrews, Glen K.

2013-01-01

Background ZIP5 localizes to the baso-lateral membranes of intestinal enterocytes and pancreatic acinar cells and is internalized and degraded coordinately in these cell-types during periods of dietary zinc deficiency. These cell-types are thought to control zinc excretion from the body. The baso-lateral localization and zinc-regulation of ZIP5 in these cells are unique among the 14 members of the Slc39a family and suggest that ZIP5 plays a role in zinc excretion. Methods/Principal Findings We created mice with floxed Zip5 genes and deleted this gene in the entire mouse or specifically in enterocytes or acinar cells and then examined the effects on zinc homeostasis. We found that ZIP5 is not essential for growth and viability but total knockout of ZIP5 led to increased zinc in the liver in mice fed a zinc-adequate (ZnA) diet but impaired accumulation of pancreatic zinc in mice fed a zinc-excess (ZnE) diet. Loss-of-function of enterocyte ZIP5, in contrast, led to increased pancreatic zinc in mice fed a ZnA diet and increased abundance of intestinal Zip4 mRNA. Finally, loss-of-function of acinar cell ZIP5 modestly reduced pancreatic zinc in mice fed a ZnA diet but did not impair zinc uptake as measured by the rapid accumulation of 67zinc. Retention of pancreatic 67zinc was impaired in these mice but the absence of pancreatic ZIP5 sensitized them to zinc-induced pancreatitis and exacerbated the formation of large cytoplasmic vacuoles containing secretory protein in acinar cells. Conclusions These studies demonstrate that ZIP5 participates in the control of zinc excretion in mice. Specifically, they reveal a paramount function of intestinal ZIP5 in zinc excretion but suggest a role for pancreatic ZIP5 in zinc accumulation/retention in acinar cells. ZIP5 functions in acinar cells to protect against zinc-induced acute pancreatitis and attenuate the process of zymophagy. This suggests that it may play a role in autophagy. PMID:24303081

Insights from engraftable immunodeficient mouse models of hyperinsulinaemia.

PubMed

Maugham, Michelle L; Thomas, Patrick B; Crisp, Gabrielle J; Philp, Lisa K; Shah, Esha T; Herington, Adrian C; Chen, Chen; Gregory, Laura S; Nelson, Colleen C; Seim, Inge; Jeffery, Penny L; Chopin, Lisa K

2017-03-28

Hyperinsulinaemia, obesity and dyslipidaemia are independent and collective risk factors for many cancers. Here, the long-term effects of a 23% Western high-fat diet (HFD) in two immunodeficient mouse strains (NOD/SCID and Rag1 -/- ) suitable for engraftment with human-derived tissue xenografts, and the effect of diet-induced hyperinsulinaemia on human prostate cancer cell line xenograft growth, were investigated. Rag1 -/- and NOD/SCID HFD-fed mice demonstrated diet-induced impairments in glucose tolerance at 16 and 23 weeks post weaning. Rag1 -/- mice developed significantly higher fasting insulin levels (2.16 ± 1.01 ng/ml, P = 0.01) and increased insulin resistance (6.70 ± 1.68 HOMA-IR, P = 0.01) compared to low-fat chow-fed mice (0.71 ± 0.12 ng/ml and 2.91 ± 0.42 HOMA-IR). This was not observed in the NOD/SCID strain. Hepatic steatosis was more extensive in Rag1 -/- HFD-fed mice compared to NOD/SCID mice. Intramyocellular lipid storage was increased in Rag1 -/- HFD-fed mice, but not in NOD/SCID mice. In Rag1 -/- HFD-fed mice, LNCaP xenograft tumours grew more rapidly compared to low-fat chow-fed mice. This is the first characterisation of the metabolic effects of long-term Western HFD in two mouse strains suitable for xenograft studies. We conclude that Rag1 -/- mice are an appropriate and novel xenograft model for studying the relationship between cancer and hyperinsulinaemia.

Cardiac mTOR rescues the detrimental effects of diet-induced obesity in the heart after ischemia-reperfusion.

PubMed

Aoyagi, Toshinori; Higa, Jason K; Aoyagi, Hiroko; Yorichika, Naaiko; Shimada, Briana K; Matsui, Takashi

2015-06-15

Diet-induced obesity deteriorates the recovery of cardiac function after ischemia-reperfusion (I/R) injury. While mechanistic target of rapamycin (mTOR) is a key mediator of energy metabolism, the effects of cardiac mTOR in ischemic injury under metabolic syndrome remains undefined. Using cardiac-specific transgenic mice overexpressing mTOR (mTOR-Tg mice), we studied the effect of mTOR on cardiac function in both ex vivo and in vivo models of I/R injury in high-fat diet (HFD)-induced obese mice. mTOR-Tg and wild-type (WT) mice were fed a HFD (60% fat by calories) for 12 wk. Glucose intolerance and insulin resistance induced by the HFD were comparable between WT HFD-fed and mTOR-Tg HFD-fed mice. Functional recovery after I/R in the ex vivo Langendorff perfusion model was significantly lower in HFD-fed mice than normal chow diet-fed mice. mTOR-Tg mice demonstrated better cardiac function recovery and had less of the necrotic markers creatine kinase and lactate dehydrogenase in both feeding conditions. Additionally, mTOR overexpression suppressed expression of proinflammatory cytokines, including IL-6 and TNF-α, in both feeding conditions after I/R injury. In vivo I/R models showed that at 1 wk after I/R, HFD-fed mice exhibited worse cardiac function and larger myocardial scarring along myofibers compared with normal chow diet-fed mice. In both feeding conditions, mTOR overexpression preserved cardiac function and prevented myocardial scarring. These findings suggest that cardiac mTOR overexpression is sufficient to prevent the detrimental effects of diet-induced obesity on the heart after I/R, by reducing cardiac dysfunction and myocardial scarring. Copyright © 2015 the American Physiological Society.

Post-sensitization administration of non-digestible oligosaccharides and Bifidobacterium breve M-16V reduces allergic symptoms in mice.

PubMed

van Esch, Betty C A M; Abbring, Suzanne; Diks, Mara A P; Dingjan, Gemma M; Harthoorn, Lucien F; Vos, A Paul; Garssen, Johan

2016-06-01

To support dietary management of severe cow's milk allergic infants, a synbiotic mixture of non-digestible oligosaccharides and Bifidobacterium breve M-16V ( B. breve ) was designed from source materials that are completely cow's milk-free. It was investigated whether this specific synbiotic concept can reduce an established food allergic response in a research model for hen's egg allergy. Mice were orally sensitized once a week for 5 weeks to ovalbumin (OVA) using cholera toxin (CT) as an adjuvant. Non-sensitized mice received CT in PBS only. Sensitized mice were fed a control diet or a diet enriched with short-chain- (scFOS) and long-chain fructo-oligosaccharides (lcFOS), B. breve or scFOSlcFOS +  B. breve for 3 weeks starting after the last sensitization. Non-sensitized mice received the control diet. Anaphylactic shock symptoms, acute allergic skin responses and serum specific IgE, mMCP-1 and galectin-9 were measured upon OVA challenge. Activated Th2-, Th1-cells and regulatory T-cells were quantified in spleen and mesenteric lymph nodes (MLN) and cytokine profiles were analyzed. Short chain fatty acids (SCFA) were measured in ceacal samples. The acute allergic skin response was reduced in mice fed the scFOSlcFOS +  B. breve diet compared to mice fed any of the other diets. A reduction in mast cell degranulation (mMCP-1) and anaphylactic shock symptoms was also observed in these mice. Unstimulated splenocyte cultures produced increased levels of IL10 and IFNg in mice fed the scFOSlcFOS +  B. breve diet. Correspondingly, increased percentages of activated Th1 cells were observed in the spleen. Allergen-specific re-stimulation of splenocytes showed a decrease in IL5 production. In summary; post-sensitization administration of scFOSlcFOS +  B. breve was effective in reducing allergic symptoms after allergen challenge. These effects coincided with changes in regulatory and effector T-cell subsets and increases in the SCFA propionic acid. These results suggest immune modulatory benefits of dietary intervention with a unique combination of scFOSlcFOS +  B. breve in established food allergy. Whether these effects translate to human applications is subject for ongoing clinical studies.

Urinary Loss of Tricarboxylic Acid Cycle Intermediates As Revealed by Metabolomics Studies: An Underlying Mechanism to Reduce Lipid Accretion by Whey Protein Ingestion?

PubMed Central

2015-01-01

Whey protein intake is associated with the modulation of energy metabolism and altered body composition both in human subjects and in animals, but the underlying mechanisms are not yet elucidated. We fed obesity-prone C57BL/6J mice high-fat diets with either casein (HF casein) or whey (HF whey) for 6 weeks. At equal energy intake and apparent fat and nitrogen digestibility, mice fed HF whey stored less energy as lipids, evident both as lower white adipose tissue mass and as reduced liver lipids, compared with HF-casein-fed mice. Explorative analyses of 48 h urine, both by 1H NMR and LC–MS metabolomic platforms, demonstrated higher urinary excretion of tricarboxylic acid (TCA) cycle intermediates citric acid and succinic acid (identified by both platforms), and cis-aconitic acid and isocitric acid (identified by LC–MS platform) in the HF whey, relative to in the HF-casein-fed mice. Targeted LC–MS analyses revealed higher citric acid and cis-aconitic acid concentrations in fed state plasma, but not in liver of HF-whey-fed mice. We propose that enhanced urinary loss of TCA cycle metabolites drain available substrates for anabolic processes, such as lipogenesis, thereby leading to reduced lipid accretion in HF-whey-fed compared to HF-casein-fed mice. PMID:24702026

Immunologic and metabolic effects of high-refined carbohydrate-containing diet in food allergic mice.

PubMed

Yamada, Letícia Tamie Paiva; de Oliveira, Marina Chaves; Batista, Nathália Vieira; Fonseca, Roberta Cristelli; Pereira, Rafaela Vaz Sousa; Perez, Denise Alves; Teixeira, Mauro Martins; Cara, Denise Carmona; Ferreira, Adaliene Versiani Matos

2016-02-01

Allergic mice show a reduction in body weight and adiposity with a higher inflammatory response in the adipose tissue similar to obese fat tissue. This study aimed to evaluate whether the low-grade inflammatory milieu of mice with diet-induced mild obesity interferes with the allergic response induced by ovalbumin (OVA). BALB/c mice were divided into four groups: 1) non-allergic (OVA-) mice fed chow diet, 2) allergic (OVA+) mice fed chow diet, 3) OVA- mice fed high-refined carbohydrate-containing (HC) diet, and 4) OVA+ mice fed HC diet. After 5 wk, allergic groups were sensitized with OVA and received a booster 14 d later. All groups received an oral OVA challenge 7 d after the booster. Allergic groups showed increased serum levels of total IgE, anti-OVA IgE, and IgG1; a high disease activity index score; aversion to OVA; and increased intestinal eosinophil infiltration. Non-allergic mild-obese mice also showed aversion to OVA and an increased number of eosinophils in the proximal jejunum. After the allergic challenge, OVA+ mice fed chow diet showed weight loss and lower adiposity in several adipose tissue depots. OVA+ mice fed HC diet showed a loss of fat mass only in the mesenteric adipose tissue. Furthermore, increased levels of TNF, IL-6, and IL-10 were observed in this tissue. Our data show that mild-obese allergic mice do not present severe pathologic features of food allergy similar to those exhibited by lean allergic mice. Mild obesity promoted by HC diet ingestion causes important intestinal disorders that appear to modulate the inflammatory response during the antigen challenge. Copyright © 2016 Elsevier Inc. All rights reserved.

Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet‐induced obesity

PubMed Central

Zlotnikov, Nataliya; Javid, Ashkan; Ahmed, Mijhgan; Eshghi, Azad; Tang, Tian Tian; Arya, Anoop; Bansal, Anil; Matar, Fatima; Parikh, Maitry; Ebady, Rhodaba; Koh, Adeline; Gupta, Nupur; Song, Peng; Zhang, Yang; Newbigging, Susan; Wormser, Gary P.; Schwartz, Ira; Inman, Robert; Glogauer, Michael

2016-01-01

Abstract Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high‐fat diet‐induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil‐ and macrophage‐based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi‐infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high‐fat diet, toll‐like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow‐derived macrophages from obese, B. burgdorferi‐infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice. PMID:27794208

Infection with the Lyme disease pathogen suppresses innate immunity in mice with diet-induced obesity.

PubMed

Zlotnikov, Nataliya; Javid, Ashkan; Ahmed, Mijhgan; Eshghi, Azad; Tang, Tian Tian; Arya, Anoop; Bansal, Anil; Matar, Fatima; Parikh, Maitry; Ebady, Rhodaba; Koh, Adeline; Gupta, Nupur; Song, Peng; Zhang, Yang; Newbigging, Susan; Wormser, Gary P; Schwartz, Ira; Inman, Robert; Glogauer, Michael; Moriarty, Tara J

2017-05-01

Obesity is a major global public health concern. Immune responses implicated in obesity also control certain infections. We investigated the effects of high-fat diet-induced obesity (DIO) on infection with the Lyme disease bacterium Borrelia burgdorferi in mice. DIO was associated with systemic suppression of neutrophil- and macrophage-based innate immune responses. These included bacterial uptake and cytokine production, and systemic, progressive impairment of bacterial clearance, and increased carditis severity. B. burgdorferi-infected mice fed normal diet also gained weight at the same rate as uninfected mice fed high-fat diet, toll-like receptor 4 deficiency rescued bacterial clearance defects, which greater in female than male mice, and killing of an unrelated bacterium (Escherichia coli) by bone marrow-derived macrophages from obese, B. burgdorferi-infected mice was also affected. Importantly, innate immune suppression increased with infection duration and depended on cooperative and synergistic interactions between DIO and B. burgdorferi infection. Thus, obesity and B. burgdorferi infection cooperatively and progressively suppressed innate immunity in mice. © 2016 The Authors Cellular Microbiology Published by John Wiley & Sons Ltd.

Deficiency of eNOS exacerbates early-stage NAFLD pathogenesis by changing the fat distribution.

PubMed

Nozaki, Yuichi; Fujita, Koji; Wada, Koichiro; Yoneda, Masato; Shinohara, Yoshiyasu; Imajo, Kento; Ogawa, Yuji; Kessoku, Takaomi; Nakamuta, Makoto; Saito, Satoru; Masaki, Naohiko; Nagashima, Yoji; Terauchi, Yasuo; Nakajima, Atsushi

2015-12-17

Although many factors and molecules that are closely associated with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) have been reported, the role of endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) in the pathogenesis of NAFLD/NASH remains unclear. We therefore investigated the role of eNOS-derived NO in NAFLD pathogenesis using systemic eNOS-knockout mice fed a high-fat diet. eNOS-knockout and wild-type mice were fed a basal diet or a high-fat diet for 12 weeks. Lipid accumulation and inflammation were evaluated in the liver, and various factors that are closely associated with NAFLD/NASH and hepatic tissue blood flow were analyzed. Lipid accumulation and inflammation were more extensive in the liver and lipid accumulation was less extensive in the visceral fat tissue in eNOS-knockout mice, compared with wild-type mice, after 12 weeks of being fed a high-fat diet. While systemic insulin resistance was comparable between the eNOS-knockout and wild-type mice fed a high-fat diet, hepatic tissue blood flow was significantly suppressed in the eNOS-knockout mice, compared with the wild-type mice, in mice fed a high-fat diet. The microsomal triglyceride transfer protein activity was down-regulated in eNOS-knockout mice, compared with wild-type mice, in mice fed a high-fat diet. A deficiency of eNOS-derived NO may exacerbate the early-stage of NASH pathogenesis by changing the fat distribution in a mouse model via the regulation of hepatic tissue blood flow.

Psychosocial stress induces hyperphagia and exacerbates diet-induced insulin resistance and the manifestations of the Metabolic Syndrome.

PubMed

Sanghez, Valentina; Razzoli, Maria; Carobbio, Stefania; Campbell, Mark; McCallum, Jacob; Cero, Cheryl; Ceresini, Graziano; Cabassi, Aderville; Govoni, Paolo; Franceschini, Paolo; de Santis, Valentina; Gurney, Allison; Ninkovic, Ivana; Parmigiani, Stefano; Palanza, Paola; Vidal-Puig, Antonio; Bartolomucci, Alessandro

2013-12-01

Stress and hypercaloric food are recognized risk factors for obesity, Metabolic Syndrome (MetS) and Type 2 Diabetes (T2D). Given the complexity of these metabolic processes and the unavailability of animal models, there is poor understanding of their underlying mechanisms. We established a model of chronic psychosocial stress in which subordinate mice are vulnerable to weight gain while dominant mice are resilient. Subordinate mice fed a standard diet showed marked hyperphagia, high leptin, low adiponectin, and dyslipidemia. Despite these molecular signatures of MetS and T2D, subordinate mice fed a standard diet were still euglycemic. We hypothesized that stress predisposes subordinate mice to develop T2D when synergizing with other risk factors. High fat diet aggravated dyslipidemia and the MetS thus causing a pre-diabetes-like state in subordinate mice. Contrary to subordinates, dominant mice were fully protected from stress-induced metabolic disorders when fed both a standard- and a high fat-diet. Dominant mice showed a hyperphagic response that was similar to subordinate but, unlike subordinates, showed a significant increase in VO2, VCO2, and respiratory exchange ratio when compared to control mice. Overall, we demonstrated a robust stress- and social status-dependent effect on the development of MetS and T2D and provided insights on the physiological mechanisms. Our results are reminiscent of the effect of the individual socioeconomic status on human health and provide an animal model to study the underlying molecular mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

MicroRNA profiles following metformin treatment in a mouse model of non-alcoholic steatohepatitis

PubMed Central

KATSURA, AKIKO; MORISHITA, ASAHIRO; IWAMA, HISAKAZU; TANI, JOJI; SAKAMOTO, TEPPEI; TATSUTA, MIWA; TOYOTA, YUKA; FUJITA, KOJI; KATO, KIYOHITO; MAEDA, EMIKO; NOMURA, TAKAKO; MIYOSHI, HISAAKI; YONEYAMA, HIROHITO; HIMOTO, TAKASHI; FUJIWARA, SHINTARO; KOBARA, HIDEKI; MORI, HIROHITO; NIKI, TOSHIRO; ONO, MASAFUMI; HIRASHIMA, MITSUOMI; MASAKI, TSUTOMU

2015-01-01

Non-alcoholic steatohepatitis (NASH) is one of the most common causes of chronic liver disease and is considered to be a causative factor of cryptogenic cirrhosis and hepatocellular carcinoma. microRNAs (miRNAs) are small non-coding RNAs that negatively regulate messenger RNA (mRNA). Recently, it was demonstrated that the aberrant expression of certain miRNAs plays a pivotal role in liver disease. The aim of the present study was to evaluate changes in miRNA profiles associated with metformin treatment in a NASH model. Eight-week-old male mice were fed a methionine- and choline-deficient (MCD) diet alone or with 0.08% metformin for 15 weeks. Metformin significantly downregulated the level of plasma transaminases and attenuated hepatic steatosis and liver fibrosis. The expression of miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p was enhanced among the 71 upregulated miRNAs, and the expression of miRNA-122, miRNA-194, miRNA-101b and miRNA-705 was decreased among 60 downregulated miRNAs in the liver of MCD-fed mice when compared with control mice. Of note, miRNA profiles were altered following treatment with metformin in MCD-fed mice. miRNA-376a, miRNA-127, miRNA-34a, miRNA-300 and miRNA-342-3p were down-regulated, but miRNA-122, miRNA-194, miRNA-101b and miRNA-705 were significantly upregulated in MCD-fed mice treated with metformin. miRNA profiles were altered in MCD-fed mice and metformin attenuated this effect on miRNA expression. Therefore, miRNA profiles are a potential tool that may be utilized to clarify the mechanism behind the metformin-induced improvement of hepatic steatosis and liver fibrosis. Furthermore, identification of targetable miRNAs may be used as a novel therapy in human NASH. PMID:25672270

Immunotoxicological Evaluation of Corn Genetically Modified with Bacillus thuringiensis Cry1Ah Gene by a 30-Day Feeding Study in BALB/c Mice

PubMed Central

Song, Yan; Liang, Chunlai; Wang, Wei; Fang, Jin; Sun, Nana; Jia, Xudong; Li, Ning

2014-01-01

This study was to investigate the immunotoxicological potential of corn genetically modified (GM) with Bacillus thuringiensis (Bt) Cry1Ah gene in BALB/c mice. Female BALB/c mice were randomly assigned to one of the four groups: the negative control group, the parental corn group, the GM corn group and the positive control group with 10 mice per group. Mice in the GM corn group and the parental corn group were fed with diets containing 70% corresponding corn for 30 days. Mice in the negative control group and the positive control group were fed with AIN93G diet, administered with saline or 200 mg/kg of cyclophosphamide (CY) via intraperitoneal injection 24 h before the termination of the study, respectively. At the end of the study, the immunotoxicological effects of the GM corn were evaluated through immunopathology parameters including body and organ weights, hematology and clinical chemistry parameters, histological examination, peripheral blood lymphocytes phenotype; humoral immunity including antibody plaque-forming cell, serum immunoglobulin, cytokine and half hemolysis value; cellular immunity such as mitogen-induced splenocyte proliferation, cytotoxic T-lymphocyte reaction, delayed-type hypersensitivity reaction; non-specific immunity including phagocytic activities of phagocytes, natural killer cell activity. A single dose of cyclophosphamide (200 mg/kg bw) was found to have significant adverse effects on immunopathology, cellular immunity, and humoral immunity in mice. The corn genetically modified with Bt Cry1Ah gene is considered consistent with the parental corn in terms of immunopathology, humoral immunity, cellular immunity and non-specific immunity. No adverse immunotoxicological effects of GM corn with Bt Cry1Ah gene were found when feeding mice for 30 days. PMID:24520311

Trans-10, cis-12-conjugated linoleic acid alters hepatic gene expression in a polygenic obese line of mice displaying hepatic lipidosis.

PubMed

Ashwell, Melissa S; Ceddia, Ryan P; House, Ralph L; Cassady, Joseph P; Eisen, Eugene J; Eling, Thomas E; Collins, Jennifer B; Grissom, Sherry F; Odle, Jack

2010-09-01

The trans-10, cis-12 isomer of conjugated linoleic acid (CLA) causes a rapid reduction of body and adipose mass in mice. In addition to changes in adipose tissue, numerous studies have reported alterations in hepatic lipid metabolism. Livers of CLA-fed mice gain mass, partly due to lipid accumulation; however, the precise molecular mechanisms are unknown. To elucidate these mechanisms, we examined fatty acid composition and gene expression profiles of livers from a polygenic obese line of mice fed 1% trans-10, cis-12-CLA for 14 days. Analysis of gene expression data led to the identification of 1393 genes differentially expressed in the liver of CLA-fed male mice at a nominal P value of .01, and 775 were considered significant using a false discovery rate (FDR) threshold of .05. While surprisingly few genes in lipid metabolism were impacted, pathway analysis found that protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) pathways signaling pathways were affected by CLA treatment and 98 of the 775 genes were found to be regulated by hepatocyte nuclear factor 4alpha, a transcription factor important in controlling liver metabolic status. Copyright 2010 Elsevier Inc. All rights reserved.

Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition

PubMed Central

May, Thaddaeus; Klatt, Kevin C.; Smith, Jacob; Castro, Eumenia; Manary, Mark; Caudill, Marie A.; Jahoor, Farook

2018-01-01

Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice (n = 9) for 6 or 13 days. An additional group of mice (n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice (n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor. PMID:29786674

Choline Supplementation Prevents a Hallmark Disturbance of Kwashiorkor in Weanling Mice Fed a Maize Vegetable Diet: Hepatic Steatosis of Undernutrition.

PubMed

May, Thaddaeus; Klatt, Kevin C; Smith, Jacob; Castro, Eumenia; Manary, Mark; Caudill, Marie A; Jahoor, Farook; Fiorotto, Marta L

2018-05-22

Hepatic steatosis is a hallmark feature of kwashiorkor malnutrition. However, the pathogenesis of hepatic steatosis in kwashiorkor is uncertain. Our objective was to develop a mouse model of childhood undernutrition in order to test the hypothesis that feeding a maize vegetable diet (MVD), like that consumed by children at risk for kwashiorkor, will cause hepatic steatosis which is prevented by supplementation with choline. A MVD was developed with locally sourced organic ingredients, and fed to weanling mice ( n = 9) for 6 or 13 days. An additional group of mice ( n = 4) were fed a choline supplemented MVD. Weight, body composition, and liver changes were compared to control mice ( n = 10) at the beginning and end of the study. The MVD resulted in reduced weight gain and hepatic steatosis. Choline supplementation prevented hepatic steatosis and was associated with increased hepatic concentrations of the methyl donor betaine. Our findings show that (1) feeding a MVD to weanling mice rapidly induces hepatic steatosis, which is a hallmark disturbance of kwashiorkor; and that (2) hepatic steatosis associated with feeding a MVD is prevented by choline supplementation. These findings support the concept that insufficient choline intake may contribute to the pathogenesis of hepatic steatosis in kwashiorkor.

Dietary n-3 LCPUFA from fish oil but not α-linolenic acid-derived LCPUFA confers atheroprotection in mice[S

PubMed Central

Degirolamo, Chiara; Kelley, Kathryn L.; Wilson, Martha D.; Rudel, Lawrence L.

2010-01-01

The atheroprotective potential of n-3 α-linolenic acid (ALA) has not yet been fully determined, even in murine models of atherosclerosis. We tested whether ALA-derived, n-3 long chain polyunsaturated fatty acids (LCPUFA) could offer atheroprotection in a dose-dependent manner. Apolipoprotein B (ApoB)100/100LDLr−/− mice were fed with diets containing two levels of ALA from flaxseed oil for 16 weeks. Fish oil- and cis-monounsaturated-fat-enriched diets were used as positive and negative controls, respectively. The mice fed cis-monounsaturated fat and ALA-enriched diets exhibited equivalent plasma total cholesterol (TPC) and LDL-cholesterol (LDL-c) levels; only mice fed the fish-oil diet had lower TPC and LDL-c concentrations. Plasma LDL-CE fatty acid composition analysis showed that ALA-enriched diets lowered the percentage of atherogenic cholesteryl oleate compared with cis-monounsaturated-fat diet (44% versus 55.6%) but not as efficiently as the fish-oil diet (32.4%). Although both ALA and fish-oil diets equally enriched hepatic phospholipids with eicosapentaenoic acid (EPA) and ALA-enriched diets lowered hepatic cholesteryl ester (CE) levels compared with cis-monounsaturated-fat diet, only fish oil strongly protected from atherosclerosis. These outcomes indicate that dietary n-3 LCPUFA from fish oil and n-3 LCPUFA (mostly EPA) synthesized endogenously from ALA were not equally atheroprotective in these mice. PMID:20154006

Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet-induced obesity.

PubMed

de Melo, T S; Lima, P R; Carvalho, K M M B; Fontenele, T M; Solon, F R N; Tomé, A R; de Lemos, T L G; da Cruz Fonseca, S G; Santos, F A; Rao, V S; de Queiroz, M G R

2017-01-05

Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20-25 g (n=6-8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses.

Ferulic acid lowers body weight and visceral fat accumulation via modulation of enzymatic, hormonal and inflammatory changes in a mouse model of high-fat diet-induced obesity

PubMed Central

de Melo, T.S.; Lima, P.R.; Carvalho, K.M.M.B.; Fontenele, T.M.; Solon, F.R.N.; Tomé, A.R.; de Lemos, T.L.G.; da Cruz Fonseca, S.G.; Santos, F.A.; Rao, V.S.; de Queiroz, M.G.R.

2017-01-01

Previous studies have reported on the glucose and lipid-lowering effects of ferulic acid (FA) but its anti-obesity potential has not yet been firmly established. This study investigated the possible anti-obesitogenic effects of FA in mice fed a high-fat diet (HFD) for 15 weeks. To assess the antiobesity potential of FA, 32 male Swiss mice, weighing 20–25 g (n=6–8 per group) were fed a normal diet (ND) or HFD, treated orally or not with either FA (10 mg/kg) or sibutramine (10 mg/kg) for 15 weeks and at the end of this period, the body weights of animals, visceral fat accumulation, plasma levels of glucose and insulin hormone, amylase and lipase activities, the satiety hormones ghrelin and leptin, and tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCH-1) were analyzed. Results revealed that FA could effectively suppress the HFD-associated increase in visceral fat accumulation, adipocyte size and body weight gain, similar to sibutramine, the positive control. FA also significantly (P<0.05) decreased the HFD-induced elevations in serum lipid profiles, amylase and lipase activities, and the levels of blood glucose and insulin hormone. The markedly elevated leptin and decreased ghrelin levels seen in HFD-fed control mice were significantly (P<0.05) reversed by FA treatment, almost reaching the values seen in ND-fed mice. Furthermore, FA demonstrated significant (P<0.05) inhibition of serum levels of inflammatory mediators TNF-α, and MCH-1. These results suggest that FA could be beneficial in lowering the risk of HFD-induced obesity via modulation of enzymatic, hormonal and inflammatory responses. PMID:28076453

Green tea diet decreases PCB 126-induced oxidative stress in mice by upregulating antioxidant enzymes

PubMed Central

Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu; Murphy, Margaret O; Eske, Katryn E; Sunkara, Manjula; Morris, Andrew J; Hennig, Bernhard

2013-01-01

Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the upregulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-Isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited five-fold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both mRNA and protein analyses, and it was determined that many genes transcriptionally controlled by AhR and Nrf2 proteins were upregulated in PCB-exposed mice fed the green tea supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126 which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants. PMID:24378064

[Effect of hedgehog hydnum on the delay of fatigue in mice].

PubMed

Lu, Y H; Xin, C L; Zhou, Y F; Liu, X W; Chi, J W; Chang, X

1996-02-01

Two groups of mice were fed with either hedgehog hydnum powder or extract for sixty days. For the assay of fatigue, the activity of serum lactate dehydrogenase, the serum urea nitrogen content, blood lactic acid, hepatic and muscular glycogen, and the physical stamina of the mice were determined. The activity of serum lactate dehydrogenase and the hepatic and muscular glycogen content in the experimental mice were evidently higher than that in the control mice (P < 0.05 or P < 0.01). After exercise, the increase in blood lactic acid and serum urea nitrogen in the experimental mice was significantly lower than that in the control mice (P < 0.05 or P < 0.01), but the rate of elimination of blood lactic acid in the experimental mice was significantly higher than that in the control mice (P < 0.05). In the physical stamina swimming, the experimental mice drowned after a longer period of time than the control mice (P < 0.05). In conclusion hedgehog hydnum had a significant effect on raising physical stamina and delaying fatigue in mice.

Muscle interleukin-6 and fasting-induced PDH regulation in mouse skeletal muscle.

PubMed

Gudiksen, Anders; Bertholdt, Laerke; Vingborg, Mikkel Birkkjaer; Hansen, Henriette Watson; Ringholm, Stine; Pilegaard, Henriette

2017-03-01

Fasting prompts a metabolic shift in substrate utilization from carbohydrate to predominant fat oxidation in skeletal muscle, and pyruvate dehydrogenase (PDH) is seen as a controlling link between the competitive oxidation of carbohydrate and fat during metabolic challenges like fasting. Interleukin (IL)-6 has been proposed to be released from muscle with concomitant effects on both glucose and fat utilization. The aim was to test the hypothesis that muscle IL-6 has a regulatory impact on fasting-induced suppression of skeletal muscle PDH. Skeletal muscle-specific IL-6 knockout (IL-6 MKO) mice and floxed littermate controls (control) were either fed or fasted for 6 or 18 h. Lack of muscle IL-6 elevated the respiratory exchange ratio in the fed and early fasting state, but not with prolonged fasting. Activity of PDH in the active form (PDHa) was higher in fed and fasted IL-6 MKO than in control mice at 18 h, but not at 6 h, whereas lack of muscle IL-6 did not prevent downregulation of PDHa activity in skeletal muscle or changes in plasma and muscle substrate levels in response to 18 h of fasting. Phosphorylation of three of four sites on PDH-E1α increased with 18 h of fasting, but was lower in IL-6 MKO mice than in control. In addition, both PDK4 mRNA and protein increased with 6 and 18 h of fasting in both genotypes, but PDK4 protein was lower in IL-6 MKO than in control. In conclusion, skeletal muscle IL-6 seems to regulate whole body substrate utilization in the fed, but not fasted, state and influence skeletal muscle PDHa activity in a circadian manner. However, skeletal muscle IL-6 is not required for maintaining metabolic flexibility in response to fasting. Copyright © 2017 the American Physiological Society.

Whole-body vibration training effect on physical performance and obesity in mice.

PubMed

Huang, Chi-Chang; Tseng, Tzu-Ling; Huang, Wen-Ching; Chung, Yi-Hsiu; Chuang, Hsiao-Li; Wu, Jyh-Horng

2014-01-01

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity.

Whole-Body Vibration Training Effect on Physical Performance and Obesity in Mice

PubMed Central

Huang, Chi-Chang; Tseng, Tzu-Ling; Huang, Wen-Ching; Chung, Yi-Hsiu; Chuang, Hsiao-Li; Wu, Jyh-Horng

2014-01-01

The purpose of this study was to verify the beneficial effects of whole-body vibration (WBV) training on exercise performance, physical fatigue and obesity in mice with obesity induced by a high-fat diet (HFD). Male C57BL/6 mice were randomly divided into two groups: normal group (n=6), fed standard diet (control), and experimental group (n=18), fed a HFD. After 4-week induction, followed by 6-week WBV of 5 days per week, the 18 obese mice were divided into 3 groups (n=6 per group): HFD with sedentary control (HFD), HFD with WBV at relatively low-intensity (5.6 Hz, 0.13 g) (HFD+VL) or high-intensity (13 Hz, 0.68 g) (HFD+VH). A trend analysis revealed that WBV increased the grip strength in mice. WBV also dose-dependently decreased serum lactate, ammonia and CK levels and increased glucose level after the swimming test. WBV slightly decreased final body weight and dose-dependently decreased weights of epididymal, retroperitoneal and perirenal fat pads and fasting serum levels of alanine aminotransferase, CK, glucose, total cholesterol and triacylglycerol. Therefore, WBV could improve exercise performance and fatigue and prevent fat accumulation and obesity-associated biochemical alterations in obese mice. It may be an effective intervention for health promotion and prevention of HFD-induced obesity. PMID:25317067

Chronic ethanol consumption disrupts diurnal rhythms of hepatic glycogen metabolism in mice

PubMed Central

Udoh, Uduak S.; Swain, Telisha M.; Filiano, Ashley N.; Gamble, Karen L.; Young, Martin E.

2015-01-01

Chronic ethanol consumption has been shown to significantly decrease hepatic glycogen content; however, the mechanisms responsible for this adverse metabolic effect are unknown. In this study, we examined the impact chronic ethanol consumption has on time-of-day-dependent oscillations (rhythms) in glycogen metabolism processes in the liver. For this, male C57BL/6J mice were fed either a control or ethanol-containing liquid diet for 5 wk, and livers were collected every 4 h for 24 h and analyzed for changes in various genes and proteins involved in hepatic glycogen metabolism. Glycogen displayed a robust diurnal rhythm in the livers of mice fed the control diet, with the peak occurring during the active (dark) period of the day. The diurnal glycogen rhythm was significantly altered in livers of ethanol-fed mice, with the glycogen peak shifted into the inactive (light) period and the overall content of glycogen decreased compared with controls. Chronic ethanol consumption further disrupted diurnal rhythms in gene expression (glycogen synthase 1 and 2, glycogenin, glucokinase, protein targeting to glycogen, and pyruvate kinase), total and phosphorylated glycogen synthase protein, and enzyme activities of glycogen synthase and glycogen phosphorylase, the rate-limiting enzymes of glycogen metabolism. In summary, these results show for the first time that chronic ethanol consumption disrupts diurnal rhythms in hepatic glycogen metabolism at the gene and protein level. Chronic ethanol-induced disruption in these daily rhythms likely contributes to glycogen depletion and disruption of hepatic energy homeostasis, a recognized risk factor in the etiology of alcoholic liver disease. PMID:25857999

Studies of UCP2 transgenic and knockout mice reveal that liver UCP2 is not essential for the antiobesity effects of fish oil.

PubMed

Tsuboyama-Kasaoka, Nobuyo; Sano, Kayo; Shozawa, Chikako; Osaka, Toshimasa; Ezaki, Osamu

2008-03-01

Uncoupling protein 2 (UCP2) is a possible target molecule for energy dissipation. Many dietary fats, including safflower oil and lard, induce obesity in C57BL/6 mice, whereas fish oil does not. Fish oil increases UCP2 expression in hepatocytes and may enhance UCP2 activity by activating the UCP2 molecule or altering the lipid bilayer environment. To examine the role of liver UCP2 in obesity, we created transgenic mice that overexpressed human UCP2 in hepatocytes and examined whether UCP2 transgenic mice showed less obesity when fed a high-fat diet (safflower oil or lard). In addition, we examined whether fish oil had antiobesity effects in UCP2 knockout mice. UCP2 transgenic and wild-type mice fed a high-fat diet (safflower oil or lard) developed obesity to a similar degree. UCP2 knockout and wild-type mice fed fish oil had lower rates of obesity than mice fed safflower oil. Remarkably, safflower oil did not induce obesity in female UCP2 knockout mice, an unexpected phenotype for which we presently have no explanation. However, this unexpected effect was not observed in male UCP2 knockout mice or in UCP2 knockout mice fed a high-lard diet. These data indicate that liver UCP2 is not essential for fish oil-induced decreases in body fat.

Deteriorated glucose metabolism with a high-protein, low-carbohydrate diet in db mice, an animal model of type 2 diabetes, might be caused by insufficient insulin secretion.

PubMed

Arimura, Emi; Pulong, Wijang Pralampita; Marchianti, Ancah Caesarina Novi; Nakakuma, Miwa; Abe, Masaharu; Ushikai, Miharu; Horiuchi, Masahisa

2017-02-01

We previously showed the deleterious effects of increased dietary protein on renal manifestations and glucose metabolism in leptin receptor-deficient (db) mice. Here, we further examined its effects on glucose metabolism, including urinary C-peptide. We also orally administered mixtures corresponding to low- or high-protein diets to diabetic mice. In diet experiments, under pair-feeding (equivalent energy and fat) conditions using a metabolic cage, mice were fed diets with different protein content (L diet: 12 % protein, 71 % carbohydrate, 17 % fat; H diet: 24 % protein, 59 % carbohydrate, 17 % fat) for 15 days. In oral administration experiments, the respective mixtures (L mixture: 12 % proline, 71 % maltose or starch, 17 % linoleic acid; H mixture: 24 % proline, 59 % maltose or starch, 17 % linoleic acid) were supplied to mice. Biochemical parameters related to glucose metabolism were measured. The db-H diet mice showed significantly higher water intake, urinary volume, and glucose levels than db-L diet mice but similar levels of excreted urinary C-peptide. In contrast, control-H diet mice showed significantly higher C-peptide excretion than control-L diet mice. Both types of mice fed H diet excreted high levels of urinary albumin. When maltose mixtures were administered, db-L mixture mice showed significantly higher blood glucose after 30 min than db-H mixture mice. However, db mice administered starch-H mixture showed significantly higher blood glucose 120-300 min post-administration than db-L mixture mice, although both groups exhibited similar insulin levels. High-protein, low-carbohydrate diets deteriorated diabetic conditions and were associated with insufficient insulin secretion in db mice. Our findings may have implications for dietary management of diabetic symptoms in human patients.

Changes in IL12A methylation pattern in livers from mice fed DDC.

PubMed

Oliva, J; French, S W

2012-04-01

Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. Proteins of the TLR pathway were shown to be involved in the formation of MDBs, in mice fed DDC. TLR genes are upregulated and SAMe supplementation prevents this up regulation and prevented the formation of MDBs. DNA of livers from control mice, from mice fed DDC 10weeks, refed 1week with DDC and with DDC+SAMe were extracted and used to study the methylation pattern of genes involves in the TLR pathway. A PCR array was used to analyze it. Using PCR arrays for the mouse TLR pathway,24 genes were found whose expression of IL12A was regulated by the methylation of its gene. DDC fed for 10weeks reduced the methylation of the IL12A gene expression. This expression was also reduced when DDC was refed. However, when SAMe was fed, the intermediate level methylation of IL12A was up regulated to the intermediate level and the methylation of the promoter decreased compared to DDC refeeding or DDC 10weeks. IL12A is known to induce the production of IFNg by NK and L(T). We showed in a previous publication that IFNg is one of the major cytokines involved in the induction of MDB formation. The low expression of IL12A associated with the intermediate methylation of its promoter could explain one step in the mechanism which leads to the formation of MDBs. Copyright © 2012 Elsevier Inc. All rights reserved.

Moringa oleifera Lam. seed extract prevents fat diet induced oxidative stress in mice and protects liver cell-nuclei from hydroxyl radical mediated damage.

PubMed

Das, Nilanjan; Ganguli, Debdutta; Dey, Sanjit

2015-12-01

High fat diet (HFD) prompts metabolic pattern inducing reactive oxygen species (ROS) production in mitochondria thereby triggering multitude of chronic disorders in human. Antioxidants from plant sources may be an imperative remedy against this disorder. However, it requires scientific validation. In this study, we explored if (i) Moringa oleifera seed extract (MoSE) can neutralize ROS generated in HFD fed mice; (ii) protect cell-nuclei damage developed by Fenton reaction in vitro. Swiss mice were fed with HFD to develop oxidative stress model (HFD group). Other groups were control, seed extract alone treated, and MoSE simultaneously (HS) treated. Treatment period was of 15 days. Antioxidant enzymes with tissue nitrite content (TNC) and lipid peroxidation (LPO) were estimated from liver homogenate. HS group showed significantly higher (P < 0.05) superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH) activity, and ferric reducing antioxidant power (FRAP) compared to only HFD fed group. Further, TNC and LPO decreased significantly (P < 0.05) in HS group compared to HFD fed group. MoSE also protected hepatocytes nuclei from the hydroxyl radicals generated by Fenton reaction. MoSE was found to be polyphenol rich with potent reducing power, free radicals and hydroxyl radicals scavenging activity. Thus, MoSE exhibited robust antioxidant prospective to neutralize ROS developed in HFD fed mice and also protected the nuclei damage from hydroxyl radicals. Hence, it can be used as herbal medication against HFD induced ROS mediated disorders.

Antitumor and Immunomodulating Activities of Exopolysaccharide Produced by Big Cup Culinary- Medicinal Mushroom Clitocybe maxima (Higher Basidiomycetes) in Liquid Submerged Culture.

PubMed

Hu, Shu-Hui; Cheung, Peter Chi Keung; Hung, Raw-Pou; Chen, Yu-Kuei; Wang, Jinn-Chyi; Chang, Sue-Joan

2015-01-01

Water-soluble polysaccharides extracted from mushrooms have been found to have some physiological effects. In this study, exopolysaccharides (EPSs) were extracted by alcohol precipitation from cultivated broth of the mushroom Clitocybe maxima. EPSs with molecular weights of 10(4) and 10(5) Da were obtained by ultrafiltration; they are referred to as EPA and EPB, respectively. The major components of these EPSs were glucose, galactose, mannose, rhamnose, and arabinose. ICR mice with artificially induced metastatic pulmonary tumors were fed a daily diet containing EPA or EPB at doses of 8, 20, or 50 mg/kg. Results showed that the proliferation of pulmonary sarcoma lesions was lower in the groups fed EPS. In addition, the numbers of total T cells, CD4+ cells, CD8+ cells, and macrophages significantly increased in EPS-fed mice compared with the negative control group. The antitumor and immunomodulating effects observed in the EPB-fed groups were higher than those of EPA-fed groups. These results demonstrate the ability of EPSs of C. maxima to inhibit tumor cells while enhancing immune response.

Fatty acid desaturase 1 knockout mice are lean with improved glycemic control and decreased development of atheromatous plaque

PubMed Central

Powell, David R; Gay, Jason P; Smith, Melinda; Wilganowski, Nathaniel; Harris, Angela; Holland, Autumn; Reyes, Maricela; Kirkham, Laura; Kirkpatrick, Laura L; Zambrowicz, Brian; Hansen, Gwenn; Platt, Kenneth A; van Sligtenhorst, Isaac; Ding, Zhi-Ming; Desai, Urvi

2016-01-01

Delta-5 desaturase (D5D) and delta-6 desaturase (D6D), encoded by fatty acid desaturase 1 (FADS1) and FADS2 genes, respectively, are enzymes in the synthetic pathways for ω3, ω6, and ω9 polyunsaturated fatty acids (PUFAs). Although PUFAs appear to be involved in mammalian metabolic pathways, the physiologic effect of isolated D5D deficiency on these pathways is unclear. After generating >4,650 knockouts (KOs) of independent mouse genes and analyzing them in our high-throughput phenotypic screen, we found that Fads1 KO mice were among the leanest of 3,651 chow-fed KO lines analyzed for body composition and were among the most glucose tolerant of 2,489 high-fat-diet-fed KO lines analyzed by oral glucose tolerance test. In confirmatory studies, chow- or high-fat-diet-fed Fads1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 38% and 31% lower in Fads1 male and female KO mice, respectively. Fads1 KO mice also had lower glucose and insulin excursions during oral glucose tolerance tests along with lower fasting glucose, insulin, triglyceride, and total cholesterol levels. In additional studies using a vascular injury model, Fads1 KO mice had significantly decreased femoral artery intima/media ratios consistent with a decreased inflammatory response in their arterial wall. Based on this result, we bred Fads1 KO and WT mice onto an ApoE KO background and fed them a Western diet for 14 weeks; in this atherogenic environment, aortic trees of Fads1 KO mice had 40% less atheromatous plaque compared to WT littermates. Importantly, PUFA levels measured in brain and liver phospholipid fractions of Fads1 KO mice were consistent with decreased D5D activity and normal D6D activity. The beneficial metabolic phenotype demonstrated in Fads1 KO mice suggests that selective D5D inhibitors may be useful in the treatment of human obesity, diabetes, and atherosclerotic cardiovascular disease. PMID:27382320

Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.

PubMed

Zhang, Ling; Du, Jianfeng; Yano, Naohiro; Wang, Hao; Zhao, Yu Tina; Dubielecka, Patrycja M; Zhuang, Shougang; Chin, Y Eugene; Qin, Gangjian; Zhao, Ting C

2017-08-01

Histone deacetylases are recently identified to act as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of histone deacetylase (HDAC) in controlling cardiac performance in Type II diabetes and obesity remains unknown. Here, we determine whether HDAC inhibition attenuates high fat diet (HFD)-induced cardiac dysfunction and improves metabolic features. Adult mice were fed with either HFD or standard chow food for 24 weeks. Starting at 12 weeks, mice were divided into four groups randomly, in which sodium butyrate (1%), a potent HDAC inhibitor, was provided to chow and HFD-fed mice in drinking water, respectively. Glucose intolerance, metabolic parameters, cardiac function, and remodeling were assessed. Histological analysis and cellular signaling were examined at 24 weeks following euthanization of mice. HFD-fed mice demonstrated myocardial dysfunction and profound interstitial fibrosis, which were attenuated by HDAC inhibition. HFD-induced metabolic syndrome features insulin resistance, obesity, hyperinsulinemia, hyperglycemia, lipid accumulations, and cardiac hypertrophy, these effects were prevented by HDAC inhibition. Furthermore, HDAC inhibition attenuated myocyte apoptosis, reduced production of reactive oxygen species, and increased angiogenesis in the HFD-fed myocardium. Notably, HFD induced decreases in MKK3, p38, p38 regulated/activated protein kinase (PRAK), and Akt-1, but not p44/42 phosphorylation, which were prevented by HDAC inhibition. These results suggest that HDAC inhibition plays a critical role to preserve cardiac performance and mitigate metabolic disorders in obesity and diabetes, which is associated with MKK3/p38/PRAK pathway. The study holds promise in developing a new therapeutic strategy in the treatment of Type II diabetic-induced heart failure and metabolic disorders. J. Cell. Biochem. 118: 2395-2408, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

High sugar and butter (HSB) diet induces obesity and metabolic syndrome with decrease in regulatory T cells in adipose tissue of mice.

PubMed

Maioli, Tatiani Uceli; Gonçalves, Juliana Lauar; Miranda, Mariana Camila Gonçalves; Martins, Vinícius Dantas; Horta, Laila Sampaio; Moreira, Thais Garcias; Godard, Ana Lucia Brunialti; Santiago, Andrezza Fernanda; Faria, Ana Maria Caetano

2016-02-01

The purpose of the study was to develop a novel diet based on standard AIN93G diet that would be able to induce experimental obesity and impair immune regulation with high concentrations of both carbohydrate and lipids. To compare the effects of this high sugar and butter (HSB) diet with other modified diets, male C57BL/6 mice were fed either mouse chow, or AIN93G diet, or high sugar (HS) diet, or high-fat (HF) diet, or high sugar and butter (HSB) diet for 11 weeks ad libitum. HSB diet induced higher weight gain. Therefore, control AIN93G and HSB groups were chosen for additional analysis. Regulatory T cells were studied by flow cytometry, and cytokine levels were measured by ELISA. Although HF and HSB diets were able to induce a higher weight gain compatible with obesity in treated mice, HSB-fed mice presented the higher levels of serum glucose after fasting and the lowest frequency of regulatory T cells in adipose tissue. In addition, mice that were fed HSB diet presented higher levels of cholesterol and triglycerides, hyperleptinemia, increased resistin and leptin levels as well as reduced adiponectin serum levels. Importantly, we found increased frequency of CD4(+)CD44(+) effector T cells, reduction of CD4(+)CD25(+)Foxp3(+) and Th3 regulatory T cells as well as decreased levels of IL-10 and TGF-β in adipose tissue of HSB-fed mice. Therefore, HSB represents a novel model of obesity-inducing diet that was efficient in triggering alterations compatible with metabolic syndrome as well as impairment in immune regulatory parameters.

Soybean meal fermented by Aspergillus awamori increases the cytochrome P-450 content of the liver microsomes of mice.

PubMed

Kishida, T; Ataki, H; Takebe, M; Ebihara, K

2000-04-01

The effect of soybean meal fermented by Aspergillus awamori on the acute lethality of acetaldehyde, pentobarbital sleeping time, and cytochrome P-450 content of the hepatic microsomes was studied in mice. Most of the daidzin and genistin in soybean meal (SBM) were converted into the respective aglycones, daidzein and genistein, by fermentation. In experiment 1, mice were fed isonitrogenic test diets with one of the following five protein sources for 28 d: casein, SBM, fermented and hot-air-dried SBM (FSBM-HD), fermented and freeze-dried SBM (FSBM-FD), or methanol-extracted FSBM-FD (FSMB-FD-R). The acute lethality of acetaldehyde in mice fed the FSBM-FD diet was significantly lower than that in mice fed the SBM, FSBM-HD, or FSBM-FD-R diet. In experiments 2 and 3, mice were fed isonitrogenic test diets with one of the following four protein sources for 28 d: casein, SBM, FSBM-FD, and FSBM-FD-R. The pentobarbital sleeping time was significantly shorter and the cytochrome P-450 content was significantly higher in the mice fed the FSBM-FD diet than the respective value in mice fed the other test diets. In experiment 4, mice were fed one of eight diets which contained different levels of aglycone obtained by varying the proportion of FSBM-FD and FSBM-FD-R, for 28 d. The cytochrome P-450 content in hepatic microsomes increased as the dietary level of isoflavonoid aglycones increased, but there was a saturation phenomenon. These results suggest that soy isoflavonoid aglycones are more potent inducers of cytochrome P-450 than isoflavonoid glycosides.

Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Anders, Lisanne C

Background: Vinyl chloride (VC) causes toxicant-associated steatohepatitis at high exposure levels. Recent work by this group suggests that underlying liver disease may predispose the liver to VC hepatotoxicity at lower exposure levels. The most common form of underlying liver disease in the developed world is non-alcoholic fatty liver disease (NAFLD). It is well-known that the type of dietary fat can play an important role in the pathogenesis of NAFLD. However, whether the combination of dietary fat and VC/metabolites promotes liver injury has not been studied. Methods: Mice were administered chloroethanol (CE - a VC metabolite) or vehicle once, 10 weeksmore » after being fed diets rich in saturated fatty acids (HSFA), rich in poly-unsaturated fatty acids (HPUFA), or the respective low-fat control diets (LSFA; LPUFA). Results: In control mice, chloroethanol caused no detectable liver injury, as determined by plasma transaminases and histologic indices of damage. In HSFA-fed mice, chloroethanol increased HSFA-induced liver damage, steatosis, infiltrating inflammatory cells, hepatic expression of proinflammatory cytokines, and markers of endoplasmic reticulum (ER) stress. Moreover, markers of inflammasome activation were increased, while markers of inflammasome inhibition were downregulated. In mice fed HPUFA all of these effects were significantly attenuated. Conclusions: Chloroethanol promotes inflammatory liver injury caused by dietary fatty acids. This effect is far more exacerbated with saturated fat, versus poly-unsaturated fat; and strongly correlates with a robust activation of the NLRP3 inflammasome in the saturated fed animals only. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD/NASH. - Highlights: • CE promotes inflammatory liver injury caused by dietary fatty acids. • This effect is stronger with saturated than with unsaturated fatty acids. • Damage caused by saturated fat and CE correlates with inflammasome activation.« less

Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers.

PubMed

Kim, Dong-Hyeon; Kim, Hyunsook; Jeong, Dana; Kang, Il-Byeong; Chon, Jung-Whan; Kim, Hong-Seok; Song, Kwang-Young; Seo, Kun-Ho

2017-06-01

Kefir is a probiotic beverage containing over 50 species of lactic acid bacteria and yeast. In this study, the anti-obesity and anti-non-alcoholic fatty liver disease (NAFLD) effects of kefir were comprehensively addressed along with targeted and untargeted community analysis of the fecal microbiota in a high-fat diet (HFD)-induced obese mouse model. HFD-fed C57BL/6 mice were orally administrated either kefir or milk (control) once a day for 12 weeks, and body and organ weight, fecal microbiota and mycobiota, histopathology, blood cholesterol and cytokines and gene expressions were analyzed. Compared to the control, mice in the kefir group exhibited a significantly lower body weight (34.18 g vs. 40.24 g; p=0.00004) and histopathological liver lesion score (1.13 vs. 3.25; p=0.002). Remarkably, the kefir-fed mice also harbored more Lactobacillus/Lactococcus (7.01 vs. 6.32 log CFU/g), total yeast (6.07 vs. 5.01 log CFU/g) and Candida (5.56 vs. 3.88 log CFU/g). Kefir administration also up-regulated genes related to fatty acid oxidation, PPARα and AOX, in both the liver and adipose tissue (PPARα, 2.95- and 2.15-fold; AOX, 1.89- and 1.9-fold, respectively). The plasma concentration of IL-6, a proinflammatory marker, was significantly reduced following kefir consumption (50.39 pg/ml vs. 111.78 pg/ml; p=0.03). Strikingly, the populations of Lactobacillus/Lactococcus, total yeast and Candida were strongly correlated with PPARα gene expression in adipose and hepatic tissue (r=0.599, 0.580 and 0.562, respectively). These data suggest that kefir consumption modulates gut microbiota and mycobiota in HFD-fed mice, which prevents obesity and NAFLD via promoting fatty acid oxidation. Copyright © 2017 Elsevier Inc. All rights reserved.

High dietary fat intake during lactation promotes development of diet-induced obesity in male offspring of mice.

PubMed

Tsuduki, Tsuyoshi; Kitano, Yasuna; Honma, Taro; Kijima, Ryo; Ikeda, Ikuo

2013-01-01

The maternal nutritional status during pregnancy and lactation influences the risk of obesity in offspring, but the details of this phenomenon are unclear. In particular, there is little information on the influence on the offspring of the maternal nutritional status during lactation only. Therefore, in this study, we examined the influence of high dietary fat intake in dams during lactation on the risk of obesity in offspring, using C57BL/6J mice. The mice were fed a control diet (CD) during pregnancy. After birth, dams were fed a CD or a high-fat diet (HD) during lactation (3 wk). Fat and energy were significantly increased in milk from dams fed a HD during lactation. Male offspring were weaned at 3 wk old and fed a CD for 4 wk, which resulted in no significant difference in their physique. Four weeks after weaning, the offspring (7 wk old) were fed a CD or HD for 4 wk to induce obesity. High dietary fat intake in dams and offspring promoted lipid accumulation in white adipose tissue and adipocyte hypertrophy in male offspring. The underlying mechanism may involve an increase in expression of Lpl and a decrease in expression of Hsl in white adipose tissue of offspring. In conclusion, our results show that high dietary fat intake during lactation promotes development of diet-induced obesity in male offspring.

Intermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice

PubMed Central

Seimon, Radhika V.; Shi, Yan-Chuan; Slack, Katy; Lee, Kailun; Fernando, Hamish A.; Nguyen, Amy D.; Zhang, Lei; Lin, Shu; Enriquez, Ronaldo F.; Lau, Jackie

2016-01-01

Background Intermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled. Methods Male C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5–6 consecutive days, and ad libitum intake for 1–3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)–(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding. Results Mice on the ID showed transient hyperphagia relative to controls during each 1–3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups. Conclusion Intermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice. PMID:26784324

Intermittent Moderate Energy Restriction Improves Weight Loss Efficiency in Diet-Induced Obese Mice.

PubMed

Seimon, Radhika V; Shi, Yan-Chuan; Slack, Katy; Lee, Kailun; Fernando, Hamish A; Nguyen, Amy D; Zhang, Lei; Lin, Shu; Enriquez, Ronaldo F; Lau, Jackie; Herzog, Herbert; Sainsbury, Amanda

2016-01-01

Intermittent severe energy restriction is popular for weight management. To investigate whether intermittent moderate energy restriction may improve this approach by enhancing weight loss efficiency, we conducted a study in mice, where energy intake can be controlled. Male C57/Bl6 mice that had been rendered obese by an ad libitum diet high in fat and sugar for 22 weeks were then fed one of two energy-restricted normal chow diets for a 12-week weight loss phase. The continuous diet (CD) provided 82% of the energy intake of age-matched ad libitum chow-fed controls. The intermittent diet (ID) provided cycles of 82% of control intake for 5-6 consecutive days, and ad libitum intake for 1-3 days. Weight loss efficiency during this phase was calculated as (total weight change) ÷ [(total energy intake of mice on CD or ID)-(total average energy intake of controls)]. Subsets of mice then underwent a 3-week weight regain phase involving ad libitum re-feeding. Mice on the ID showed transient hyperphagia relative to controls during each 1-3-day ad libitum feeding period, and overall ate significantly more than CD mice (91.1±1.0 versus 82.2±0.5% of control intake respectively, n = 10, P<0.05). There were no significant differences between CD and ID groups at the end of the weight loss or weight regain phases with respect to body weight, fat mass, circulating glucose or insulin concentrations, or the insulin resistance index. Weight loss efficiency was significantly greater with ID than with CD (0.042±0.007 versus 0.018±0.001 g/kJ, n = 10, P<0.01). Mice on the CD exhibited significantly greater hypothalamic mRNA expression of proopiomelanocortin (POMC) relative to ID and control mice, with no differences in neuropeptide Y or agouti-related peptide mRNA expression between energy-restricted groups. Intermittent moderate energy restriction may offer an advantage over continuous moderate energy restriction, because it induces significantly greater weight loss relative to energy deficit in mice.

Sterol O-acyltransferase 1 deficiency improves defective insulin signaling in the brains of mice fed a high-fat diet.

PubMed

Xu, Ning; Meng, Hao; Liu, Tian-Yi; Feng, Ying-Li; Qi, Yuan; Zhang, Dong-Huan; Wang, Hong-Lei

2018-05-05

Insulin resistance induced by a high-fat diet (HFD) is related to metabolic diseases, and sterol O-acyltransferase 1 (SOAT1) is a key enzyme for the biosynthesis of cholesteryl ester. In the present study, wild-type (WT) mice and SOAT1-knockout (KO) mice with a C57BL6 background fed a HFD were used to explore the role of SOAT1 in the hypothalamus. The results show that the WT mice exhibited a significant increase in body weight as well as hepatic histologic changes; they also had a lower glucose and insulin tolerance than the WT mice fed a normal diet. However, the metabolic syndrome was attenuated in the SOAT1-KO HFD-fed mice. With regard to brain function, the SOAT1-KO HFD-fed mice showed improved cognitive function; they also manifested reduced levels of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, which would otherwise be raised by a HFD. In addition, the HFD led to the overexpression of GFAP and phosphorylated NF-κB in the hypothalamus, changes that were reversed in the SOAT1-KO HFD-fed mice. Moreover, SOAT1-KO mice improved HFD-caused defective hypothalamic insulin resistance, as evidenced by the upregulation of p-insulin receptor (INSR), p-AKT and p-glycogen synthase kinase (GSK)-3β, while the downregulation of p-AMP-activated protein kinase (AMPK)-α and p-acetyl-CoA carboxylase (ACC)-α. In addition, similar results were observed in high fructose (HFR)-stimulated astrocytes (ASTs) isolated from WT or KO mice. These results suggest that SOAT1 plays an important role in hypothalamic insulin sensitivity, linked to cognitive impairment, in HFD-fed mice. Copyright © 2018. Published by Elsevier Inc.

Eicosapentaenoic acid prevents arterial calcification in klotho mutant mice.

PubMed

Nakamura, Kazufumi; Miura, Daiji; Saito, Yukihiro; Yunoki, Kei; Koyama, Yasushi; Satoh, Minoru; Kondo, Megumi; Osawa, Kazuhiro; Hatipoglu, Omer F; Miyoshi, Toru; Yoshida, Masashi; Morita, Hiroshi; Ito, Hiroshi

2017-01-01

The klotho gene was identified as an "aging-suppressor" gene that accelerates arterial calcification when disrupted. Serum and vascular klotho levels are reduced in patients with chronic kidney disease, and the reduced levels are associated with arterial calcification. Intake of eicosapentaenoic acid (EPA), an n-3 fatty acid, reduces the risk of fatal coronary artery disease. However, the effects of EPA on arterial calcification have not been fully elucidated. The aim of this study was to determine the effect of EPA on arterial calcification in klotho mutant mice. Four-week-old klotho mutant mice and wild-type (WT) mice were given a diet containing 5% EPA (EPA food, klotho and WT: n = 12, each) or not containing EPA (control food, klotho and WT: n = 12, each) for 4 weeks. Calcium volume scores of thoracic and abdominal aortas assessed by computed tomography were significantly elevated in klotho mice after 4 weeks of control food, but they were not elevated in klotho mice after EPA food or in WT mice. Serum levels of EPA and resolvin E1, an active metabolite of EPA, in EPA food-fed mice were significantly increased compared to those in control food-fed mice. An oxidative stress PCR array followed by quantitative PCR revealed that NADPH oxidase-4 (NOX4), an enzyme that generates superoxide, gene expression was up-regulated in arterial smooth muscle cells (SMCs) of klotho mice. Activity of NOX was also significantly higher in SMCs of klotho mice than in those of WT mice. EPA decreased expression levels of the NOX4 gene and NOX activity. GPR120, a receptor of n-3 fatty acids, gene knockdown by siRNA canceled effects of EPA on NOX4 gene expression and NOX activity in arterial SMCs of klotho mice. EPA prevents arterial calcification together with reduction of NOX gene expression and activity via GPR120 in klotho mutant mice.

Consumption of fig fruits grown in Oman can improve memory, anxiety, and learning skills in a transgenic mice model of Alzheimer's disease.

PubMed

Subash, Selvaraju; Essa, Musthafa Mohamed; Braidy, Nady; Al-Jabri, Ahood; Vaishnav, Ragini; Al-Adawi, Samir; Al-Asmi, Abdullah; Guillemin, Gilles J

2016-12-01

Alzheimer disease (AD) is one of the most common forms of dementia in the elderly. Several reports have suggested neurotoxic effects of amyloid beta protein (Aβ) and role of oxidative stress in AD. Figs are rich in fiber, copper, iron, manganese, magnesium, potassium, calcium, vitamin K, and are a good source of proanthocyanidins and quercetin which demonstrate potent antioxidant properties. We studied the effect of dietary supplementation with 4% figs grown in Oman on the memory, anxiety, and learning skills in APPsw/Tg2576 (Tg mice) mice model for AD. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4 months and after 15 months using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. Tg mice that were fed a control diet without figs showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial, position discrimination learning ability, and motor coordination compared to the wild-type control mice on the same diet, and Tg mice fed on 4% fig diet supplementation for 15 months. Our results suggest that dietary supplementation of figs may be useful for the improvement of cognitive and behavioral deficits in AD.

EPA prevents fat mass expansion and metabolic disturbances in mice fed with a Western diet.

PubMed

Pinel, Alexandre; Pitois, Elodie; Rigaudiere, Jean-Paul; Jouve, Chrystele; De Saint-Vincent, Sarah; Laillet, Brigitte; Montaurier, Christophe; Huertas, Alain; Morio, Beatrice; Capel, Frederic

2016-08-01

The impact of alpha linolenic acid (ALA), EPA, and DHA on obesity and metabolic complications was studied in mice fed a high-fat, high-sucrose (HF) diet. HF diets were supplemented with ALA, EPA, or DHA (1% w/w) and given to C57BL/6J mice for 16 weeks and to Ob/Ob mice for 6 weeks. In C57BL/6J mice, EPA reduced plasma cholesterol (-20%), limited fat mass accumulation (-23%) and adipose cell hypertrophy (-50%), and reduced plasma leptin concentration (-60%) compared with HF-fed mice. Furthermore, mice supplemented with EPA exhibited a higher insulin sensitivity (+24%) and glucose tolerance (+20%) compared with HF-fed mice. Similar effects were observed in EPA-supplemented Ob/Ob mice, although fat mass accumulation was not prevented. By contrast, in comparison with HF-fed mice, DHA did not prevent fat mass accumulation, increased plasma leptin concentration (+128%) in C57BL/6J mice, and did not improve glucose homeostasis in C57BL/6J and Ob/Ob mice. In 3T3-L1 adipocytes, DHA stimulated leptin expression whereas EPA induced adiponectin expression, suggesting that improved leptin/adiponectin balance may contribute to the protective effect of EPA. In conclusion, supplementation with EPA, but not ALA and DHA, could preserve glucose homeostasis in an obesogenic environment and limit fat mass accumulation in the early stage of weight gain. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Early obesity leads to increases in hepatic arginase I and related systemic changes in nitric oxide and L-arginine metabolism in mice.

PubMed

Ito, Tatsuo; Kubo, Masayuki; Nagaoka, Kenjiro; Funakubo, Narumi; Setiawan, Heri; Takemoto, Kei; Eguchi, Eri; Fujikura, Yoshihisa; Ogino, Keiki

2018-02-01

Obesity is a risk factor for vascular endothelial cell dysfunction characterized by low-grade, chronic inflammation. Increased levels of arginase I and concomitant decreases in L-arginine bioavailability are known to play a role in the pathogenesis of vascular endothelial cell dysfunction. In the present study, we focused on changes in the systemic expression of arginase I as well as L-arginine metabolism in the pre-disease state of early obesity prior to the onset of atherosclerosis. C57BL/6 mice were fed a control diet (CD; 10% fat) or high-fat diet (HFD; 60% fat) for 8 weeks. The mRNA expression of arginase I in the liver, adipose tissue, aorta, and muscle; protein expression of arginase I in the liver and plasma; and systemic levels of L-arginine bioavailability and NO 2 - were assessed. HFD-fed mice showed early obesity without severe disease symptoms. Arginase I mRNA and protein expression levels in the liver were significantly higher in HFD-fed obese mice than in CD-fed mice. Arginase I levels were slightly increased, whereas L-arginine levels were significantly reduced, and these changes were followed by reductions in NO 2 - levels. Furthermore, hepatic arginase I levels positively correlated with plasma arginase I levels and negatively correlated with L-arginine bioavailability in plasma. These results suggested that increases in the expression of hepatic arginase I and reductions in plasma L-arginine and NO 2 - levels might lead to vascular endothelial dysfunction in the pre-disease state of early obesity.

Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota.

PubMed

Hussain, Ahtesham; Yadav, Mukesh Kumar; Bose, Shambhunath; Wang, Jing-Hua; Lim, Dongwoo; Song, Yun-Kyung; Ko, Seong-Gyu; Kim, Hojun

2016-01-01

Obesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer. In the present study we evaluated the anti-obesity property of Daesiho-tang (DSHT), an herbal medicine, using high fat diet (HFD)-induced obese mice as a model. Our results showed that DSHT ameliorated body weight gain, decreased total body fat, regulated expression of leptin and adiponectin genes of adipose tissue and exerted an anti-diabetic effect by attenuating fasting glucose level and serum insulin level in HFD-fed animals. In addition, DSHT-treatment significantly reduced total cholesterol (TC), triglycerides (TG) and increased high density lipoprotein-cholesterol (HDL), glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in serum and reduced deposition of fat droplets in liver. DSHT treatment resulted in significantly increased relative abundance of bacteria including Bacteroidetes, Bacteroidetes/Firmicutes ratio, Akkermansia Bifidobacterium., Lactobacillus, and decreased the level of Firmicutes. Using RT2 profiler PCR array, 39 (46%) genes were found to be differentially expressed in HFD-fed mice compared to normal control. However, normal gene expressions were restored in 36 (92%) genes of HFD-fed mice, when co-exposed to DSHT. The results of this study demonstrated that DSHT is an effective herbal formulation in attenuation of obesity in HFD-fed mice through alteration of gene expressions and modulation of intestinal microbiota.

Obesity impairs skeletal muscle AMPK signaling during exercise: role of AMPKα2 in the regulation of exercise capacity in vivo.

PubMed

Lee-Young, R S; Ayala, J E; Fueger, P T; Mayes, W H; Kang, L; Wasserman, D H

2011-07-01

Skeletal muscle AMP-activated protein kinase (AMPK)α2 activity is impaired in obese, insulin-resistant individuals during exercise. We determined whether this defect contributes to the metabolic dysregulation and reduced exercise capacity observed in the obese state. C57BL/6J wild-type (WT) mice and/or mice expressing a kinase dead AMPKα2 subunit in skeletal muscle (α2-KD) were fed chow or high-fat (HF) diets from 3 to 16 weeks of age. At 15 weeks, mice performed an exercise stress test to determine exercise capacity. In WT mice, muscle glucose uptake and skeletal muscle AMPKα2 activity was assessed in chronically catheterized mice (carotid artery/jugular vein) at 16 weeks. In a separate study, HF-fed WT and α2-KD mice performed 5 weeks of exercise training (from 15 to 20 weeks of age) to test whether AMPKα2 is necessary to restore work tolerance. HF-fed WT mice had reduced exercise tolerance during an exercise stress test, and an attenuation in muscle glucose uptake and AMPKα2 activity during a single bout of exercise (P<0.05 versus chow). In chow-fed α2-KD mice, running speed and time were impaired ∼45 and ∼55%, respectively (P<0.05 versus WT chow); HF feeding further reduced running time ∼25% (P<0.05 versus α2-KD chow). In response to 5 weeks of exercise training, HF-fed WT and α2-KD mice increased maximum running speed ∼35% (P<0.05 versus pre-training) and maintained body weight at pre-training levels, whereas body weight increased in untrained HF WT and α2-KD mice. Exercise training restored running speed to levels seen in healthy, chow-fed mice. HF feeding impairs AMPKα2 activity in skeletal muscle during exercise in vivo. Although this defect directly contributes to reduced exercise capacity, findings in HF-fed α2-KD mice show that AMPKα2-independent mechanisms are also involved. Importantly, α2-KD mice on a HF-fed diet adapt to regular exercise by increasing exercise tolerance, demonstrating that this adaptation is independent of skeletal muscle AMPKα2 activity.

Adaptive changes in amino acid metabolism permit normal longevity in mice consuming a low-carbohydrate ketogenic diet.

PubMed

Douris, Nicholas; Melman, Tamar; Pecherer, Jordan M; Pissios, Pavlos; Flier, Jeffrey S; Cantley, Lewis C; Locasale, Jason W; Maratos-Flier, Eleftheria

2015-10-01

Ingestion of very low-carbohydrate ketogenic diets (KD) is associated with weight loss, lowering of glucose and insulin levels and improved systemic insulin sensitivity. However, the beneficial effects of long-term feeding have been the subject of debate. We therefore studied the effects of lifelong consumption of this diet in mice. Complete metabolic analyses were performed after 8 and 80weeks on the diet. In addition we performed a serum metabolomic analysis and examined hepatic gene expression. Lifelong consumption of KD had no effect on morbidity or mortality (KD vs. Chow, 676 vs. 630days) despite hepatic steatosis and inflammation in KD mice. The KD fed mice lost weight initially as previously reported (Kennnedy et al., 2007) and remained lighter and had less fat mass; KD consuming mice had higher levels of energy expenditure, improved glucose homeostasis and higher circulating levels of β-hydroxybutyrate and triglycerides than chow-fed controls. Hepatic expression of the critical metabolic regulators including fibroblast growth factor 21 were also higher in KD-fed mice while expression levels of lipogenic enzymes such as stearoyl-CoA desaturase-1 was reduced. Metabolomic analysis revealed compensatory changes in amino acid metabolism, primarily involving down-regulation of catabolic processes, demonstrating that mice eating KD can shift amino acid metabolism to conserve amino acid levels. Long-term KD feeding caused profound and persistent metabolic changes, the majority of which are seen as health promoting, and had no adverse effects on survival in mice. Copyright © 2015. Published by Elsevier B.V.

Microalgal Oil Supplementation Has an Anti-Obesity Effect in C57BL/6J Mice Fed a High Fat Diet

PubMed Central

Yook, Jin-Seon; Kim, Kyung-Ah; Park, Jeong Eun; Lee, Seon-Hwa; Cha, Youn-Soo

2015-01-01

This study investigated the impact of microalgal oil (MO) on body weight management in C57BL/6J mice. Obesity was induced for 8 weeks and animals were orally supplemented with the following for 8 additional weeks: beef tallow (BT), corn oil, fish oil (FO), microalgal oil (MO), or none, as a high fat diet control group (HD). A normal control group was fed with a normal diet. After completing the experiment, the FO and MO groups showed significant decreases in body weight gain, epididymal fat pad weights, serum triglycerides, and total cholesterol levels compared to the HD and BT groups. A lower mRNA expression level of lipid anabolic gene and higher levels of lipid catabolic genes were observed in both FO and MO groups. Serum insulin and leptin concentrations were lower in the MO group. These results indicated that microalgal oil has an anti-obesity effect that can combat high fat diet-induced obesity in mice. PMID:26770909

Regression of Lingual Lymphatic Vessels in Sodium-restricted Mice.

PubMed

He, Lianying; McCluskey, Lynnette Phillips

2018-05-01

Lymphatic vessel networks can expand and regress, with consequences for interstitial fluid drainage and nutrient supply to tissues, inflammation, and tumor spread. A diet high in sodium stimulates hyperplasia of cutaneous lymphatic capillaries. We hypothesized that dietary sodium restriction would have the opposite effect, shrinking lymphatic capillaries in the tongue. Lingual lymphatic capillary density and size was significantly reduced in mice fed a low-sodium diet (0.03%) for 3 weeks compared with control-fed mice. Blood vessel density was unchanged. Despite lymphatic capillary shrinkage, lingual edema was not observed. The effect on lymphatic capillaries was reversible, as lymphatic density and size in the tongue were restored by 3 weeks on a control diet. Lymphatic hyperplasia induced by a high-sodium diet is dependent on infiltrating macrophages. However, lingual CD68+ macrophage density was unchanged by sodium deficiency, indicating that distinct mechanisms may mediate lymphatic regression. Further studies are needed to test whether dietary sodium restriction is an effective, non-invasive co-therapy for oral cancer.

Conjugated linoleic acid ameliorates inflammation-induced colorectal cancer in mice through activation of PPARgamma.

PubMed

Evans, Nicholas P; Misyak, Sarah A; Schmelz, Eva M; Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-03-01

Conjugated linoleic acid (CLA) exerts a protective effect on experimental inflammatory bowel disease and shows promise as a chemopreventive agent against colorectal cancer (CRC) in mice, although the mechanisms by which it exerts its beneficial effects against malignancies in the gut are not completely understood. Mice lacking PPARgamma in immune and epithelial cells and PPARgamma-expressing littermates were fed either control or CLA-supplemented (1 g CLA/100 g) diets to determine the role of PPARgamma in inflammation-induced CRC. To induce tumor formation and colitis, mice were treated with azoxymethane and then challenged with 2% dextran sodium sulfate, respectively. Dietary CLA ameliorated disease activity, decreased colitis, and prevented adenocarcinoma formation in the PPARgamma-expressing floxed mice but not in the tissue-specific PPARgamma-null mice. Dietary CLA supplementation significantly decreased the percentages of macrophages in the mesenteric lymph nodes (MLN) regardless of the genotype and increased regulatory T cell numbers in MLN of PPARgamma-expressing, but not in the tissue-specific, PPARgamma-null mice. Colonic tumor necrosis factor-alpha mRNA expression was significantly suppressed in CLA-fed, PPARgamma-expressing mice. This study suggests CLA ameliorates colitis and prevents tumor formation in part through a PPARgamma-dependent mechanism.

Effect of Dietary Purified Xanthohumol from Hop (Humulus lupulus L.) Pomace on Adipose Tissue Mass, Fasting Blood Glucose Level, and Lipid Metabolism in KK-Ay Mice.

PubMed

Takahashi, Koki; Osada, Kyoichi

2017-05-01

We previously showed that xanthohumol-rich hop extract (XRHE, ~18% xanthohumol) exerts anti-obesity effects in rats fed a high-fat diet through regulation of fatty acid metabolism. In this study, we examined the effects of dietary purified xanthohumol from XRHE (PX, ~91.9% xanthohumol) in KK-Ay mice in order to understand the anti-obesity effects of xanthohumol alone because XRHE contains 82% unknown compounds. Dietary consumption of PX significantly inhibited an increase in the visceral fat weight of mice compared to those fed control diet without PX. Plasma leptin level was significantly lower in the PX-fed group than in the control group. Dietary PX lowered hepatic fatty acid synthesis by down-regulation of SREBP1c mRNA expression in the liver. On the other hand, fatty acid β-oxidation in the liver was promoted by dietary PX through the up-regulation of PPARα mRNA expression. Moreover, the fecal levels of fatty acids and carbohydrates increased by dietary PX. PX inhibited lipase or α-amylase activity in vitro. Thus, we found that PX may exert anti-obesity effects through the regulation of lipid metabolism and inhibition of intestinal fat and carbohydrate absorption, and that xanthohumol alone may exert anti-obesity effects.

Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet.

PubMed

Al Rajabi, Ala; Castro, Gabriela S F; da Silva, Robin P; Nelson, Randy C; Thiesen, Aducio; Vannucchi, Helio; Vine, Donna F; Proctor, Spencer D; Field, Catherine J; Curtis, Jonathan M; Jacobs, René L

2014-03-01

Dietary choline is required for proper structure and dynamics of cell membranes, lipoprotein synthesis, and methyl-group metabolism. In mammals, choline is synthesized via phosphatidylethanolamine N-methyltransferase (Pemt), which converts phosphatidylethanolamine to phosphatidylcholine. Pemt(-/-) mice have impaired VLDL secretion and developed fatty liver when fed a high-fat (HF) diet. Because of the reduction in plasma lipids, Pemt(-/-)/low-density lipoprotein receptor knockout (Ldlr(-/-)) mice are protected from atherosclerosis. The goal of this study was to investigate the importance of dietary choline in the metabolic phenotype of Pemt(-/-)/Ldlr(-/-) male mice. At 10-12 wk of age, Pemt(+/+)/Ldlr(-/-) (HF(+/+)) and half of the Pemt(-/-)/Ldlr(-/-) (HF(-/-)) mice were fed an HF diet with normal (1.3 g/kg) choline. The remaining Pemt(-/-)/Ldlr(-/-) mice were fed an HF diet supplemented (5 g/kg) with choline (HFCS(-/-) mice). The HF diet contained 60% of calories from fat and 1% cholesterol, and the mice were fed for 16 d. HF(-/-) mice lost weight and developed hepatomegaly, steatohepatitis, and liver damage. Hepatic concentrations of free cholesterol, cholesterol-esters, and triglyceride (TG) were elevated by 30%, 1.1-fold and 3.1-fold, respectively, in HF(-/-) compared with HF(+/+) mice. Choline supplementation normalized hepatic cholesterol, but not TG, and dramatically improved liver function. The expression of genes involved in cholesterol transport and esterification increased by 50% to 5.6-fold in HF(-/-) mice when compared with HF(+/+) mice. Markers of macrophages, oxidative stress, and fibrosis were elevated in the HF(-/-) mice. Choline supplementation normalized the expression of these genes. In conclusion, HF(-/-) mice develop liver failure associated with altered cholesterol metabolism when fed an HF/normal choline diet. Choline supplementation normalized cholesterol metabolism, which was sufficient to prevent nonalcoholic steatohepatitis development and improve liver function. Our data suggest that choline can promote liver health by maintaining cholesterol homeostasis.

Effects of voluntary running with defined distances on body adiposity and its associated inflammation in mice fed a high-fat diet

USDA-ARS?s Scientific Manuscript database

Sedentary lifestyle contributes to obesity. This study examined the effect of quantitative voluntary running on body adiposity and its associated inflammation in mice fed a high-fat diet. Male C57BL/6 mice were assigned into six groups and fed the AIN93G (sedentary) or a high-fat diet (sedentary, ...

Bardoxolone methyl prevents fat deposition and inflammation in the visceral fat of mice fed a high-fat diet.

PubMed

Dinh, Chi H L; Szabo, Alexander; Camer, Danielle; Yu, Yinghua; Wang, Hongqin; Huang, Xu-Feng

2015-03-05

Key features of diet-induced obesity are visceral fat deposition, macrophage infiltration and inflammation that can lead to metabolic disorders. This study examined the effects of bardoxolone methyl (BARD) in preventing obesity and inflammation in the visceral fat of mice fed high-fat diet. Male C57BL/6J mice were fed a high-fat diet (HFD), a low-fat diet (LFD, i.e., lab chow diet) or a high-fat diet supplemented with BARD (HFD/BARD) for 21weeks. BARD at a dosage of 10mg/kg body weight was administered orally in drinking water. Histology, immunohistochemistry and Western blot were used for the analysis of epididymal adipose tissue. Morphological results demonstrated that HFD fed mice treated with BARD had smaller adipocytes and fewer macrophages present in epididymal adipose tissue than the HFD group. Furthermore, BARD administration reduced the inflammatory profile in this tissue by increasing the expression of nuclear factor of kappa-light-polypeptide gene enhancer in B-cells inhibitor, alpha (IκB-α) protein and decreasing the protein expression of tumour necrosis factor alpha (TNF-α). BARD also prevented oxidative stress reflected by a reduction in stress activated proteins, including signal transducer and activator of transcription 3 (STAT3), protein kinase B (Akt), extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). BARD administration activated the sympathetic nervous system in epididymal adipose tissue assessed by the increased synthesis of tyrosine hydroxylase (TH) and uncoupling protein 2 (UCP2). The expression of inflammatory and sympathetic nervous system proteins in BARD mice fed a HFD was equivalent to that of the LFD control mice, indicating the anti-inflammatory and anti-obesity properties of this drug. In conclusion, the oral administration of BARD in HFD mice prevented fat deposition, inflammation and oxidative stress, and improved sympathetic activity in visceral fat. This study suggests a potential therapeutic role of BARD in preventing the development of obesity. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Investigating the effects of dietary folic acid on sperm count, DNA damage and mutation in Balb/c mice.

PubMed

Swayne, Breanne G; Kawata, Alice; Behan, Nathalie A; Williams, Andrew; Wade, Mike G; Macfarlane, Amanda J; Yauk, Carole L

2012-09-01

To date, fewer than 50 mutagens have been studied for their ability to cause heritable mutations. The majority of those studied are classical mutagens like radiation and anti-cancer drugs. Very little is known about the dietary variables influencing germline mutation rates. Folate is essential for DNA synthesis and methylation and can impact chromatin structure. We therefore determined the effects of folic acid-deficient (0mg/kg), control (2mg/kg) and supplemented (6mg/kg) diets in early development and during lactation or post-weaning on mutation rates and chromatin quality in sperm of adult male Balb/c mice. The sperm chromatin structure assay and mutation frequencies at expanded simple tandem repeats (ESTRs) were used to evaluate germline DNA integrity. Treatment of a subset of mice fed the control diet with the mutagen ethylnitrosourea (ENU) at 8 weeks of age was included as a positive control. ENU treated mice exhibited decreased cauda sperm counts, increased DNA fragmentation and increased ESTR mutation frequencies relative to non-ENU treated mice fed the control diet. Male mice weaned to the folic acid deficient diet had decreased cauda sperm numbers, increased DNA fragmentation index, and increased ESTR mutation frequency. Folic acid deficiency in early development did not lead to changes in sperm counts or chromatin integrity in adult mice. Folic acid supplementation in early development or post-weaning did not affect germ cell measures. Therefore, adequate folic acid intake in adulthood is important for preventing chromatin damage and mutation in the male germline. Folic acid supplementation at the level achieved in this study does not improve nor is it detrimental to male germline chromatin integrity. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Tea Dietary Fiber Improves Serum and Hepatic Lipid Profiles in Mice Fed a High Cholesterol Diet.

PubMed

Guo, Wenxin; Shu, Yang; Yang, Xiaoping

2016-06-01

Tea dietary fiber (TDF) was prepared from tea residues and modified to get cellulose-modified TDF (CTDF) by cellulase or micronized TDF (MTDF) by ultrafine grinding. The in vitro lipid-binding capacities of the three fibers and their effects on serum and hepatic lipid profiles in mice fed a high cholesterol diet were evaluated. The results showed that the three fibers had excellent lipid-binding capacities, and the cholesterol- and sodium cholate-binding capacities of CTDF and MTDF were significantly higher than those of TDF. Animal studies showed that, compared to model control, the three fibers significantly decreased mice average daily gain, gain: feed, and liver index, reduced total cholesterol (TC), triglyceride, and low density lipoprotein-cholesterol of serum and liver, increased serum and hepatic high density lipoprotein-cholesterol to TC ratio, and promoted the excretion of fecal lipids, and they also significantly increased the activities of superoxide dismutase and glutathione peroxidase of serum and liver, and decreased lipid peroxidation; moreover, the effects of CTDF and MTDF were better than that of TDF. It was concluded that the three fibers could improve serum and hepatic lipid profiles in mice fed a high cholesterol diet and the mechanism of action might be due to the promotion of fecal excretion of lipids through their lipid-binding ability and the inhibition of lipid peroxidation. These findings suggest that tea dietary fiber has the potential to be used as a functional ingredient to control cardiovascular disease.

PGC-1α and fasting-induced PDH regulation in mouse skeletal muscle.

PubMed

Gudiksen, Anders; Pilegaard, Henriette

2017-04-01

The purpose of the present study was to examine whether lack of skeletal muscle peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 α ) affects the switch in substrate utilization from a fed to fasted state and the fasting-induced pyruvate dehydrogenase (PDH) regulation in skeletal muscle. Skeletal muscle-specific PGC-1 α knockout (MKO) mice and floxed littermate controls were fed or fasted for 24 h. Fasting reduced PDHa activity, increased phosphorylation of all four known sites on PDH-E1 α and increased pyruvate dehydrogenase kinase (PDK4) and sirtuin 3 (SIRT3) protein levels, but did not alter total acetylation of PDH-E1 α Lack of muscle PGC-1 α did not affect the switch from glucose to fat oxidation in the transition from the fed to fasted state, but was associated with lower and higher respiratory exchange ratio (RER) in the fed and fasted state, respectively. PGC-1 α MKO mice had lower skeletal muscle PDH-E1 α , PDK1, 2, 4, and pyruvate dehydrogenase phosphatase (PDP1) protein content than controls, but this did not prevent the fasting-induced increase in PDH-E1 α phosphorylation in PGC-1 α MKO mice. However, lack of skeletal muscle PGC-1 α reduced SIRT3 protein content, increased total lysine PDH-E1 α acetylation in the fed state, and prevented a fasting-induced increase in SIRT3 protein. In conclusion, skeletal muscle PGC-1 α is required for fasting-induced upregulation of skeletal muscle SIRT3 and maintaining high fat oxidation in the fasted state, but is dispensable for preserving the capability to switch substrate during the transition from the fed to the fasted state and for fasting-induced PDH regulation in skeletal muscle. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Prior exercise training blunts short-term high-fat diet-induced weight gain.

PubMed

Snook, Laelie A; MacPherson, Rebecca E K; Monaco, Cynthia M F; Frendo-Cumbo, Scott; Castellani, Laura; Peppler, Willem T; Anderson, Zachary G; Buzelle, Samyra L; LeBlanc, Paul J; Holloway, Graham P; Wright, David C

2016-08-01

High-fat diets rapidly cause weight gain and glucose intolerance. We sought to determine whether these changes could be mitigated with prior exercise training. Male C57BL/6J mice were exercise-trained by treadmill running (1 h/day, 5 days/wk) for 4 wk. Twenty-four hours after the final bout of exercise, mice were provided with a high-fat diet (HFD; 60% kcal from lard) for 4 days, with no further exercise. In mice fed the HFD prior to exercise training, the results were blunted weight gain, reduced fat mass, and a slight attenuation in glucose intolerance that was mirrored by greater insulin-induced Akt phosphorylation in skeletal muscle compared with sedentary mice fed the HFD. When ad libitum-fed sedentary mice were compared with sedentary high-fat fed mice that were calorie restricted (-30%) to match the weight gain of the previously trained high-fat fed mice, the same attenuated impairments in glucose tolerance were found. Blunted weight gain was associated with a greater capacity to increase energy expenditure in trained compared with sedentary mice when challenged with a HFD. Although mitochondrial enzymes in white adipose tissue and UCP-1 protein content in brown adipose tissue were increased in previously exercised compared with sedentary mice fed a HFD, ex vivo mitochondrial respiration was not increased in either tissue. Our data suggest that prior exercise training attenuates high-fat diet-induced weight gain and glucose intolerance and is associated with a greater ability to increase energy expenditure in response to a high-fat diet. Copyright © 2016 the American Physiological Society.

IL-23 promotes intestinal Th17 immunity and ameliorates obesity associated metabolic syndrome in a murine high-fat diet model.

PubMed

Martins, Larissa M S; Perez, Malena M; Pereira, Camila A; Costa, Frederico R C; Dias, Murilo S; Tostes, Rita C; Ramos, Simone G; de Zoete, Marcel R; Ryffel, Bernhard; Silva, João S; Carlos, Daniela

2018-05-02

We addressed the role of IL-23 in driving the intestinal Th17 response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese (DIO) and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23R expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for nine weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinemia and hyperlipidemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes (MLNs) of the HFD mice. Of importance, IL-23 deficient mice exhibited increased gut permeability and blood bacterial translocation compared to WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the feces of IL-23 deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Instigation of NLRP3 inflammasome activation and glomerular injury in mice on the high fat diet: role of acid sphingomyelinase gene

PubMed Central

Boini, Krishna M.; Xia, Min; Koka, Saisudha; Gehr, Todd W.; Li, Pin-Lan

2016-01-01

Ceramide has been reported to initiate inflammasome formation and activation in obesity and different pathological conditions. The present study was performed to explore the role of acid sphingomyelinase (Asm) in the development of high fat diet (HFD)-induced inflammasome and activation and consequent glomerular injury. Asm knockout (Asm−/−) and wild type (Asm+/+) mice with or without Asm short hairpin RNA (shRNA) transfection were fed a HFD or normal chow for 12 weeks to produce obesity and associated glomerular injury. HFD significantly enhanced the Asm activity, ceramide production, colocalization of Nlrp3 (Nod-like receptor protein 3) with ASC (apoptosis-associated speck-like protein) or Caspase-1, NADPH-dependent superoxide (O2•−) production in glomeruli of Asm+/+mice than in control diet-fed mice. However, such HFD-induced increases in Asm activity, ceramide production, colocalization of Nlrp3 with ASC or Caspase-1, superoxide (O2•−) production was attenuated in Asm−/− or Asm shRNA-transfected wild-type mice. In consistency with decreased inflammasome formation, the caspase-1 activity and IL-1β production was significantly attenuated in Asm−/− or Asm shRNA-transfected wild-type mice fed a HFD. Morphological examinations showed that HFD-induced profound injury in glomeruli of Asm+/+ mice which was markedly attenuated in Asm−/− mice. The decreased glomerular damage index in Asm−/− mice was accompanied by attenuated proteinuria. Fluorescent immunohistochemical examinations using podocin as a podocyte marker showed that inflammasome formation induced by the HFD were mostly located in podocytes as demonstrated by co-localization of podocin with Nlrp3. In conclusion, these observations disclose a pivotal role of Asm in the HFD-induced inflammasome formation and consequent glomerular inflammation and injury. PMID:26980705

The new total Western diet for rodents does not induce an overweight phenotype or alter parameters of metabolic syndrome in mice.

PubMed

Monsanto, Stephany P; Hintze, Korry J; Ward, Robert E; Larson, Deanna P; Lefevre, Michael; Benninghoff, Abby D

2016-09-01

In this study, we determined the impact of the total Western diet (TWD) for rodents and its macro- and micronutrient components on weight gain and biomarkers of metabolic function in mice compared to a 45% fat diet-induced obesity (DIO) diet and the standard AIN93G diet. We hypothesized that mice fed the TWD would have increased body fat with indicators of metabolic syndrome similar to mice consuming the DIO diet. As expected, DIO-fed mice acquired a metabolic syndrome phenotype typified by increased energy intake, increased body weight gain, increased fat mass, higher fasting glucose, impaired glucose tolerance, and higher plasma leptin relative to the AIN93G diet. Mice fed a macronutrient-modified (MM) diet (with standard vitamin and mineral composition) had a similar response, albeit to a lesser degree than mice fed the DIO diet. Mice fed a vitamin- and mineral-modified diet (with standard macronutrient composition) were not different from mice fed the AIN93G diet. Surprisingly, the TWD (with modified macronutrients, vitamins and minerals) did not significantly affect any of these parameters, despite the fact that the TWD macronutrient profile was identical to the MM diet. These data suggest that, in the context of the TWD, vitamin and mineral intakes in mice that reflect a Western dietary pattern inhibit the hyperphagia and resulting increased weight gain associated with the higher fat content of the TWD. In conclusion, these observations underscore the need to consider the influence of micronutrient intakes in pre-clinical models of obesity and metabolic syndrome. Copyright © 2016 Elsevier Inc. All rights reserved.

Diet and Epigenetic Interactions in Prostate Cancer Prevention

DTIC Science & Technology

2011-06-01

for pathology. In this study, dietary SFN, fed as freeze-dried broccoli sprouts, increased SFN content in the prostate (Figure 5A) and decreased the...and Exercise Sciences seminar (April 2010) “Cancer Prevention with Broccoli – from Cellular to Human Studies” Cancer chemoprevention seminar...mice. (A) Liver, kidney, colon and prostates were collected from mice fed standard diet and mice fed a 15% broccoli diet and processed according to

Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet

USDA-ARS?s Scientific Manuscript database

A sedentary lifestyle contributes to obesity. This study determined the effects of quantitative voluntary running on body adiposity and its associated inflammation in mice fed a high-fat diet. Male C57BL/6 mice were assigned to six groups and fed an AIN93G (sedentary) or a high-fat diet (sedentary...

Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism.

PubMed

Caesar, Robert; Nygren, Heli; Orešič, Matej; Bäckhed, Fredrik

2016-03-01

The gut microbiota influences many aspects of host metabolism. We have previously shown that the presence of a gut microbiota remodels lipid composition. Here we investigated how interaction between gut microbiota and dietary lipids regulates lipid composition in the liver and plasma, and gene expression in the liver. Germ-free and conventionally raised mice were fed a lard or fish oil diet for 11 weeks. We performed lipidomics analysis of the liver and serum and microarray analysis of the liver. As expected, most of the variation in the lipidomics dataset was induced by the diet, and abundance of most lipid classes differed between mice fed lard and fish oil. However, the gut microbiota also affected lipid composition. The gut microbiota increased hepatic levels of cholesterol and cholesteryl esters in mice fed lard, but not in mice fed fish oil. Serum levels of cholesterol and cholesteryl esters were not affected by the gut microbiota. Genes encoding enzymes involved in cholesterol biosynthesis were downregulated by the gut microbiota in mice fed lard and were expressed at a low level in mice fed fish oil independent of microbial status. In summary, we show that gut microbiota-induced regulation of hepatic cholesterol metabolism is dependent on dietary lipid composition. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

Mitochondrial-Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation.

PubMed

Lee, Hui-Young; Lee, Jae Sung; Alves, Tiago; Ladiges, Warren; Rabinovitch, Peter S; Jurczak, Michael J; Choi, Cheol Soo; Shulman, Gerald I; Samuel, Varman T

2017-08-01

We explored the role of reactive oxygen species (ROS) in the pathogenesis of muscle insulin resistance. We assessed insulin action in vivo with a hyperinsulinemic-euglycemic clamp in mice expressing a mitochondrial-targeted catalase (MCAT) that were fed regular chow (RC) or a high-fat diet (HFD) or underwent an acute infusion of a lipid emulsion. RC-fed MCAT mice were similar to littermate wild-type (WT) mice. However, HFD-fed MCAT mice were protected from diet-induced insulin resistance. In contrast, an acute lipid infusion caused muscle insulin resistance in both MCAT and WT mice. ROS production was decreased in both HFD-fed and lipid-infused MCAT mice and cannot explain the divergent response in insulin action. MCAT mice had subtly increased energy expenditure and muscle fat oxidation with decreased intramuscular diacylglycerol (DAG) accumulation, protein kinase C-θ (PKCθ) activation, and impaired insulin signaling with HFD. In contrast, the insulin resistance with the acute lipid infusion was associated with increased muscle DAG content in both WT and MCAT mice. These studies suggest that altering muscle mitochondrial ROS production does not directly alter the development of lipid-induced insulin resistance. However, the altered energy balance in HFD-fed MCAT mice protected them from DAG accumulation, PKCθ activation, and impaired muscle insulin signaling. © 2017 by the American Diabetes Association.

Calcium- and Phosphorus-Supplemented Diet Increases Bone Mass after Short-Term Exercise and Increases Bone Mass and Structural Strength after Long-Term Exercise in Adult Mice

PubMed Central

Friedman, Michael A.; Bailey, Alyssa M.; Rondon, Matthew J.; McNerny, Erin M.; Sahar, Nadder D.; Kohn, David H.

2016-01-01

Exercise has long-lasting benefits to bone health that may help prevent fractures by increasing bone mass, bone strength, and tissue quality. Long-term exercise of 6–12 weeks in rodents increases bone mass and bone strength. However, in growing mice, a short-term exercise program of 3 weeks can limit increases in bone mass and structural strength, compared to non-exercised controls. Short-term exercise can, however, increase tissue strength, suggesting that exercise may create competition for minerals that favors initially improving tissue-level properties over structural-level properties. It was therefore hypothesized that adding calcium and phosphorus supplements to the diet may prevent decreases in bone mass and structural strength during a short-term exercise program, while leading to greater bone mass and structural strength than exercise alone after a long-term exercise program. A short-term exercise experiment was done for 3 weeks, and a long-term exercise experiment was done for 8 weeks. For each experiment, male 16-week old C57BL/6 mice were assigned to 4 weight-matched groups–exercise and non-exercise groups fed a control or mineral-supplemented diet. Exercise consisted of treadmill running at 12 m/min, 30 min/day for 7 days/week. After 3 weeks, exercised mice fed the supplemented diet had significantly increased tibial tissue mineral content (TMC) and cross-sectional area over exercised mice fed the control diet. After 8 weeks, tibial TMC, cross-sectional area, yield force, and ultimate force were greater from the combined treatments than from either exercise or supplemented diet alone. Serum markers of bone formation (PINP) and resorption (CTX) were both decreased by exercise on day 2. In exercised mice, day 2 PINP was significantly positively correlated with day 2 serum Ca, a correlation that was weaker and negative in non-exercised mice. Increasing dietary mineral consumption during an exercise program increases bone mass after 3 weeks and increases structural strength after 8 weeks, making bones best able to resist fracture. PMID:27008546

Anti-obesity effects of hot water extract from Wasabi (Wasabia japonica Matsum.) leaves in mice fed high-fat diets

PubMed Central

Ogawa, Tetsuro; Wang, Li; Katsube, Takuya; Yamasaki, Yukikazu; Sun, Xufeng; Shiwaku, Kuninori

2013-01-01

The anti-obesity effects of a hot water extract from wasabi (Wasabia japonica Matsum.) leaves (WLE), without its specific pungent constituents, such as allyl-isothiocyanate, were investigated in high fat-diet induced mice. C57J/BL mice were fed a high-fat diet (control group) or a high-fat diet supplemented with 5% WLE (WLE group). Physical parameters and blood profiles were determined. Gene expression associated with lipid metabolism in liver and white adipose tissue were analyzed. After 120 days of feeding, significantly lower body weight gain, liver weight and epididymal white adipose tissue weight was observed in the WLE group compared to the control group. In liver gene expression within the WLE group, PPARα was significantly enhanced and SREBP-1c was significantly suppressed. Subsequent downstream genes controlled by these regulators were significantly suppressed. In epididymal white adipose tissue of the WLE group, expression of leptin, PPARγ, and C/EBPα were significantly suppressed and adiponectin was significantly enhanced. Acox, related to fatty acid oxidization in adipocytes, was also enhanced. Our results demonstrate that the WLE dietary supplement induces mild suppression of obesity in a high-fat diet induced mice, possibly due to suppression of lipid accumulation in liver and white adipose tissue. PMID:23964313

Anti-obesity effects of hot water extract from Wasabi (Wasabia japonica Matsum.) leaves in mice fed high-fat diets.

PubMed

Yamasaki, Masayuki; Ogawa, Tetsuro; Wang, Li; Katsube, Takuya; Yamasaki, Yukikazu; Sun, Xufeng; Shiwaku, Kuninori

2013-08-01

The anti-obesity effects of a hot water extract from wasabi (Wasabia japonica Matsum.) leaves (WLE), without its specific pungent constituents, such as allyl-isothiocyanate, were investigated in high fat-diet induced mice. C57J/BL mice were fed a high-fat diet (control group) or a high-fat diet supplemented with 5% WLE (WLE group). Physical parameters and blood profiles were determined. Gene expression associated with lipid metabolism in liver and white adipose tissue were analyzed. After 120 days of feeding, significantly lower body weight gain, liver weight and epididymal white adipose tissue weight was observed in the WLE group compared to the control group. In liver gene expression within the WLE group, PPARα was significantly enhanced and SREBP-1c was significantly suppressed. Subsequent downstream genes controlled by these regulators were significantly suppressed. In epididymal white adipose tissue of the WLE group, expression of leptin, PPARγ, and C/EBPα were significantly suppressed and adiponectin was significantly enhanced. Acox, related to fatty acid oxidization in adipocytes, was also enhanced. Our results demonstrate that the WLE dietary supplement induces mild suppression of obesity in a high-fat diet induced mice, possibly due to suppression of lipid accumulation in liver and white adipose tissue.

Protonated nanostructured aluminosilicate (NSAS) reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet

PubMed Central

Sivak, Olena; Darlington, Jerry; Gershkovich, Pavel; Constantinides, Panayiotis P; Wasan, Kishor M

2009-01-01

The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w) and stigmastanol at 2% (w/w) treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w) NSAS and 2% (w/w) stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model. PMID:19638223

Protonated nanostructured aluminosilicate (NSAS) reduces plasma cholesterol concentrations and atherosclerotic lesions in Apolipoprotein E deficient mice fed a high cholesterol and high fat diet.

PubMed

Sivak, Olena; Darlington, Jerry; Gershkovich, Pavel; Constantinides, Panayiotis P; Wasan, Kishor M

2009-07-28

The aim of this work was to assess the effect of chronic administration of protonated nanostructured aluminosilicate (NSAS) on the plasma cholesterol levels and development of atherosclerotic lesions in Apolipoprotein (ApoE) deficient mice fed a high cholesterol and high fat diet. Apolipoprotein E (ApoE) deficient mice were divided into the following treatment groups: protonated NSAS 1.4% (w/w), untreated control and 2% (w/w) stigmastanol mixed with high-cholesterol/high-fat diet. Animals were treated for 12 weeks, blood samples were withdrawn every 4 weeks for determination of plasma cholesterol and triglyceride levels. At the end of the study the aortic roots were harvested for assessment of atherosclerotic lesions. NSAS at 1.4% (w/w) and stigmastanol at 2% (w/w) treatment groups showed significant decreases in plasma cholesterol concentrations at all time points relative to the control animals. The lesion sum area in 1.4% (w/w) NSAS and 2% (w/w) stigmastanol groups were significantly less from the control animals. In conclusion, in this study, the effectiveness of chronic administration of protonated NSAS material in the reduction of plasma cholesterol levels and decrease in development of atherosclerotic lesions was demonstrated in Apo-E deficient mice model.

Circulating metabolites of strawberry mediate reductions in vascular inflammation and endothelial dysfunction in db/db mice.

PubMed

Petersen, Chrissa; Bharat, Divya; Cutler, Brett Ronald; Gholami, Samira; Denetso, Christopher; Mueller, Jennifer Ellen; Cho, Jae Min; Kim, Ji-Seok; Symons, J David; Anandh Babu, Pon Velayutham

2018-07-15

Cardiovascular disease is 2-4-fold more prevalent in patients with diabetes. Human studies support the cardiovascular benefits of strawberry consumption but the effects of strawberry on diabetic vasculature are unknown. We tested the hypothesis that dietary strawberry supplementation attenuates vascular inflammation and dysfunction in diabetic mice. Seven-week-old diabetic db/db mice that consumed standard diet (db/db) or diet supplemented with 2.35% freeze-dried strawberry (db/db + SB) for ten weeks were compared to non-diabetic control mice (db/+). Indices of vascular inflammation and dysfunction were measured. Endothelial cells (ECs) were isolated from the vasculature to determine the influence of strawberry on them. The effect of metabolites of strawberry on endothelial inflammation was determined by incubating mouse aortic ECs (MAECs) with ±5% serum, obtained from strawberry fed mice (metabolites serum) or standard diet fed mice (control serum) ± 25 mM glucose and 100 μM palmitate. db/db mice exhibited an increased monocyte binding to vessel, elevated blood pressure, and reduced endothelial-dependent vasorelaxation compared with db/+ mice but each defect was attenuated in db/db + SB mice. The elevation of inflammatory molecules, NOX2 and inhibitor-κB kinase observed in ECs from db/db vs. db/+ mice was suppressed in db/db + SB mice. Glucose and palmitate increased endothelial inflammation in MAECs but were normalized by co-incubation with metabolites serum. Dietary supplementation of strawberry attenuates indices of vascular inflammation and dysfunction in diabetic db/db mice. The effect of strawberry on vasculature is endothelial-dependent and possibly mediated through their circulating metabolites. Strawberry might complement conventional therapies to improve vascular complications in diabetics. Copyright © 2017 Elsevier B.V. All rights reserved.

Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Yu-Kun Jennifer; Wu, Kai Connie; Liu, Jie

Nrf2, a master regulator of intracellular redox homeostasis, is indicated to participate in fatty acid metabolism in liver. However, its role in diet-induced obesity remains controversial. In the current study, genetically engineered Nrf2-null, wild-type (WT), and Nrf2-activated, Keap1-knockdown (K1-KD) mice were fed either a control or a high-fat Western diet (HFD) for 12 weeks. The results indicate that the absence or enhancement of Nrf2 activity did not prevent diet-induced obesity, had limited effects on lipid metabolism, but affected blood glucose homeostasis. Whereas the Nrf2-null mice were resistant to HFD-induced glucose intolerance, the Nrf2-activated K1-KD mice exhibited prolonged elevation of circulatingmore » glucose during a glucose tolerance test even on the control diet. Feeding a HFD did not activate the Nrf2 signaling pathway in mouse livers. Fibroblast growth factor 21 (Fgf21) is a liver-derived anti-diabetic hormone that exerts glucose- and lipid-lowering effects. Fgf21 mRNA and protein were both elevated in livers of Nrf2-null mice, and Fgf21 protein was lower in K1-KD mice than WT mice. The inverse correlation between Nrf2 activity and hepatic expression of Fgf21 might explain the improved glucose tolerance in Nrf2-null mice. Furthermore, a more oxidative cellular environment in Nrf2-null mice could affect insulin signaling in liver. For example, mRNA of insulin-like growth factor binding protein 1, a gene repressed by insulin in hepatocytes, was markedly elevated in livers of Nrf2-null mice. In conclusion, genetic alteration of Nrf2 does not prevent diet-induced obesity in mice, but deficiency of Nrf2 improves glucose homeostasis, possibly through its effects on Fgf21 and/or insulin signaling. -- Highlights: ► Nrf2 deficiency improves glucose tolerance in mice fed a high-fat diet. ► The anti-diabetic hormone, Fgf21, is highly expressed in livers of Nrf2-null mice. ► The absence of Nrf2 increases the insulin-regulated Igfbp-1 mRNA in liver. ► Nrf2 deficiency improves glucose tolerance by influencing Fgf21 and insulin signaling.« less

High-fat diets rich in ω-3 or ω-6 polyunsaturated fatty acids have distinct effects on lipid profiles and lipid peroxidation in mice selected for either high body weight or leanness.

PubMed

Dannenberger, Dirk; Nuernberg, Gerd; Renne, Ulla; Nuernberg, Karin; Langhammer, Martina; Huber, Korinna; Breier, Bernhard

2013-05-01

The aim of the study is to determine the response of muscle lipid peroxidation and the fatty-acid profile of three groups of mice-high body weight (DU6) obesity-prone mice, high treadmill performance (DUhTP) lean mice, and unselected control mice (DUK) fed high-fat diets (HFDs) rich in ω-3 or ω-6 polyunsaturated fatty acids (PUFA). The isocaloric HFDs were enriched with either ω-3 PUFA (27% fish oil, ω-3 HFD) or ω-6 PUFA (27% sunflower oil, ω-6 HFD), and the control group was fed standard chow (7.2% fat). Statistical calculations were done with procedure GLM of SAS. As expected, the ω-3 and ω-6 PUFA-rich HFDs showed significant effects on fatty-acid concentrations of skeletal muscle in all three lines of mice compared with the standard chow. The investigations of muscle lipid peroxidation revealed that the ω-3 PUFA-rich HFD caused the highest lipid peroxidation values in muscle of lean DUhTP mice and unselected control DUK mice. However, lower lipid peroxidation levels were observed in the obesity-prone DU6 mice. In contrast, the ω-6 PUFA-rich HFD did not influence lipid peroxidation in muscle of any of the different lines of mice. The present study suggests that a higher overall antioxidant capacity in the muscle tissue of obesity-prone DU6 mice may lead to lower levels of reactive oxygen species formation by ω-3 PUFA-rich HFDs in comparison with lean DUhTP mice. These studies raise the possibility that obesity per se may be protective against oxidative damage when high ω-3 PUFA diets are used. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of super-hard rice bread blended with black rice bran on amyloid β peptide production and abrupt increase in postprandial blood glucose levels in mice.

PubMed

Nakamura, Sumiko; Hara, Takashi; Joh, Toshio; Kobayashi, Atsushi; Yamazaki, Akira; Kasuga, Kensaku; Ikeuchi, Takeshi; Ohtsubo, Ken'ichi

2017-02-01

Alzheimer's disease and type 2 diabetes are very serious diseases with the latter having been suggested to cause the former. We prepared super-hard rice bread blended with black rice bran (SRBBB), which contained a high amount of resistant starch that showed strong inhibitory activities against β-secretase and acetylcholinesterase even after heating. Black rice bran showed greater β-secretase inhibitory activity (3.6-fold) than Koshihikari rice. The bran contained more oleic acid and anthocyanin, meaning that it is potentially a biofunctional food with a high antioxidant capacity. Furthermore, aged mice, which were fed a SRBBB diet for four weeks, showed lower amyloid β 40 peptide in the blood than mice fed a commercial diet (p < 0.01). Additionally, their initial blood glucose levels (BGLs) after 12 weeks of being fed SRBBB were significantly lower than those in the control group. Taken together, our results indicate SRBBB shows promise for inhibiting not only amyloid β production, but also abrupt increases in postprandial BGLs.

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice

PubMed Central

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A.; Xu, Hui; Katiyar, Santosh K.

2013-01-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DCs). Co-culture of CD4+ T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of Th-1 type cytokines that was ameliorated when the DCs were obtained from GSPs-fed mice; whereas, DCs obtained from GSPs-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4, dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. PMID:23321928

Role of aramchol in steatohepatitis and fibrosis in mice

PubMed Central

Iruarrizaga‐Lejarreta, Marta; Varela‐Rey, Marta; Fernández‐Ramos, David; Martínez‐Arranz, Ibon; Delgado, Teresa C; Simon, Jorge; Gutiérrez‐de Juan, Virginia; delaCruz‐Villar, Laura; Azkargorta, Mikel; Lavin, José L.; Mayo, Rebeca; Van Liempd, Sebastiaan M.; Aurrekoetxea, Igor; Buqué, Xabier; Delle Cave, Donatella; Peña, Arantza; Rodríguez‐Cuesta, Juan; Aransay, Ana M.; Elortza, Felix; Falcón‐Pérez, Juan M.; Aspichueta, Patricia; Hayardeny, Liat; Noureddin, Mazen; Sanyal, Arun J.; Alonso, Cristina; Anguita, Juan; Martínez‐Chantar, María Luz; Lu, Shelly C.

2017-01-01

Nonalcoholic steatohepatitis (NASH) is the advanced form of nonalcoholic fatty liver disease (NAFLD) that sets the stage for further liver damage. The mechanism for the progression of NASH involves multiple parallel hits, including oxidative stress, mitochondrial dysfunction, inflammation, and others. Manipulation of any of these pathways may be an approach to prevent NASH development and progression. Arachidyl‐amido cholanoic acid (Aramchol) is presently in a phase IIb NASH study. The aim of the present study was to investigate Aramchol's mechanism of action and its effect on fibrosis using the methionine‐ and choline‐deficient (MCD) diet model of NASH. We collected liver and serum from mice fed an MCD diet containing 0.1% methionine (0.1MCD) for 4 weeks; these mice developed steatohepatitis and fibrosis. We also collected liver and serum from mice receiving a control diet, and metabolomes and proteomes were determined for both groups. The 0.1MCD‐fed mice were given Aramchol (5 mg/kg/day for the last 2 weeks), and liver samples were analyzed histologically. Aramchol administration reduced features of steatohepatitis and fibrosis in 0.1MCD‐fed mice. Aramchol down‐regulated stearoyl‐coenyzme A desaturase 1, a key enzyme involved in triglyceride biosynthesis and the loss of which enhances fatty acid β‐oxidation. Aramchol increased the flux through the transsulfuration pathway, leading to a rise in glutathione (GSH) and the GSH/oxidized GSH ratio, the main cellular antioxidant that maintains intracellular redox status. Comparison of the serum metabolomic pattern between 0.1MCD‐fed mice and patients with NAFLD showed a substantial overlap. Conclusion: Aramchol treatment improved steatohepatitis and fibrosis by 1) decreasing stearoyl‐coenyzme A desaturase 1 and 2) increasing the flux through the transsulfuration pathway maintaining cellular redox homeostasis. We also demonstrated that the 0.1MCD model resembles the metabolic phenotype observed in about 50% of patients with NAFLD, which supports the potential use of Aramchol in NASH treatment. (Hepatology Communications 2017;1:911–927) PMID:29159325

Effects of Fortunella margarita fruit extract on metabolic disorders in high-fat diet-induced obese C57BL/6 mice.

PubMed

Tan, Si; Li, Mingxia; Ding, Xiaobo; Fan, Shengjie; Guo, Lu; Gu, Ming; Zhang, Yu; Feng, Li; Jiang, Dong; Li, Yiming; Xi, Wanpeng; Huang, Cheng; Zhou, Zhiqin

2014-01-01

Obesity is a nutritional disorder associated with many health problems such as dyslipidemia, type 2 diabetes and cardiovascular diseases. In the present study, we investigated the anti-metabolic disorder effects of kumquat (Fortunella margarita Swingle) fruit extract (FME) on high-fat diet-induced C57BL/6 obese mice. The kumquat fruit was extracted with ethanol and the main flavonoids of this extract were analyzed by HPLC. For the preventive experiment, female C57BL/6 mice were fed with a normal diet (Chow), high-fat diet (HF), and high-fat diet with 1% (w/w) extract of kumquat (HF+FME) for 8 weeks. For the therapeutic experiment, female C57BL/6 mice were fed with high-fat diet for 3 months to induce obesity. Then the obese mice were divided into two groups randomly, and fed with HF or HF+FME for another 2 weeks. Body weight and daily food intake amounts were recorded. Fasting blood glucose, glucose tolerance test, insulin tolerance test, serum and liver lipid levels were assayed and the white adipose tissues were imaged. The gene expression in mice liver and brown adipose tissues were analyzed with a quantitative PCR assay. In the preventive treatment, FME controlled the body weight gain and the size of white adipocytes, lowered the fasting blood glucose, serum total cholesterol (TC), serum low density lipoprotein cholesterol (LDL-c) levels as well as liver lipid contents in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, FME decreased the serum triglyceride (TG), serum TC, serum LDL-c, fasting blood glucose levels and liver lipid contents, improved glucose tolerance and insulin tolerance. Compared with the HF group, FME significantly increased the mRNA expression of PPARα and its target genes. Our study suggests that FME may be a potential dietary supplement for preventing and ameliorating the obesity and obesity-related metabolic disturbances.

Effects of Dietary Zinc Manipulation on Growth Performance, Zinc Status and Immune Response during Giardia lamblia Infection: A Study in CD-1 Mice

PubMed Central

Iñigo-Figueroa, Gemma; Méndez-Estrada, Rosa O.; Quihui-Cota, Luis; Velásquez-Contreras, Carlos A.; Garibay-Escobar, Adriana; Canett-Romero, Rafael; Astiazarán-García, Humberto

2013-01-01

Associations between Giardia lamblia infection and low serum concentrations of zinc have been reported in young children. Interestingly, relatively few studies have examined the effects of different dietary zinc levels on the parasite-infected host. The aims of this study were to compare the growth performance and zinc status in response to varying levels of dietary zinc and to measure the antibody-mediated response of mice during G. lamblia infection. Male CD-1 mice were fed using 1 of 4 experimental diets: adequate-zinc (ZnA), low-zinc (ZnL), high-zinc (ZnH) and supplemented-zinc (ZnS) diet containing 30, 10, 223 and 1383 mg Zn/kg respectively. After a 10 days feeding period, mice were inoculated orally with 5 × 106 G. lamblia trophozoites and were maintained on the assigned diet during the course of infection (30 days). Giardia-free mice fed ZnL diets were able to attain normal growth and antibody-mediated response. Giardia-infected mice fed ZnL and ZnA diets presented a significant growth retardation compared to non-infected controls. Zinc supplementation avoided this weight loss during G. lamblia infection and up-regulated the host’s humoral immune response by improving the production of specific antibodies. Clinical outcomes of zinc supplementation during giardiasis included significant weight gain, higher anti-G. lamblia IgG antibodies and improved serum zinc levels despite the ongoing infection. A maximum growth rate and antibody-mediated response were attained in mice fed ZnH diet. No further increases in body weight, zinc status and humoral immune capacity were noted by feeding higher zinc levels (ZnS) than the ZnH diet. These findings probably reflect biological effect of zinc that could be of public health importance in endemic areas of infection. PMID:24002196

Dietary rice bran promotes resistance to Salmonella enterica serovar Typhimurium colonization in mice.

PubMed

Kumar, Ajay; Henderson, Angela; Forster, Genevieve M; Goodyear, Andrew W; Weir, Tiffany L; Leach, Jan E; Dow, Steven W; Ryan, Elizabeth P

2012-07-04

Dietary rice bran consists of many bioactive components with disease fighting properties; including the capacity to modulate the gut microbiota. Studies point to the important roles of the gut microbiota and the mucosal epithelium in the establishment of protection against enteric pathogens, such as Salmonella. The ability of rice bran to reduce the susceptibility of mice to a Salmonella infection has not been previously investigated. Therefore, we hypothesized that the incorporation of rice bran into the diet would inhibit the colonization of Salmonella in mice through the induction of protective mucosal responses. Mice were fed diets containing 0%, 10% and 20% rice bran for one week prior to being orally infected with Salmonella enterica serovar Typhimurium. We found that mice consuming the 10 and 20% rice bran diets exhibited a reduction in Salmonella fecal shedding for up to nine days post-infection as compared to control diet fed animals (p < 0.05). In addition, we observed decreased concentrations of the pro-inflammatory cytokines, TNF-alpha, IFN-gamma, and IL-12 (p < 0.05) as well as increased colonization of native Lactobacillus spp. in rice bran fed mice (p < 0.05). Furthermore, in vitro experiments revealed the ability of rice bran extracts to reduce Salmonella entry into mouse small intestinal epithelial cells. Increasing rice bran consumption represents a novel dietary means for reducing susceptibility to enteric infection with Salmonella and potentially via induction of native Lactobacillus spp.

Dietary rice bran promotes resistance to Salmonella enterica serovar Typhimurium colonization in mice

PubMed Central

2012-01-01

Background Dietary rice bran consists of many bioactive components with disease fighting properties; including the capacity to modulate the gut microbiota. Studies point to the important roles of the gut microbiota and the mucosal epithelium in the establishment of protection against enteric pathogens, such as Salmonella. The ability of rice bran to reduce the susceptibility of mice to a Salmonella infection has not been previously investigated. Therefore, we hypothesized that the incorporation of rice bran into the diet would inhibit the colonization of Salmonella in mice through the induction of protective mucosal responses. Results Mice were fed diets containing 0%, 10% and 20% rice bran for one week prior to being orally infected with Salmonella enterica serovar Typhimurium. We found that mice consuming the 10 and 20% rice bran diets exhibited a reduction in Salmonella fecal shedding for up to nine days post-infection as compared to control diet fed animals (p < 0.05). In addition, we observed decreased concentrations of the pro-inflammatory cytokines, TNF-alpha, IFN-gamma, and IL-12 (p < 0.05) as well as increased colonization of native Lactobacillus spp. in rice bran fed mice (p < 0.05). Furthermore, in vitro experiments revealed the ability of rice bran extracts to reduce Salmonella entry into mouse small intestinal epithelial cells. Conclusions Increasing rice bran consumption represents a novel dietary means for reducing susceptibility to enteric infection with Salmonella and potentially via induction of native Lactobacillus spp. PMID:22583915

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

PubMed Central

Garbow, Joel R.; Doherty, Jason M.; Schugar, Rebecca C.; Travers, Sarah; Weber, Mary L.; Wentz, Anna E.; Ezenwajiaku, Nkiruka; Cotter, David G.; Brunt, Elizabeth M.

2011-01-01

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis. PMID:21454445

Effects of Low Carbohydrate High Protein (LCHP) diet on atherosclerotic plaque phenotype in ApoE/LDLR-/- mice: FT-IR and Raman imaging.

PubMed

Wrobel, T P; Marzec, K M; Chlopicki, S; Maślak, E; Jasztal, A; Franczyk-Żarów, M; Czyżyńska-Cichoń, I; Moszkowski, T; Kostogrys, R B; Baranska, M

2015-09-22

Low Carbohydrate High Protein (LCHP) diet displays pro-atherogenic effects, however, the exact mechanisms involved are still unclear. Here, with the use of vibrational imaging, such as Fourier transform infrared (FT-IR) and Raman (RS) spectroscopies, we characterize biochemical content of plaques in Brachiocephalic Arteries (BCA) from ApoE/LDLR(-/-) mice fed LCHP diet as compared to control, recomended by American Institute of Nutrition, AIN diet. FT-IR images were taken from 6-10 sections of BCA from each mice and were complemented with RS measurements with higher spatial resolution of chosen areas of plaque sections. In aortic plaques from LCHP fed ApoE/LDLR(-/-) mice, the content of cholesterol and cholesterol esters was increased, while that of proteins was decreased as evidenced by global FT-IR analysis. High resolution imaging by RS identified necrotic core/foam cells, lipids (including cholesterol crystals), calcium mineralization and fibrous cap. The decreased relative thickness of the outer fibrous cap and the presence of buried caps were prominent features of the plaques in ApoE/LDLR(-/-) mice fed LCHP diet. In conclusion, FT-IR and Raman-based imaging provided a complementary insight into the biochemical composition of the plaque suggesting that LCHP diet increased plaque cholesterol and cholesterol esters contents of atherosclerotic plaque, supporting the cholesterol-driven pathogenesis of LCHP-induced atherogenesis.

Are you also what your mother eats? Distinct proteomic portrait as a result of maternal high-fat diet in the cerebral cortex of the adult mouse.

PubMed

Manousopoulou, A; Woo, J; Woelk, C H; Johnston, H E; Singhania, A; Hawkes, C; Garbis, S D; Carare, R O

2015-08-01

Epidemiological studies suggest an association between maternal obesity and adverse neurodevelopmental outcomes in offspring. Our aim was to compare the global proteomic portrait in the cerebral cortex between mice born to mothers on a high-fat or control diet who themselves were fed a high-fat or control diet. Male mice born to dams fed a control (C) or high-fat (H) diet 4 weeks before conception and during gestation, and lactation were assigned to either C or H diet at weaning. Mice were killed at 19 weeks and their cerebral cortices were analysed using a two-dimensional liquid chromatography-mass spectrometry methodology. In total, 6 695 proteins were identified (q<0.01), 10% of which were modulated in at least one of the groups relative to controls. In silico analysis revealed that mice clustered based on the diet of the mother and not their own diet and that maternal high-fat diet was significantly associated with response to hypoxia/oxidative stress and apoptosis in the cerebral cortex of the adult offspring. Maternal high-fat diet resulted in distinct endophenotypic changes of the adult offspring cerebral cortex independent of its current diet. The identified proteins could represent novel therapeutic targets for the prevention of neuropathological features resulting from maternal obesity.

Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice.

PubMed

Masuyama, Hisashi; Hiramatsu, Yuji

2012-07-15

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance even during pregnancy, while exposure to a high-fat diet (HFD) in utero in mice can induce a type 2 diabetes phenotype that can be transmitted to the progeny. Therefore, we examined whether treatment with a CAR ligand during pregnancy could prevent hypertension, insulin resistance, and hyperlipidemia in the offspring from HFD-induced obese pregnant mice (OH mice). We employed four groups of offspring from HFD-fed and control diet-fed pregnant mice with or without treatment with a CAR ligand. Treatment with a CAR ligand during pregnancy improved glucose tolerance and the levels of triglyceride and adipocytokine and restored the changes induced by HFD with amelioration of hypertension in the adult OH mice. This treatment also increased adiponectin mRNA expression, suppressed leptin expression in adipose tissues of OH mice, and abolished the effect of HFD on the epigenetic modifications of the genes encoding adiponectin and leptin in the offspring during immaturity and adulthood. Our data suggest that CAR might be a potential therapeutic target to prevent metabolic syndrome in adulthood of offspring exposed to an HFD in utero.

Effect of a nutrient mixture on the localization of extracellular matrix proteins in HeLa human cervical cancer xenografts in female nude mice.

PubMed

Roomi, M Waheed; Cha, John; Kalinovsky, Tatiana; Roomi, Nusrath; Niedzwiecki, Aleksandra; Rath, Matthias

2015-09-01

Cervical cancer is one of the most commonly diagnosed cancers and a significant cause of mortality in women worldwide. Although cervical cancer is fully treatable in the early stages, once it has metastasized, patient outcome is poor. The objective of the present study was to investigate the effect of dietary supplementation with a nutrient mixture (NM) containing lysine, ascorbic acid, proline, green tea extract and other micronutrients on the expression of extracellular matrix (ECM) proteins in HeLa cell xenografts in nude female mice. After housing for 1 week, female athymic nude mice between 5 and 6 weeks of age (n=12) were inoculated subcutaneously with 3×10 6 HeLa cells in phosphate-buffered saline and Matrigel and randomly divided into two groups. These were the control group, in which the mice were fed with regular mouse chow, and the NM group, in which the mice were fed with the regular diet supplemented with 0.5% NM (w/w). After 4 weeks, the tumors were excised and processed for histology. Tumor growth was evaluated and the tumors were stained for the ECM proteins collagen I, collagen IV, fibronectin, laminin, periodic acid-Schiff (PAS) and elastin. NM strongly inhibited (by 59%, P=0.001) the growth of HeLa xenografts in nude mice. Tumors from control mice exhibited little to no collagen I expression either internally or in the fibrous capsule, while tumors from the NM group expressed collagen I in the fibrous capsule and within the tumor. Tumors from the control group showed diffuse cytoplasmic and capsular collagen IV with abundant nucleated cells. NM treatment substantially increased collagen IV production and induced a dense fibrous network of collagen IV with chambers that surrounded live nucleated cells and large amounts of necrotic cell debris. Tumors from the mice fed with the NM exhibited a well-defined border of fibronectin in the capsule and intense areas of staining internally whereas control group tumors showed less overall fibronectin with sporadic internal staining and little in the fibrous capsule. Although laminin appeared abundantly in control and NM-treated tumors, the NM group tumors exhibited a chamber-like network of laminin internally. Tumors from the control group exhibited internal areas of intense PAS staining, whereas tumors from the NM-treated group exhibited a more uniform diffuse pattern of PAS staining. In conclusion, NM supplementation of HeLa xenograft-bearing female nude mice demonstrated a potent inhibition of tumor growth and enhancement of ECM proteins, suggesting the therapeutic value of this specific nutrient complex in the treatment of cervical cancer.

The antibody rHIgM22 facilitates hippocampal remyelination and ameliorates memory deficits in the cuprizone mouse model of demyelination.

PubMed

Cui, Charlene; Wang, Jing; Mullin, Ariana P; Caggiano, Anthony O; Parry, Tom J; Colburn, Raymond W; Pavlopoulos, Elias

2018-05-15

Multiple sclerosis (MS) is a chronic, inflammatory demyelinating disease of the CNS. In addition to motor, sensory and visual deficits, MS is also characterized by hippocampal demyelination and memory impairment. We recently demonstrated that a recombinant human-derived monoclonal IgM antibody, which is designated rHIgM22 and currently in clinical development for people with MS, accelerates remyelination of the corpus callosum in the brains of cuprizone-treated mice. Here, we investigated the effects of rHIgM22 in the hippocampus and on hippocampal-dependent learning and memory in the same mouse model of cuprizone-induced demyelination and spontaneous remyelination. The degree of hippocampal myelination of cuprizone-fed mice treated with a single dose of rHIgM22 (10 mg/kg of body weight) was examined immediately after the end of the cuprizone diet as well as at different time points during the recovery period with regular food, and compared with that of cuprizone-fed animals treated with either vehicle or human IgM isotype control antibody. Mice fed only regular food were used as controls. Four or five mice per treatment group were examined for each time point. We demonstrate that treatment with rHIgM22 accelerated remyelination of the demyelinated hippocampus. Using two additional cohorts of mice and eight animals per treatment group for each cohort, we also demonstrate that the enhancing effects of rHIgM22 on hippocampal remyelination were accompanied by improved performance in the Morris water maze and amelioration of the memory deficits induced by cuprizone. These results further confirm the remyelination-promoting capabilities of rHIgM22 and support additional investigation of its therapeutic potential in MS. Copyright © 2018. Published by Elsevier B.V.

Serum alkylresorcinols as biomarkers of dietary gluten exposure in coeliac disease.

PubMed

Choung, R S; Murray, J A; Marietta, E V; Van Dyke, C T; Ross, A B

2017-03-01

Therapy for coeliac disease (CD) mainly relies on following a gluten-free diet (GFD); however, a serum marker for gluten intake has yet to be established. To evaluate the utility of alkylresorcinol concentrations for detecting gluten intake in studies of human and mouse. Alkylresorcinol concentrations were compared among treated patients with coeliac disease (n = 34), untreated coeliac disease patients (n = 36) and controls (n = 33). Furthermore, seven additional coeliac disease patients whose serum samples were available at diagnosis and after GFD were evaluated. In mice studies, alkylresorcinol concentrations were compared in the serum of five mice fed a regular chow and 10 mice fed lifelong with a gluten-free chow. In addition, the effect of adding gluten on changes of alkylresorcinol concentrations was also evaluated. Total alkylresorcinol concentrations were significantly lower in treated with coeliac disease [median (IQR), 3 (2-8) nmol/L], compared to untreated patients [median (IQR), 32 (11-74) nmol/L; P < 0.0001] or healthy controls [median (IQR), 54 (23-112) nmol/L; P < 0.0001]. Moreover, alkylresorcinol concentrations in coeliac disease patients significantly decreased after introduction of a GFD (median, 34 nmol/L at diagnosis vs. 5 nmol/L after GFD, P = 0.02). In the mice, median (IQR) total alkylresorcinol concentrations in serum samples of mice fed lifelong with a gluten-free chow was 1.8 (1.6-2.3) nmol/L, which was further significantly increased to 16 (11-22) nmol/L after 8 days of feeding with the gluten-free chow that had gluten added to it. (P = 0.008). Serum alkylresorcinol concentrations could be a useful marker for dietary gluten in coeliac disease. © 2017 John Wiley & Sons Ltd.

Complement C5 controls liver lipid profile, promotes liver homeostasis and inflammation in C57BL/6 genetic background.

PubMed

Bavia, Lorena; de Castro, Íris Arantes; Cogliati, Bruno; Dettoni, Juliano Bertollo; Alves, Venancio Avancini Ferreira; Isaac, Lourdes

2016-07-01

Innate immunity contributes effectively to the development of alcoholic liver disease (ALD). In special, the activation of the complement system is involved in the pathogenesis of this disease. Here we investigated the contribution of complement C5 protein to the establishment and maintenance of ALD. Eight- to ten-week-old B6C5(+) and B6C5(-) male mice were fed with high fat diet (HFD) only or the same diet containing equicaloric supplements of ethanol (HFDE) or maltodextrin (HFDM) for 10 weeks. Serum parameters of liver function as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), albumin, glucose, triglycerides (TG) and cholesterol were evaluated. Liver tissue samples were collected for histopathological analysis, lipid extraction (TG and cholesterol), cytokines (TNF-α, IL-6, IL-1β, IL-10, IL-12, IL-17, IFN-γ, TGF-β) measurement and NO production. We observed that B6C5(-) mice HFDE-fed accumulated more liver cholesterol and TG, increased liver IL-17 and IL-10 levels and reduced liver TGF-β levels when compared to HFD-fed mice. We also observed that serum AST, AP and albumin were increased in B6C5(-) mice. Liver IL-1β, IL-6, IL-12 and IFN-γ were decreased in B6C5(-) mice independently of diet. We conclude that C5 acts in the control of serum TG and cholesterol, liver cholesterol deposition, liver homeostasis and C5 promotes a pro-inflammatory liver environment in our mouse model of ALD. Copyright © 2016 Elsevier GmbH. All rights reserved.

Chronic plus binge ethanol exposure causes more severe pancreatic injury and inflammation.

PubMed

Ren, Zhenhua; Yang, Fanmuyi; Wang, Xin; Wang, Yongchao; Xu, Mei; Frank, Jacqueline A; Ke, Zun-Ji; Zhang, Zhuo; Shi, Xianglin; Luo, Jia

2016-10-01

Alcohol abuse increases the risk for pancreatitis. The pattern of alcohol drinking may impact its effect. We tested a hypothesis that chronic ethanol consumption in combination with binge exposure imposes more severe damage to the pancreas. C57BL/6 mice were divided into four groups: control, chronic ethanol exposure, binge ethanol exposure and chronic plus binge ethanol exposure. For the control group, mice were fed with a liquid diet for two weeks. For the chronic ethanol exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks. In the binge ethanol exposure group, mice were treated with ethanol by gavage (5g/kg, 25% ethanol w/v) daily for 3days. For the chronic plus binge exposure group, mice were fed with a liquid diet containing 5% ethanol for two weeks and exposed to ethanol by gavage during the last 3days. Chronic and binge exposure alone caused minimal pancreatic injury. However, chronic plus binge ethanol exposure induced significant apoptotic cell death. Chronic plus binge ethanol exposure altered the levels of alpha-amylase, glucose and insulin. Chronic plus binge ethanol exposure caused pancreatic inflammation which was shown by the macrophages infiltration and the increase of cytokines and chemokines. Chronic plus binge ethanol exposure increased the expression of ADH1 and CYP2E1. It also induced endoplasmic reticulum stress which was demonstrated by the unfolded protein response. In addition, chronic plus binge ethanol exposure increased protein oxidation and lipid peroxidation, indicating oxidative stress. Therefore, chronic plus binge ethanol exposure is more detrimental to the pancreas. Copyright © 2016 Elsevier Inc. All rights reserved.

Daily supplementation with fresh pomegranate juice increases paraoxonase 1 expression and activity in mice fed a high-fat diet.

PubMed

Estrada-Luna, D; Martínez-Hinojosa, E; Cancino-Diaz, J C; Belefant-Miller, H; López-Rodríguez, G; Betanzos-Cabrera, G

2018-02-01

Studies have found that pomegranate juice (PJ) consumption increases the binding of high-density lipoproteins (HDL) to paraoxonase 1 (PON1), thus increasing the catalytic activity of this enzyme. PON1 is an antioxidant arylesterase synthesized in the liver and transported in plasma in association with HDL. Decreased levels of PON1 are associated with higher levels of cholesterol. We determined the effects of PJ on body weight, cholesterol, and triacylglycerols through 5 months of supplementation. In addition, the effect of PJ on pon1 gene expression in the liver was also measured by RT-qPCR as well as the activity in serum by a semiautomated method using paraoxon as a substrate. CD-1 mice were either fed a control diet or were fed a high-fat diet 1.25% (wt/wt) cholesterol, 0.5% (wt/wt) sodium cholate, and 15% (wt/wt) saturated fat. 300 μL of PJ containing 0.35 mmol total polyphenols was administered by oral gavage to half of the high fat mice daily. The rest of the high fat mice and the control mice were administered with 300 μL of water. PJ-supplemented animals had significantly higher levels of expression of pon1 compared to the unsupplemented group. PJ-supplemented animals had twice the PON1 activity of the unsupplemented group. In addition, PJ-supplemented animals had the lowest body weight and significantly reduced cholesterol and triacylglycerol levels, although the tricylglycerol levels were not consistently decreased. These results suggest that PJ protects against the effects of a high-fat diet in body weight, and cholesterol levels.

Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice.

PubMed

Muñoz, Vitor Rosetto; Gaspar, Rafael Calais; Crisol, Barbara Moreira; Formigari, Guilherme Pedron; Sant'Ana, Marcella Ramos; Botezelli, José Diego; Gaspar, Rodrigo Stellzer; da Silva, Adelino S R; Cintra, Dennys Esper; de Moura, Leandro Pereira; Ropelle, Eduardo Rochete; Pauli, José Rodrigo

2018-07-01

The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice.

An optimized swine dysentery murine model to characterize shedding and clinical disease associated with "Brachyspira hampsonii" infection.

PubMed

Ek, Courtney E; Nosach, Roman; Fernando, Champika; Huang, Yanyun; Perez, Jason Byron D S; Costa, Matheus O; Ekanayake, Samantha; Hill, Janet E; Harding, John C S

2017-08-22

The development of a mouse model as an in vivo pathogenicity screening tool for Brachyspira spp. has advanced the study of these economically important pathogens in recent years. However, none of the murine models published to date have been used to characterize the clinical signs of disease in mice, instead focusing on pathology following oral inoculation with various Brachyspira spp. The experiments described herein explore modifications of published models to characterize faecal consistency, faecal shedding and pathology in mice challenged with "Brachyspira hampsonii" clade II (Bhamp). In Experiment 1, 24 CF-1 mice were randomly allocated to one of three inoculation groups: sham (Ctrl), Bhamp, or B. hyodysenteriae (Bhyo; positive control). Half of each group was fed normal mouse chow (RMH) while the other received a low-zinc diet (TD85420). In Experiment 2, eight CF-1 mice and nine C3H/HeN mice were divided into Ctrl or Bhamp inoculation groups, and all fed TD85420. In Experiment 1, mice fed TD85420 demonstrated more severe mucoid faeces (P = 0.001; Kruskal Wallis) and faecal shedding for a significantly greater number of days (P = 0.005; Kruskal Wallis). Mean faecal scores of Bhamp inoculated mice trended higher than Ctrl (P = 0.06; Wilcoxon rank-sum) as did those of Bhyo mice (P = 0.0; Wilcoxon rank-sum). In Experiment 2, mean faecal scores of inoculated CF-1 mice were significantly greater than in C3H mice (P = 0.049; Kruskal Wallis) but no group differences in faecal shedding were observed. In both experiments, mice clustered based on the severity of colonic and caecal histopathology but high lesion scores were not always concurrent with high fecal scores. In our laboratory, CF-1 mice and the lower-zinc TD85420 diet provide a superior murine challenge model of "Brachyspira hampsonii" clade II.

Metabolic alterations due to caloric restriction and every other day feeding in normal and growth hormone receptor knockout mice.

PubMed

Westbrook, Reyhan; Bonkowski, Michael S; Arum, Oge; Strader, April D; Bartke, Andrzej

2014-01-01

Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice. To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice. GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

Hydrolyzed collagen improves bone metabolism and biomechanical parameters in ovariectomized mice: an in vitro and in vivo study.

PubMed

Guillerminet, Fanny; Beaupied, Hélène; Fabien-Soulé, Véronique; Tomé, Daniel; Benhamou, Claude-Laurent; Roux, Christian; Blais, Anne

2010-03-01

Collagen has an important structural function in several organs of the body, especially in bone and cartilage. The aim of this study was to investigate the effect of hydrolyzed collagen on bone metabolism, especially in the perspective of osteoporosis treatment and understanding of its mechanism of action. An in vivo study was carried out in 12-week-old female C3H/HeN mice. These were either ovariectomized (OVX) or sham-operated (SHAM) and fed for 12 weeks with a diet containing 10 or 25 g/kg of hydrolyzed collagen. We measured bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA). C-terminal telopeptide of type I collagen (CTX), marker of bone resorption, and alkaline phosphatase (ALP), marker of bone formation, were assayed after 4 and 12 weeks. Femur biomechanical properties were studied by a 3-point bending test and bone architecture by microtomography. The BMD for OVX mice fed the diet including 25 g/kg of hydrolyzed collagen was significantly higher as compared to OVX mice. The blood CTX level significantly decreased when mice were fed with either of the diets containing hydrolyzed collagen. Finally, we have shown a significant increase in bone strength correlated to geometrical changes for the OVX mice fed the 25 g/kg hydrolyzed collagen diet. Primary cultures of murine bone cells were established from the tibia and femur marrow of BALB/c mice. The growth and differentiation of osteoclasts and osteoblasts cultured with different concentrations (from 0.2 to 1.0 mg/mL) of bovine, porcine or fish hydrolyzed collagens (2 or 5 kDa) were measured. Hydrolyzed collagens (2 or 5 kDa) in the tissue culture medium did not have any significant effects on cell growth as compared to controls. However, there was a significant and dose-dependent increase in ALP activity, a well-known marker of osteogenesis, and a decrease in octeoclast activity in primary culture of bone cells cultured with hydrolyzed collagens (2 kDa only) as compared to the control. It is concluded that dietary hydrolyzed collagen increases osteoblast activity (as measured in primary tissue culture), which acts on bone remodeling and increases the external diameter of cortical areas of the femurs.

Brown rice and retrograded brown rice alleviate inflammatory response in dextran sulfate sodium (DSS)-induced colitis mice.

PubMed

Praengam, Kemika; Sahasakul, Yuraporn; Kupradinun, Piengchai; Sakarin, Siriwan; Sanitchua, Wanwisa; Rungsipipat, Anudep; Rattanapinyopituk, Kasem; Angkasekwinai, Pornpimon; Changsri, Khaimuk; Mhuantong, Wuttichai; Tangphatsornruang, Sithichoke; Tuntipopipat, Siriporn

2017-12-13

The present study was aimed to investigate the impacts of brown rice (BR) and retrograded brown rice (R-BR) consumption on colonic health and gut microbiota in dextran sulfate sodium (DSS) induced colitis mice. Thirty two female C57Bl/6Mlac mice were fed with modified AIN 93G diets by replacing cornstarch in the original composition with white rice (WR), BR and R-BR powder. The mice were divided into 4 groups and fed with the following experimental diets for 4 weeks: (1) negative control (WR: diet with WR), (2) positive control (DSS_WR: DSS and diet with WR), (3) DSS_BR: DSS and diet with BR, and (4) DSS_R-BR: DSS and diet with R-BR. BR and R-BR had a greater content of fat, dietary fiber, GABA, γ-oryzanol, γ-tocotrienol, ferulic acid and p-coumaric acid than WR (p < 0.05). No significant difference in the level of these bioactive compounds was noted between BR and R-BR. Nevertheless, R-BR had a 1.8 fold resistant starch (RS) content of BR (p < 0.05). The DSS_BR and DSS_R-BR groups showed a lower ratio of colonic weight to length, and a lower content of iNOS, COX-2, MPO, IL-6 and INF-γ in colonic homogenates than the DSS_WR group. However, the DSS treated mice fed with the R-BR diet had significantly milder histopathological inflammatory injury and lower colonic iNOS expression than the DSS_BR and DSS_WR groups. The percentage of mesenteric regulatory T cells significantly increased in the DSS_R-BR group compared to that in the DSS_WR group. The DSS treated mice fed with the R-BR diet showed a significant increase in cecal bacterial diversity and abundance of genera Prevotella, Ruminococcus, Dorea, Coprococcus and Dehalobacterium but a significant decrease in pathogenic bacteria including Bacteroides and Enterococcus compared to the DSS_WR group. Thus, the present data indicate that BR and R-BR ameliorate colonic inflammation in experimental colitis induced by DSS in mice by suppressing inflammatory mediators and modulating regulatory T cell responses as well as bacterial diversity in the cecum.

Voluntary running of defined distances reduces body adiposity and its associated inflammation in C57BL/6 mice fed a high-fat diet.

PubMed

Yan, Lin; Sundaram, Sneha; Nielsen, Forrest H

2017-11-01

This study investigated the effect of voluntary running of defined distances on body adiposity in male C57BL/6 mice fed a high-fat diet. Mice were assigned to 6 groups and fed a standard AIN93G diet (sedentary) or a modified high-fat AIN93G diet (sedentary; unrestricted running; or 75%, 50%, or 25% of unrestricted running) for 12 weeks. The average running distance was 8.3, 6.3, 4.2, and 2.1 km/day for the unrestricted, 75%, 50%, and 25% of unrestricted runners, respectively. Body adiposity was 46% higher in sedentary mice when fed the high-fat diet instead of the standard diet. Running decreased adiposity in mice fed the high-fat diet in a dose-dependent manner but with no significant difference between sedentary mice and those running 2.1 km/day. In sedentary mice, the high-fat instead of the standard diet increased insulin resistance, hepatic triacylglycerides, and adipose and plasma concentrations of leptin and monocyte chemotactic protein-1 (MCP-1). Running reduced these variables in a dose-dependent manner. Adipose adiponectin was lowest in sedentary mice fed the high-fat diet; running raised adiponectin in both adipose tissue and plasma. Running 8.3 and 6.3 km/day had the greatest, but similar, effects on the aforementioned variables. Running 2.1 km/day did not affect these variables except, when compared with sedentariness, it significantly decreased MCP-1. The findings showed that running 6.3 kg/day was optimal for reducing adiposity and associated inflammation that was increased in mice by feeding a high-fat diet. The findings suggest that voluntary running of defined distances may counteract the obesogenic effects of a high-fat diet.

Antioxidant Diet Protects Against Emphysema, but Increases Mortality in Cigarette Smoke-Exposed Mice

PubMed Central

Nyunoya, Toru; March, Thomas H.; Tesfaigzi, Yohannes; Seagrave, JeanClare

2012-01-01

Oxidative stress plays an important role in cigarette smoke-induced lung inflammation and emphysema. We produced an enriched diet by adding freeze-dried fruits and vegetables and additional supplements to the 8604 Teklad Rodent Diet, a standard rodent diet. In this study, we examined the effects of the antioxidant-enriched diet on cigarette smoke-induced lung inflammation and emphysema. CH3/HeN mice were fed either a regular diet or an antioxidant diet. These mice were exposed to filtered air, a low concentration of cigarette smoke (total particulate matter: 100 mg/m3) or a high concentration of cigarette smoke (total particulate matter: 250mg/m3) for 6 hours/day, 5 days/week for total 16 weeks. Surprisingly, increased mortality (53%) was observed in the high concentration of cigarette smoke-exposed mice fed the antioxidant diet compared to the high concentration of cigarette smoke-exposed mice that were fed a regular diet (13%). The necropsy analysis revealed nasal passage obstruction due to mucous plugging in cigarette smoke-exposed mice on the antioxidant diet. However, the antioxidant diet significantly reduced neutrophilic inflammation and emphysema in the high concentration of cigarette smoke-exposed mice as compared to the regular diet /high concentration of cigarette smoke controls. The antioxidant capacity in the bronchoalveolar fluid or oxidative damage to the lung tissue was not affected by the antioxidant diet. Pro-MMP-2, MMP-2, and MMP-9 activity did not correlate with the protective effects of AOD on cigarette smoke-induced emphysema. These data suggest that the antioxidant diet reduced cigarette smoke -induced inflammation and emphysema, but increased mortality in the obligate nose-breathing mice. PMID:21834692

Transgenic expression of human neutrophil peptide-1 enhances hepatic fibrosis in mice fed a choline-deficient, L-amino acid-defined diet.

PubMed

Ibusuki, Rie; Uto, Hirofumi; Arima, Shiho; Mawatari, Seiichi; Setoguchi, Yoshiko; Iwashita, Yuji; Hashimoto, Shinichi; Maeda, Takuro; Tanoue, Shiro; Kanmura, Shuji; Oketani, Makoto; Ido, Akio; Tsubouchi, Hirohito

2013-11-01

Neutrophils infiltrate the livers of patients with nonalcoholic steatohepatitis (NASH). Human neutrophil peptides (HNPs) induce cytokine and chemokine production under inflammatory conditions, which may contribute to the progression of NASH. In this study, we focused on the effects of HNP-1 on hepatic steatosis and fibrosis in a mouse model of NASH induced by a choline-deficient, L-amino acid-defined (CDAA) diet. We generated transgenic mice expressing HNP-1 under the control of a β-actin-based promoter. HNP-1 transgenic and wild-type C57BL/6N mice were fed a CDAA diet for 16 weeks to induce hepatic steatosis and fibrosis. Serological and histological features were examined, and the effects of HNP-1 on hepatic stellate cell lines were assessed. HNP-1 transgenic and wild-type mice fed the CDAA diet showed no significant differences in serum alanine aminotransferase levels or the degree of hepatic steatosis based on Oil red O staining and hepatic triglyceride content. In contrast, Sirius Red and Azan staining showed significantly more severe hepatic fibrosis in HNP-1 transgenic mice compared with wild-type mice. In addition, significantly more α-smooth muscle actin-positive hepatic stellate cells were observed in the transgenic mice than in the wild-type mice. Finally, the proliferation of the LI90 hepatic stellate cell line increased in response to HNP-1. Our data indicate that HNP-1 enhances hepatic fibrosis in fatty liver by inducing hepatic stellate cell proliferation. Thus, neutrophil-derived HNP-1 may contribute to the progression of NASH. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Troxerutin abrogates mitochondrial oxidative stress and myocardial apoptosis in mice fed calorie-rich diet.

PubMed

Geetha, Rajagopalan; Sathiya Priya, Chandrasekaran; Anuradha, Carani Venkatraman

2017-12-25

Mitochondrial oxidative stress plays a major role in the pathogenesis of myocardial apoptosis in metabolic syndrome (MS) patients. In this study, we investigated the effect of troxerutin (TX), an antioxidant on mitochondrial oxidative stress and apoptotic markers in heart of mice fed fat and fructose-rich diet. Adult male Mus musculus mice were fed either control diet or high fat, high fructose diet (HFFD) for 60 days to induce MS. Mice from each dietary group were divided into two on the 16th day and were either treated or untreated with TX (150 mg/kg bw, p.o) for the next 45 days. At the end of the study, mitochondrial reactive oxygen species (ROS) generation, oxidative stress markers, levels of intracellular calcium, cardiolipin content, cytochrome c release and apoptotic markers were examined in the myocardium. HFFD-feeding resulted in diminution of antioxidants and increased ROS production, lipid peroxidation and oxidatively modified adducts of 8-OHG, 4-HNE and 3-NT. Further increase in Ca 2+ levels, low levels of calcium transporters and decrease in cardiolipin content were noted. Changes in the mitochondrial structure were observed by electron microscopy. Furthermore, cytochrome c release, increase in proapoptotic proteins (APAF-1, BAX, caspases-9 and-3) and decrease in antiapoptotic protein (BCL-2) in HFFD-fed mice suggest myocardial apoptosis. These changes were significantly restored by TX supplementation. TX administration effectively attenuated cardiac apoptosis and exerted a protective role by increasing antioxidant potential and by improving mitochondrial function. Thus, TX could be a promising therapeutic candidate for treating cardiac disease in MS patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Validation of the Antidiabetic and Hypolipidemic Effects of Hawthorn by Assessment of Gluconeogenesis and Lipogenesis Related Genes and AMP-Activated Protein Kinase Phosphorylation.

PubMed

Shih, Chun-Ching; Lin, Cheng-Hsiu; Lin, Yih-Jiun; Wu, Jin-Bin

2013-01-01

Since with the increased use of antidiabetic and antihyperlipidemic effect of phytonutrients for daily supplement has gained considerable attention worldwide, we examine the effect and molecular mechanism of Crataegus pinnatifida Bge. var. major N.E. Br. (hawthorn) by quantifying the expression of hepatic gluconeogenesis and lipogenesis on diabetes and dyslipidemia in high-fat (HF)-fed C57BL/6J mice. Firstly, mice were divided randomly into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was given orally hawthorn extract (including 0.2, 0.5, 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks afterward. Diabetic mice showed an increase in plasma glucose and insulin. Glucose lowering was comparable with Rosi-treated mice. This study demonstrated that hawthorn was effective in ameliorating the HF diet-induced hyperglycemia, hypertriglyceridemia and hypercholesterolaemia. Hawthorn extract significantly increases the hepatic protein contents of AMP-activated protein kinase (AMPK) phosphorylation and reduces expression of phosphenol pyruvate carboxykinase (PEPCK) and glucose production. Furthermore, hawthorn decreased in hepatic triacylglycerol and cholesterol synthesis (including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), SREBP2). An increase in expressions of apoA-I gene and high-density lipoprotein cholesterol (HDL-C) was detected in HF-fed mice treated with high dose hawthorn. Our data suggest that hawthorn extract are capable of decreasing glucose production and triacylglycerol synthesis by inducing AMPK-phosphorylation and hawthorn is a candidate source of antidiabetic and antihyperlipidemic phytonutrients factors.

Validation of the Antidiabetic and Hypolipidemic Effects of Hawthorn by Assessment of Gluconeogenesis and Lipogenesis Related Genes and AMP-Activated Protein Kinase Phosphorylation

PubMed Central

Shih, Chun-Ching; Lin, Cheng-Hsiu; Lin, Yih-Jiun; Wu, Jin-Bin

2013-01-01

Since with the increased use of antidiabetic and antihyperlipidemic effect of phytonutrients for daily supplement has gained considerable attention worldwide, we examine the effect and molecular mechanism of Crataegus pinnatifida Bge. var. major N.E. Br. (hawthorn) by quantifying the expression of hepatic gluconeogenesis and lipogenesis on diabetes and dyslipidemia in high-fat (HF)-fed C57BL/6J mice. Firstly, mice were divided randomly into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed a 45% HF diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and was given orally hawthorn extract (including 0.2, 0.5, 1.0 g/kg/day extracts) or rosiglitazone (Rosi) or vehicle for 4 weeks afterward. Diabetic mice showed an increase in plasma glucose and insulin. Glucose lowering was comparable with Rosi-treated mice. This study demonstrated that hawthorn was effective in ameliorating the HF diet-induced hyperglycemia, hypertriglyceridemia and hypercholesterolaemia. Hawthorn extract significantly increases the hepatic protein contents of AMP-activated protein kinase (AMPK) phosphorylation and reduces expression of phosphenol pyruvate carboxykinase (PEPCK) and glucose production. Furthermore, hawthorn decreased in hepatic triacylglycerol and cholesterol synthesis (including sterol regulatory element binding protein-1c (SREBP-1c), fatty acid synthase (FAS), SREBP2). An increase in expressions of apoA-I gene and high-density lipoprotein cholesterol (HDL-C) was detected in HF-fed mice treated with high dose hawthorn. Our data suggest that hawthorn extract are capable of decreasing glucose production and triacylglycerol synthesis by inducing AMPK-phosphorylation and hawthorn is a candidate source of antidiabetic and antihyperlipidemic phytonutrients factors. PMID:23690849

Supplementation with macular carotenoids improves visual performance of transgenic mice.

PubMed

Li, Binxing; Rognon, Gregory T; Mattinson, Ty; Vachali, Preejith P; Gorusupudi, Aruna; Chang, Fu-Yen; Ranganathan, Arunkumar; Nelson, Kelly; George, Evan W; Frederick, Jeanne M; Bernstein, Paul S

2018-07-01

Carotenoid supplementation can improve human visual performance, but there is still no validated rodent model to test their effects on visual function in laboratory animals. We recently showed that mice deficient in β-carotene oxygenase 2 (BCO2) and/or β-carotene oxygenase 1 (BCO1) enzymes can accumulate carotenoids in their retinas, allowing us to investigate the effects of carotenoids on the visual performance of mice. Using OptoMotry, a device to measure visual function in rodents, we examined the effect of zeaxanthin, lutein, and β-carotene on visual performance of various BCO knockout mice. We then transgenically expressed the human zeaxanthin-binding protein GSTP1 (hGSTP1) in the rods of bco2 -/- mice to examine if delivering more zeaxanthin to retina will improve their visual function further. The visual performance of bco2 -/- mice fed with zeaxanthin or lutein was significantly improved relative to control mice fed with placebo beadlets. β-Carotene had no significant effect in bco2 -/- mice but modestly improved cone visual function of bco1 -/- mice. Expression of hGSTP1 in the rods of bco2 -/- mice resulted in a 40% increase of retinal zeaxanthin and further improvement of visual performance. This work demonstrates that these "macular pigment mice" may serve as animal models to study carotenoid function in the retina. Copyright © 2018 Elsevier Inc. All rights reserved.

Can a genetically-modified organism-containing diet influence embryo development? A preliminary study on pre-implantation mouse embryos.

PubMed

Cisterna, B; Flach, F; Vecchio, L; Barabino, S M L; Battistelli, S; Martin, T E; Malatesta, M; Biggiogera, M

2008-01-01

In eukaryotic cells, pre-mRNAs undergo several transformation steps to generate mature mRNAs. Recent studies have demonstrated that a diet containing a genetically modified (GM) soybean can induce modifications of nuclear constituents involved in RNA processing in some tissues of young, adult and old mice. On this basis, we have investigated the ultrastructural and immunocytochemical features of pre-implantation embryos from mice fed either GM or non- GM soybean in order to verify whether the parental diet can affect the morpho-functional development of the embryonic ribonucleoprotein structural constituents involved in pre-mRNA pathways. Morphological observations revealed that the general aspect of embryo nuclear components is similar in the two experimental groups. However, immunocytochemical and in situ hybridization results suggest a temporary decrease of pre-mRNA transcription and splicing in 2-cell embryos and a resumption in 4-8-cell embryos from mice fed GM soybean; moreover, pre-mRNA maturation seems to be less efficient in both 2-cell and 4-8-cell embryos from GM-fed mice than in controls. Although our results are still preliminary and limited to the pre-implantation phases, the results of this study encourage deepening on the effects of food components and/or contaminants on embryo development.

Supplementation with antioxidant-rich extra virgin olive oil prevents hepatic oxidative stress and reduction of desaturation capacity in mice fed a high-fat diet: Effects on fatty acid composition in liver and extrahepatic tissues.

PubMed

Rincón-Cervera, Miguel Angel; Valenzuela, Rodrigo; Hernandez-Rodas, María Catalina; Marambio, Macarena; Espinosa, Alejandra; Mayer, Susana; Romero, Nalda; Barrera M Sc, Cynthia; Valenzuela, Alfonso; Videla, Luis A

2016-01-01

The aim of this study was to assess the effect of dietary supplementation with extra virgin olive oil (EVOO) in mice on the reduction of desaturase and antioxidant enzymatic activities in liver, concomitantly with long-chain polyunsaturated fatty acids (LCPUFA) profiles in liver and extrahepatic tissues induced by a high-fat diet (HFD). Male mice C57 BL/6 J were fed with a control diet (CD; 10% fat, 20% protein, 70% carbohydrates) or an HFD (60% fat, 20% protein, 20% carbohydrates) for 12 wk. Animals were supplemented with 100 mg/d EVOO with different antioxidant contents (EVOO I, II, and III). After the intervention, blood and several tissues were analyzed. Dietary supplementation with EVOO with the highest antioxidant content and antioxidant capacity (EVOO III) significantly reduced fat accumulation in liver and the plasmatic metabolic alterations caused by HFD and produced a normalization of oxidative stress-related parameters, desaturase activities, and LCPUFA content in tissues. Data suggest that dietary supplementation with EVOO III may prevent oxidative stress and reduction of biosynthesis and accretion of ω-3 LCPUFA in the liver of HFD-fed mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Echium Oil Reduces Plasma Triglycerides by Increasing Intravascular Lipolysis in apoB100-Only Low Density Lipoprotein (LDL) Receptor Knockout Mice

PubMed Central

Forrest, Lolita M.; Lough, Christopher M.; Chung, Soonkyu; Boudyguina, Elena Y.; Gebre, Abraham K.; Smith, Thomas L.; Colvin, Perry L.; Parks, John S.

2013-01-01

Echium oil (EO), which is enriched in SDA (18:4 n-3), reduces plasma triglyceride (TG) concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO) reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%), EO (10% EO + 10% PO), or FO (10% FO + 10% PO). Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE) content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL) particle size was ordered: PO (63 ± 4 nm) > EO (55 ± 3 nm) > FO (40 ± 2 nm). Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model. PMID:23857172

Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice.

PubMed

Forrest, Lolita M; Lough, Christopher M; Chung, Soonkyu; Boudyguina, Elena Y; Gebre, Abraham K; Smith, Thomas L; Colvin, Perry L; Parks, John S

2013-07-12

Echium oil (EO), which is enriched in SDA (18:4 n-3), reduces plasma triglyceride (TG) concentrations in humans and mice. We compared mechanisms by which EO and fish oil (FO) reduce plasma TG concentrations in mildly hypertriglyceridemic male apoB100-only LDLrKO mice. Mice were fed one of three atherogenic diets containing 0.2% cholesterol and palm oil (PO; 20%), EO (10% EO + 10% PO), or FO (10% FO + 10% PO). Livers from PO- and EO-fed mice had similar TG and cholesteryl ester (CE) content, which was significantly higher than in FO-fed mice. Plasma TG secretion was reduced in FO vs. EO-fed mice. Plasma very low density lipoprotein (VLDL) particle size was ordered: PO (63 ± 4 nm) > EO (55 ± 3 nm) > FO (40 ± 2 nm). Post-heparin lipolytic activity was similar among groups, but TG hydrolysis by purified lipoprotein lipase was significantly greater for EO and FO VLDL compared to PO VLDL. Removal of VLDL tracer from plasma was marginally faster in EO vs. PO fed mice. Our results suggest that EO reduces plasma TG primarily through increased intravascular lipolysis of TG and VLDL clearance. Finally, EO may substitute for FO to reduce plasma TG concentrations, but not hepatic steatosis in this mouse model.

Morphometric and functional abnormalities of kidneys in the progeny of mice fed chocolate during pregnancy and lactation.

PubMed

Patera, Janusz; Chorostowska-Wynimko, Joanna; Słodkowska, Janina; Borowska, Adamina; Skopiński, Piotr; Sommer, Ewa; Wasiutyński, Aleksander; Skopińska-Rózewska, Ewa

2006-01-01

Even most commonly consumed beverages like tea, coffee, chocolate and cocoa contain methylxanthines, biogenic amines and polyphenols, among them catechins, that exhibit significant biological activity and might profoundly affect the organism homeostasis. We have previously shown that 400 mg of bitter chocolate or 6 mg of theobromine added to the daily diet of pregnant and afterwards lactating mice affected embryonic angiogenesis and caused bone mineralization disturbances as well as limb shortening in 4-weeks old offspring. The aim of the present study was the morphometric and functional evaluation of kidneys in the 4-weeks old progeny mice fed according to the protocol mentioned above. Progeny from the mice fed chocolate presented considerable morphometric abnormalities in the kidney structure, with the lower number of glomeruli per mm2 and their increased diameter. Moreover, higher serum creatinine concentration was observed in that group of offspring. No morphometric or functional irregularities were found in the progeny of mice fed theobromine. Abnormalities demonstrated in the offspring of mice fed chocolate are not related to its theobromine content. Consequently, identification of active compound(s) responsible for the observed effects is of vital importance.

A novel mice model of metabolic syndrome: the high-fat-high-fructose diet-fed ICR mice.

PubMed

Zhuhua, Zhang; Zhiquan, Wang; Zhen, Yang; Yixin, Niu; Weiwei, Zhang; Xiaoyong, Li; Yueming, Liu; Hongmei, Zhang; Li, Qin; Qing, Su

2015-01-01

Currently, the metabolic syndrome (MS) is occurring at growing rates worldwide, raising extensive concerns on the mechanisms and therapeutic interventions for this disorder. Herein, we described a novel method of establishing MS model in rodents. Male Institute of Cancer Research (ICR) mice were fed with high-fat-high-fructose (HFHF) diet or normal chow (NC) respectively for 12 weeks. Metabolic phenotypes were assessed by glucose tolerance test, insulin tolerance test and hyperinsulinemic-euglycemic clamp. Blood pressure was measured by a tail-cuff system. At the end of the experiment, mice were sacrificed, and blood and tissues were harvested for subsequent analysis. Serum insulin levels were measured by ELISA, and lipid profiles were determined biochemically. The HFHF diet-fed ICR mice exhibited obvious characteristics of the components of MS, including obvious obesity, severe insulin resistance, hyperinsulinemia, dislipidemia, significant hypertension and hyperuricemia. Our data suggest that HFHF diet-fed ICR mice may be a robust and efficient animal model that could well mimic the basic pathogenesis of human MS.

Fish oil feeding enhances lymphocyte proliferation but impairs virus-specific T lymphocyte cytotoxicity in mice following challenge with influenza virus

PubMed Central

Byleveld, M; Pang, G T; Clancy, R L; Roberts, D C K

2000-01-01

The effect of a fish oil diet on virus-specific cytotoxicity and lymphocyte proliferation was investigated. Mice were fed fish oil (17 g fish oil and 3 g sunflower/100 g) or beef tallow (17 g tallow and 3 g sunflower/100 g) diets for 14 days before intranasal challenge with influenza virus. At day 5 after infection, lung virus-specific T lymphocyte, but not macrophage or natural killer (NK) cell, cytotoxicity was significantly lower in mice fed fish oil, while bronchial lymph node cell proliferation to virus was significantly higher. In mice fed fish oil, spleen cell proliferation to virus was also significantly higher following immunization. The results showed that, despite improved lymphocyte proliferation, fish oil impairs primary virus-specific T lymphocyte cytotoxicity. This impairment may explain the delayed virus clearance that we have previously reported in infected mice fed the fish oil diet. PMID:10632664

Fish oil feeding enhances lymphocyte proliferation but impairs virus-specific T lymphocyte cytotoxicity in mice following challenge with influenza virus.

PubMed

Byleveld, M; Pang, G T; Clancy, R L; Roberts, D C

2000-02-01

The effect of a fish oil diet on virus-specific cytotoxicity and lymphocyte proliferation was investigated. Mice were fed fish oil (17 g fish oil and 3 g sunflower/100 g) or beef tallow (17 g tallow and 3 g sunflower/100 g) diets for 14 days before intranasal challenge with influenza virus. At day 5 after infection, lung virus-specific T lymphocyte, but not macrophage or natural killer (NK) cell, cytotoxicity was significantly lower in mice fed fish oil, while bronchial lymph node cell proliferation to virus was significantly higher. In mice fed fish oil, spleen cell proliferation to virus was also significantly higher following immunization. The results showed that, despite improved lymphocyte proliferation, fish oil impairs primary virus-specific T lymphocyte cytotoxicity. This impairment may explain the delayed virus clearance that we have previously reported in infected mice fed the fish oil diet.

A platelet-activating factor (PAF) receptor deficiency exacerbates diet-induced obesity but PAF/PAF receptor signaling does not contribute to the development of obesity-induced chronic inflammation.

PubMed

Yamaguchi, Masahiko; Matsui, Masakazu; Higa, Ryoko; Yamazaki, Yasuhiro; Ikari, Akira; Miyake, Masaki; Miwa, Masao; Ishii, Satoshi; Sugatani, Junko; Shimizu, Takao

2015-02-15

Platelet-activating factor (PAF) is a well-known phospholipid that mediates acute inflammatory responses. In the present study, we investigated whether PAF/PAF receptor signaling contributed to chronic inflammation in the white adipose tissue (WAT) of PAF receptor-knockout (PAFR-KO) mice. Body and epididymal WAT weights were higher in PAFR-KO mice fed a high-fat diet (HFD) than in wild-type (WT) mice. TNF-α mRNA expression levels in epididymal WAT and the infiltration of CD11c-positive macrophages into epididymal WAT, which led to chronic inflammation, were also elevated in HFD-fed PAFR-KO mice. HFD-fed PAFR-KO mice had higher levels of fasting serum glucose than HFD-fed WT mice as well as impaired glucose tolerance. Although PAF receptor signaling up-regulated the expression of TNF-α and lipopolysaccharide induced the expression of acyl-CoA:lysophosphatidylcholine acyltransferase 2 (LPCAT2) mRNA in bone marrow-derived macrophages, no significant differences were observed in the expression of LPCAT2 mRNA and PAF levels in epididymal WAT between HFD-fed mice and normal diet-fed mice. In addition to our previous finding in which energy expenditure in PAF receptor (PAFR)-deficient mice was low due to impaired brown adipose tissue function, the present study demonstrated that PAF/PAF receptor signaling up-regulated the expression of Ucp1 mRNA, which is essential for cellular thermogenesis, in 3T3-L1 adipocytes. We concluded that the marked accumulation of abdominal fat due to HFD feeding led to more severe chronic inflammation in WAT, which is associated with glucose metabolism disorders, in PAFR-KO mice than in WT mice, and PAF/PAF receptor signaling may regulate energy expenditure and adiposity. Copyright © 2015 Elsevier Inc. All rights reserved.

Therapeutic effect of tyndallized Lactobacillus rhamnosus IDCC 3201 on atopic dermatitis mediated by down-regulation of immunoglobulin E in NC/Nga mice.

PubMed

Lee, Seung-Hun; Yoon, Jong-Min; Kim, Young-Hoo; Jeong, Dong-Gu; Park, Soobong; Kang, Dae-Jung

2016-07-01

The therapeutic effect of oral administration of Lactobacillus rhamnosus IDCC 3201 tyndallizate (RHT3201) on atopic dermatitis (AD)-like skin lesions in NC/Nga mice were investigated. After induction of dermatitis in NC/Nga mice with house-dust mite extract, each group was fed RHT3201 with 1 × 10(8) , 1 × 10(9) , or 1 × 10(10) cells orally once a day for 8 weeks. Dermatitis scores and frequency of scratching were improved by oral feeding with RHT3201. In contrast to the control group, RHT3201-fed mice showed significantly down-regulated mast cell numbers and serum immunoglobulin E (IgE) concentrations had significantly less IL4 in their axillary lymph node cells. The therapeutic effect of RHT3201 was found to be dose-dependent. These findings indicate that RHT3201 has potential for treating AD. © 2016 The Societies and John Wiley & Sons Australia, Ltd.

Dietary choice affects Shiga toxin-producing Escherichia coli (STEC) O157:H7 colonization and disease

PubMed Central

Zumbrun, Steven D.; Melton-Celsa, Angela R.; Smith, Mark A.; Gilbreath, Jeremy J.; Merrell, D. Scott; O’Brien, Alison D.

2013-01-01

The likelihood that a single individual infected with the Shiga toxin (Stx)-producing, food-borne pathogen Escherichia coli O157:H7 will develop a life-threatening sequela called the hemolytic uremic syndrome is unpredictable. We reasoned that conditions that enhance Stx binding and uptake within the gut after E. coli O157:H7 infection should result in greater disease severity. Because the receptor for Stx, globotriaosylceramide, is up-regulated in the presence of butyrate in vitro, we asked whether a high fiber diet (HFD) that reportedly enhances butyrate production by normal gut flora can influence the outcome of an E. coli O157 infection in mice. To address that question, groups of BALB/c mice were fed high (10%) or low (2%) fiber diets and infected with E. coli O157:H7 strain 86-24 (Stx2+). Mice fed an HFD exhibited a 10- to 100-fold increase in colonization, lost 15% more body weight, exhibited signs of morbidity, and had 25% greater mortality relative to the low fiber diet (LFD)-fed group. Additionally, sections of intestinal tissue from HFD-fed mice bound more Stx1 and expressed more globotriaosylceramide than did such sections from LFD-fed mice. Furthermore, the gut microbiota of HFD-fed mice compared with LFD-fed mice contained reduced levels of native Escherichia species, organisms that might protect the gut from colonization by incoming E. coli O157:H7. Taken together, these results suggest that susceptibility to infection and subsequent disease after ingestion of E. coli O157:H7 may depend, at least in part, on individual diet and/or the capacity of the commensal flora to produce butyrate. PMID:23690602

Effect of the Capsicoside G-rich Fraction from Pepper (Capsicum annuum L.) Seeds on High-fat Diet-induced Obesity in Mice.

PubMed

Sung, Jeehye; Jeong, Heon Sang; Lee, Junsoo

2016-11-01

Obesity is one of the most common metabolic syndromes and is a major threat to human health worldwide. Given the size of this problem, there is growing interest in natural agents that may decrease obesity. In this study, we investigated the anti-obesity effect of a capsicoside G-rich fraction (CRF; 13.35% capsicoside G) isolated from pepper seeds in diet-induced obese mice. C57BL/6J mice were fed either a normal diet or a high-fat diet (HFD), with or without CRF (HFD + CRF; 10 and 100 mg/kg body weight). The body weight and food efficiency ratio of mice fed HFD + CRF were lower in comparison to that of mice fed only an HFD. Epididymal adipose tissue weight and adipocyte hypertrophy were significantly lower in HFD + CRF mice than in HFD mice. The fat deposition in the liver of mice fed HFD + CRF was lower compared to that of mice fed only an HFD. CRF significantly reversed the HFD-induced elevation of the expression of key adipocyte differentiation regulators, including peroxisome proliferator-activated receptor γ, CCAAT/enhancer-binding protein α, sterol regulatory element binding protein 1c, and their target genes. These results suggest that CRF could be used as dietary therapy for the prevention of obesity and obesity-related metabolic diseases. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Bioactive grape proanthocyanidins enhance immune reactivity in UV-irradiated skin through functional activation of dendritic cells in mice.

PubMed

Vaid, Mudit; Singh, Tripti; Prasad, Ram; Elmets, Craig A; Xu, Hui; Katiyar, Santosh K

2013-03-01

Ultraviolet (UV) radiation-induced immunosuppression has been implicated in skin carcinogenesis. Grape seed proanthocyanidins (GSPs) have anti-skin carcinogenic effects in mice and GSPs-fed mice exhibit a reduction in UV-induced suppression of allergic contact hypersensitivity (CHS), a prototypic T-cell-mediated response. Here, we report that dietary GSPs did not inhibit UVB-induced suppression of CHS in xeroderma pigmentosum complementation group A (XPA)-deficient mice, which lack nucleotide excision repair mechanisms. GSPs enhanced repair of UVB-induced DNA damage (cyclobutane pyrimidine dimers) in wild-type, but not XPA-deficient, dendritic cells (DC). Co-culture of CD4(+) T cells with DCs from UVB-irradiated wild-type mice resulted in suppression of T-cell proliferation and secretion of T-helper (TH) 1-type cytokines that was ameliorated when the DCs were obtained from GSP-fed mice, whereas DCs obtained from GSP-fed XPA-KO mice failed to restore T-cell proliferation. In adoptive transfer experiments, donor DCs were positively selected from the draining lymph nodes of UVB-exposed donor mice that were sensitized to 2,4,-dinitrofluorobenzene were transferred into naïve recipient mice and the CHS response assessed. Naïve recipients that received DCs from UVB-exposed wild-type donors that had been fed GSPs exhibited a full CHS response, whereas no significant CHS was observed in mice that received DCs from XPA-KO mice fed GSPs. These results suggest that GSPs prevent UVB-induced immunosuppression through DNA repair-dependent functional activation of dendritic cells in mice. Cancer Prev Res; 6(3); 242-52. ©2013 AACR. ©2013 AACR.

Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice.

PubMed

Wang, Xiaoyu; Zhao, Shiqi; Su, Mengqi; Sun, Li; Zhang, Song; Wang, Dingyu; Liu, Zhaorui; Yuan, Yue; Liu, Yang; Li, Yue

2016-05-20

Endothelial dysfunction occurs in obese patients and high-fat diet (HFD) fed experimental animals. While geraniol has been reported to ameliorate inflammation and oxidative stress, inhibit tumor cell proliferation, and improve atherosclerosis, its direct effect on endothelial function remains uncharacterized. The present study therefore investigated the effect of geraniol on endothelial function in HFD mice and its underlying mechanisms. C57 BL/6 mice were fed an HFD (n = 40) or a normal diet (n = 20) for 8 weeks. HFD fed mice then were randomized to intraperitoneal treatment with geraniol (n = 20) or vehicle (n = 20) for another 6 weeks. Acetylcholine (Ach)-induced endothelial dependent vasorelaxation was measured on wire myography; reactive oxygen species (ROS) generation was assessed by fluorescence imaging, and NADPH oxidases (NOXs) and adhesive molecules VCAM-1 and ICAM-1 protein expression by western blotting. Geraniol improved endothelial function in HFD fed mice, as evidenced by its: 1. restoring endothelial dependent vasorelaxation induced by Ach, and reversing increased VCAM-1 and ICAM-1 expression; 2. attenuating HFD induced increased serum TBARS and aortic ROS generation; and 3. downregulating aortic NOX-2 expression in both HFD fed mice and in palmitic acid treated endothelial cells. Geraniol therefore protects against endothelial dysfunction induced by HFD through reducing NOX-2 associated ROS generation. Copyright © 2016 Elsevier Inc. All rights reserved.

Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.

PubMed

Hwang, M; Go, Y; Park, J-H; Shin, S-K; Song, S E; Oh, B-C; Im, S-S; Hwang, I; Jeon, Y H; Lee, I-K; Seino, S; Song, D-K

2017-02-01

The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic disorders.

Scavenger Receptor Class B Type 1 Deletion Led to Coronary Atherosclerosis and Ischemic Heart Disease in Low-density Lipoprotein Receptor Knockout Mice on Modified Western-type Diet

PubMed Central

Liao, Jiawei; Guo, Xin; Wang, Mengyu; Dong, Chengyan; Gao, Mingming; Wang, Huan; Kayoumu, Abudurexiti; Shen, Qiang; Wang, Yuhui; Wang, Fan; Liu, George

2017-01-01

Aim: Atherosclerosis-prone apolipoprotein E (apoE) or low-density lipoprotein receptor (LDL-R) knockout (KO) mice are generally resistant to developing coronary atherosclerosis (CA) and ischemic heart disease (IHD). However, studies have demonstrated the occurrence of spontaneous CA and IHD in scavenger receptor class B type 1 (SR-BI)/apoE double KO (dKO) mice, which suggests that SR-BI could be a potential target for the prevention and therapy of CA and IHD. This possibility was later investigated in SR-BI/LDL-R dKO mice, but no signs of CA or IHD was identified when mice were fed a normal western-type diet. Here we explored whether SR-BI deletion could result in CA and IHD in LDL-R KO mice when fed a modified western-type diet containing higher (0.5%) cholesterol. Methods: Cardiac functions were detected by electrocardiography, single photon emission computed tomography (SPECT), echocardiography (Echo) and 2,3,5-triphenyltetrazolium chloride staining. CA was visualized by hematoxylin-eosin staining. Results: After 12 weeks on the modified diet, SR-BI/LDL-R dKO mice developed cardiac ischemia/infarction, together with systolic dysfunction and left ventricular dilatation. CA was most severe at the aortic sinus level to an extent that no dKO mice survived to 20 weeks on the modified diet. None of control mice, however, developed CA or IHD. Conclusions: SR-BI deletion led to CA and IHD in LDL-R KO mice when fed the modified western-type diet. We established SR-BI/LDL-R dKO mice as a diet-induced murine model of human IHD and developed detection methods, using a combination of SPECT and Echo, for effective in vivo evaluation of cardiac functions. PMID:27373983

Reduced Susceptibility of DNA Methyltransferase 1 Hypomorphic (Dnmt1N/+) Mice to Hepatic Steatosis upon Feeding Liquid Alcohol Diet

PubMed Central

Yu, Lianbo; Zhang, Xiaoli; Majumder, Sarmila; Motiwala, Tasneem; Khan, Nuzhat; Belury, Martha; McClain, Craig; Jacob, Samson; Ghoshal, Kalpana

2012-01-01

Background Methylation at C-5 (5-mdC) of CpG base pairs, the most abundant epigenetic modification of DNA, is catalyzed by 3 essential DNA methyltransferases (Dnmt1, Dnmt3a and Dnmt3b). Aberrations in DNA methylation and Dnmts are linked to different diseases including cancer. However, their role in alcoholic liver disease (ALD) has not been elucidated. Methodology/Principal Findings Dnmt1 wild type (Dnmt1 +/+) and hypomorphic (Dnmt1 N/+) male mice that express reduced level of Dnmt1 were fed Lieber-DeCarli liquid diet containing ethanol for 6 weeks. Control mice were pair-fed calorie-matched alcohol-free liquid diet, and Dnmtase activity, 5-mdC content, gene expression profile and liver histopathology were evaluated. Ethanol feeding caused pronounced decrease in hepatic Dnmtase activity in Dnmt1 +/+ mice due to decrease in Dnmt1 and Dnmt3b protein levels and upregulation of miR-148 and miR-152 that target both Dnmt1 and Dnmt3b. Microarray and qPCR analysis showed that the genes involved in lipid, xenobiotic and glutathione metabolism, mitochondrial function and cell proliferation were dysregulated in the wild type mice fed alcohol. Surprisingly, Dnmt1 N/+ mice were less susceptible to alcoholic steatosis compared to Dnmt1 +/+ mice. Expression of several key genes involved in alcohol (Aldh3b1), lipid (Ppara, Lepr, Vldlr, Agpat9) and xenobiotic (Cyp39a1) metabolism, and oxidative stress (Mt-1, Fmo3) were significantly (P<0.05) altered in Dnmt1 N/+ mice relative to the wild type mice fed alcohol diet. However, CpG islands encompassing the promoter regions of Agpat9, Lepr, Mt1 and Ppara were methylation-free in both genotypes irrespective of the diet, suggesting that promoter methylation does not regulate their expression. Similarly, 5-mdC content of the liver genome, as measured by LC-MS/MS analysis, was not affected by alcohol diet in the wild type or hypomorphic mice. Conclusions/Significance Although feeding alcohol diet reduced Dnmtase activity, the loss of one copy of Dnmt1 protected mice from alcoholic hepatosteatosis by dysregulating genes involved in lipid metabolism and oxidative stress. PMID:22905112

High-Fat-Diet Intake Enhances Cerebral Amyloid Angiopathy and Cognitive Impairment in a Mouse Model of Alzheimer's Disease, Independently of Metabolic Disorders.

PubMed

Lin, Bowen; Hasegawa, Yu; Takane, Koki; Koibuchi, Nobutaka; Cao, Cheng; Kim-Mitsuyama, Shokei

2016-06-13

The high-fat Western diet is postulated to be associated with the onset and progression of Alzheimer's disease (AD). However, the role of high-fat-diet consumption in AD pathology is unknown. This study was undertaken to examine the role of high-fat-diet intake in AD. 5XFAD mice, a useful mouse model of AD, and control wild-type mice were fed (1) high-fat diet or (2) control diet for 10 weeks. The effects on cerebral AD pathology, cognitive function, and metabolic parameters were compared between each group of mice. High-fat diet significantly enhanced cerebrovascular β-amyloid (Aβ) deposition (P<0.05) and impaired cognitive function (P<0.05) in 5XFAD mice, but not in wild-type mice. High-fat diet enhanced hippocampal oxidative stress (P<0.05) and NADPH oxidase subunits, gp91(phox) (P<0.01) and p22(phox) (P<0.01) in 5XFAD mice, but not in wild-type mice. Furthermore, high-fat diet reduced cerebral occludin (P<0.05) in 5XFAD mice, but not in wild-type mice. Thus, 5XFAD mice exhibited greater susceptibility to high-fat diet than wild-type mice regarding cerebrovascular injury and cognitive impairment. On the other hand, 5XFAD mice fed high-fat diet exhibited much less increase in body weight, white adipose tissue weight, and adipocyte size than their wild-type counterparts. High-fat diet significantly impaired glucose tolerance in wild-type mice but not in 5XFAD mice. Thus, 5XFAD mice had much less susceptibility to high-fat-diet-induced metabolic disorders than wild-type mice. High-fat diet, independently of metabolic disorders, significantly promotes the progression of AD-like pathology through enhancement of cerebral amyloid angiopathy and oxidative stress. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Conjugated Linoleic Acid Ameliorates Inflammation-Induced Colorectal Cancer in Mice through Activation of PPARγ1–3

PubMed Central

Evans, Nicholas P.; Misyak, Sarah A.; Schmelz, Eva M.; Guri, Amir J.; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-01-01

Conjugated linoleic acid (CLA) exerts a protective effect on experimental inflammatory bowel disease and shows promise as a chemopreventive agent against colorectal cancer (CRC) in mice, although the mechanisms by which it exerts its beneficial effects against malignancies in the gut are not completely understood. Mice lacking PPARγ in immune and epithelial cells and PPARγ-expressing littermates were fed either control or CLA-supplemented (1 g CLA/100 g) diets to determine the role of PPARγ in inflammation-induced CRC. To induce tumor formation and colitis, mice were treated with azoxymethane and then challenged with 2% dextran sodium sulfate, respectively. Dietary CLA ameliorated disease activity, decreased colitis, and prevented adenocarcinoma formation in the PPARγ-expressing floxed mice but not in the tissue-specific PPARγ-null mice. Dietary CLA supplementation significantly decreased the percentages of macrophages in the mesenteric lymph nodes (MLN) regardless of the genotype and increased regulatory T cell numbers in MLN of PPARγ-expressing, but not in the tissue-specific, PPARγ-null mice. Colonic tumor necrosis factor-α mRNA expression was significantly suppressed in CLA-fed, PPARγ-expressing mice. This study suggests CLA ameliorates colitis and prevents tumor formation in part through a PPARγ-dependent mechanism. PMID:20089779

Adiponectin gene therapy ameliorates high-fat, high-sucrose diet-induced metabolic perturbations in mice

PubMed Central

Kandasamy, A D; Sung, M M; Boisvenue, J J; Barr, A J; Dyck, J R B

2012-01-01

Background and Design: Adiponectin is an adipokine secreted primarily from adipose tissue that can influence circulating plasma glucose and lipid levels through multiple mechanisms involving a variety of organs. In humans, reduced plasma adiponectin levels induced by obesity are associated with insulin resistance and type 2 diabetes, suggesting that low adiponectin levels may contribute the pathogenesis of obesity-related insulin resistance. Methods and Results: The objective of the present study was to investigate whether gene therapy designed to elevate circulating adiponectin levels is a viable strategy for ameliorating insulin resistance in mice fed a high-fat, high-sucrose (HFHS) diet. Electroporation-mediated gene transfer of mouse adiponectin plasmid DNA into gastrocnemius muscle resulted in elevated serum levels of globular and high-molecular weight adiponectin compared with control mice treated with empty plasmid. In comparison to HFHS-fed mice receiving empty plasmid, mice receiving adiponectin gene therapy displayed significantly decreased weight gain following 13 weeks of HFHS diet associated with reduced fat accumulation, and exhibited increased oxygen consumption and locomotor activity as measured by indirect calorimetry, suggesting increased energy expenditure in these mice. Consistent with improved whole-body metabolism, mice receiving adiponectin gene therapy also had lower blood glucose and insulin levels, improved glucose tolerance and reduced hepatic gluconeogenesis compared with control mice. Furthermore, immunoblot analysis of livers from mice receiving adiponectin gene therapy showed an increase in insulin-stimulated phosphorylation of insulin signaling proteins. Conclusion: Based on these data, we conclude that adiponectin gene therapy ameliorates the metabolic abnormalities caused by feeding mice a HFHS diet and may be a potential therapeutic strategy to improve obesity-mediated impairments in insulin sensitivity. PMID:23446660

Voluntary exercise and increased food intake after mild chronic stress improve social avoidance behavior in mice.

PubMed

Otsuka, Airi; Shiuchi, Tetsuya; Chikahisa, Sachiko; Shimizu, Noriyuki; Séi, Hiroyoshi

2015-11-01

It is well-established that exercise can influence psychological conditions, cognitive function, and energy metabolism in peripheral tissues including the skeletal muscle. However, it is not clear whether exercise can influence social interaction with others and alleviate defeat stress. This study investigated the effect of voluntary wheel running on impaired social interaction induced by chronic social defeat stress (SDS) using the resident-intruder social defeat model. Mice were divided into three groups: control, stress alone, and stress+exercise. SDS was performed by exposing C57BL/6 mice to retired ICR mice for 2.5 min. The C57BL/6 mice were continuously defeated by these resident (aggressor) mice and, following 5 days of SDS, experienced 2 days of rest with no SDS. Mice in the stress+exercise group were allowed to voluntarily run on a wheel for 2h after every SDS exposure. Two weeks later, compared to the control group, the stress group showed a higher ratio of time spent in the corner zone of a social interaction paradigm even though SDS did not elicit depressive- and anxiety-like behaviors. We also observed that voluntary exercise, which did not affect muscle weight and gene expression, decreased social avoidance behavior of stressed mice without clear changes in brain monoamine levels. Interestingly, food intake in the stress+exercise group was the greatest among the three groups. To test the effect of the exercise-induced increase in food intake on social behavior, we set up a pair-fed group where food intake was restricted. We then compared these mice to mice in the stress alone group. We found that the ratio of time spent in the corner zone of the social interaction test was not different between ad libitum- and pair-fed groups, although pair-fed mice spent more time in the corner zone when an aggressor mouse was present than when it was absent. In addition, pair-feeding did not show exercise-induced reductions of adrenal gland weight and enhanced the loss of body fat. Our findings indicate that voluntary exercise reduces social avoidance behavior induced by SDS. Further, we determined that SDS and exercise-induced increases in food intake partially influence energy metabolism and social avoidance behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

High-fat diet induces protein kinase A and G-protein receptor kinase phosphorylation of β2 -adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts.

PubMed

Fu, Qin; Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan; Xiang, Yang K

2017-03-15

Patients with diabetes show a blunted cardiac inotropic response to β-adrenergic stimulation despite normal cardiac contractile reserve. Acute insulin stimulation impairs β-adrenergically induced contractile function in isolated cardiomyocytes and Langendorff-perfused hearts. In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high-fat diet (HFD) feeding on the cardiac β 2 -adrenergic receptor signalling and the impacts on cardiac contractile function. We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β-adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β 2 -adrenergic receptor phosphorylation at protein kinase A and G-protein receptor kinase sites in the myocardium. The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high-fat diet (HFD) on the insulin-adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD-fed mice displayed a significant elevation of phosphorylation of the β 2 -adrenergic receptor (β 2 AR) at both the protein kinase A site serine 261/262 and the G-protein-coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD-fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β 2 AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD-fed mice. Together, these data indicate that HFD promotes phosphorylation of the β 2 AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin-adrenergic signalling network might be effective in prevention of cardiac complications in diabetes. © 2016 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

High‐fat diet induces protein kinase A and G‐protein receptor kinase phosphorylation of β2‐adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts

PubMed Central

Hu, Yuting; Wang, Qingtong; Liu, Yongming; Li, Ning; Xu, Bing; Kim, Sungjin; Chiamvimonvat, Nipavan

2017-01-01

Key points Patients with diabetes show a blunted cardiac inotropic response to β‐adrenergic stimulation despite normal cardiac contractile reserve.Acute insulin stimulation impairs β‐adrenergically induced contractile function in isolated cardiomyocytes and Langendorff‐perfused hearts.In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high‐fat diet (HFD) feeding on the cardiac β2‐adrenergic receptor signalling and the impacts on cardiac contractile function.We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β‐adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2‐adrenergic receptor phosphorylation at protein kinase A and G‐protein receptor kinase sites in the myocardium.The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications. Abstract Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high‐fat diet (HFD) on the insulin–adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD‐fed mice displayed a significant elevation of phosphorylation of the β2‐adrenergic receptor (β2AR) at both the protein kinase A site serine 261/262 and the G‐protein‐coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD‐fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD‐fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin–adrenergic signalling network might be effective in prevention of cardiac complications in diabetes. PMID:27983752

Mouse strain-dependent caspase activation during acetaminophen hepatotoxicity does not result in apoptosis or modulation of inflammation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Williams, C. David; Koerner, Michael R., E-mail: mkoern2@illinois.edu; Lampe, Jed N.

The mechanisms of acetaminophen (APAP)-mediated hepatic oncotic necrosis have been extensively characterized. However, it was recently demonstrated that fed CD-1 mice have a transient caspase activation which initiates apoptosis. To evaluate these findings in more detail, outbred (Swiss Webster, SW) and inbred (C57BL/6) mice were treated with APAP with or without pan-caspase inhibitor and compared to the apoptosis model of galactosamine (GalN)/endotoxin (ET). Fasted or fed APAP-treated C57BL/6 mice showed no evidence of caspase-3 processing or activity. Interestingly, a minor, temporary increase in caspase-3 processing and activity (150% above baseline) was observed after APAP treatment only in fed SW mice.more » The degree of caspase-3 activation in SW mice after APAP was minor compared to that observed in GalN/ET-treated mice (1600% above baseline). The pancaspase inhibitor attenuated caspase activation and resulted in increased APAP-induced injury (plasma ALT, necrosis scoring). The caspase inhibitor did not affect apoptosis because regardless of treatment only < 0.5% of hepatocytes showed consistent apoptotic morphology after APAP. In contrast, > 20% apoptotic cells were observed in GalN/ET-treated mice. Presence of the caspase inhibitor altered hepatic glutathione levels in SW mice, which could explain the exacerbation of injury. Additionally, the infiltration of hepatic neutrophils was not altered by the fed state of either mouse strain. Conclusion: Minor caspase-3 activation without apoptotic cell death can be observed only in fed mice of some outbred strains. These findings suggest that although the severity of APAP-induced liver injury varies between fed and fasted animals, the mechanism of cell death does not fundamentally change. -- Highlights: Black-Right-Pointing-Pointer During acetaminophen overdose caspase-3 can be activated in fed mice of certain outbred strains. Black-Right-Pointing-Pointer Hepatic ATP levels are not the determining factor for caspase activity. Black-Right-Pointing-Pointer Caspase-3 activity does not result in increased hepatocellular apoptotic cell death. Black-Right-Pointing-Pointer Neutrophil recruitment during acetaminophen occurs independently of nutritional status. Black-Right-Pointing-Pointer Fed or fasted state does not alter the mechanisms of acetaminophen-induced cell death.« less

Animal model of alcoholic pancreatitis: role of viral infections.

PubMed

Jerrells, Thomas R; Chapman, Nora; Clemens, Dahn L

2003-11-01

Pancreatitis is clearly associated with alcohol abuse, but only a relatively small percentage of people who abuse alcohol develops obvious pancreatitis. These observations have led to the concept that the development of alcoholic pancreatitis requires cofactors. Although diet and smoking have been studied, a clear cofactor has not been identified. The study results presented in this paper were obtained to determine whether viral infection of the pancreas would be a cofactor for alcoholic pancreatitis similar to the role of hepatitis virus infections in the development of alcoholic liver disease. To test this hypothesis, mice were fed ethanol with a liquid diet protocol and infected with coxsackievirus B3 (CVB3). It was found that consumption of alcohol alone did not result in pancreatitis as determined by serum levels of amylase or histologic changes in the pancreas. Two strains of CVB3 that are tropic for the pancreas were used; a virulent and an avirulent strain. Infection of alcohol-fed animals with the virulent CVB3 strain 28 resulted in a more severe pancreatitis than the pancreatitis noted in control animals. Alcohol-fed mice infected with the avirulent strain (GA) showed severe pancreatitis, whereas the infection of control mice did not result in obvious pathologic effects in the pancreas. This model allows mechanistic studies to define the role of viral infection as a cofactor for alcoholic pancreatitis.

Cholesterol kinetic effects of dietary fat in CBA/J and C57BR/cdJ mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Stewart, J.; Kuan, Soniu; Seagrave, R.

1990-02-26

Small differences in dietary fats cause marked differences in cholesterol metabolism in different strains of mice. CBA/J mice adjust HMGCOA reductase activity and C57BR/cdJ mice change fecal excretion of cholesterol. Phenomenological compartmental modeling of movement of 4{sup 14}C-cholesterol in the two strains of mice fed 40 en % fat, P/S = 0.24 (SFA) or 30 en % fat, P/S = 1 (PUFA) was used to analyze rates of movement between serum, liver, heart, and carcass. The C57 mice had slower movement between all compartments than CBA. Residence times in tissues were longer in mice fed SFA than those fed PUFAmore » diet. The kinetic results are in agreement with the organ concentrations and enzyme activities measured.« less

Supplementation with Natural Forms of Vitamin E Augments Antigen-Specific TH1-Type Immune Response to Tetanus Toxoid

PubMed Central

Radhakrishnan, Ammu Kutty; Mahalingam, Dashayini; Selvaduray, Kanga Rani; Nesaretnam, Kalanithi

2013-01-01

This study compared the ability of three forms of vitamin E [tocotrienol-rich fraction (TRF), alpha-tocopherol (α-T), and delta-tocotrienol (δ-T3)] to enhance immune response to tetanus toxoid (TT) immunisation in a mouse model. Twenty BALB/c mice were divided into four groups of five mice each. The mice were fed with the different forms of vitamin E (1 mg) or vehicle daily for two weeks before they were given the TT vaccine [4 Lf] intramuscularly (i.m.). Booster vaccinations were given on days 28 and 42. Serum was collected (days 0, 28, and 56) to quantify anti-TT levels. At autopsy, splenocytes harvested were cultured with TT or mitogens. The production of anti-TT antibodies was augmented (P < 0.05) in mice that were fed with δ-T3 or TRF compared to controls. The production of IFN-γ and IL-4 by splenocytes from the vitamin E treated mice was significantly (P < 0.05) higher than that from controls. The IFN-γ production was the highest in animals supplemented with δ-T3 followed by TRF and finally α-T. Production of TNF-α was suppressed in the vitamin E treated group compared to vehicle-supplemented controls. Supplementation with δ-T3 or TRF can enhance immune response to TT immunisation and production of cytokines that promote cell-mediated (TH1) immune response. PMID:23936847

L-arginine supplementation prevents increases in intestinal permeability and bacterial translocation in male Swiss mice subjected to physical exercise under environmental heat stress.

PubMed

Costa, Kátia Anunciação; Soares, Anne Danieli Nascimento; Wanner, Samuel Penna; Santos, Rosana das Graças Carvalho dos; Fernandes, Simone Odília Antunes; Martins, Flaviano dos Santos; Nicoli, Jacques Robert; Coimbra, Cândido Celso; Cardoso, Valbert Nascimento

2014-02-01

Dietary supplementation with l-arginine has been shown to improve the intestinal barrier in many experimental models. This study investigated the effects of arginine supplementation on the intestinal permeability and bacterial translocation (BT) induced by prolonged physical exercise under heat stress. Under anesthesia, male Swiss mice (5-wk-old) were implanted with an abdominal sensor to record their core body temperature (T(core)). After recovering from surgery, the mice were divided into 3 groups: a non-supplemented group that was fed the standard diet formulated by the American Institute of Nutrition (AIN-93G; control), a non-supplemented group that was fed the AIN-93G diet and subjected to exertional hyperthermia (H-NS), and a group supplemented with l-arginine at 2% and subjected to exertional hyperthermia (H-Arg). After 7 d of treatment, the H-NS and H-Arg mice were forced to run on a treadmill (60 min, 8 m/min) in a warm environment (34°C). The control mice remained at 24°C. Thirty min before the exercise or control trials, the mice received a diethylenetriamine pentaacetic acid (DTPA) solution labeled with technetium-99m ((99m)Tc-DTPA) or (99m)Tc-Escherichia coli by gavage to assess intestinal permeability and BT, respectively. The H-NS mice terminated the exercise with T(core) values of ∼40°C, and, 4 h later, presented a 12-fold increase in the blood uptake of (99m)Tc-DTPA and higher bacterial contents in the blood and liver than the control mice. Although supplementation with arginine did not change the exercise-induced increase in T(core), it prevented the increases in intestinal permeability and BT caused by exertional hyperthermia. Our results indicate that dietary l-arginine supplementation preserves the integrity of the intestinal epithelium during exercise under heat stress, acting through mechanisms that are independent of T(core) regulation.

Degradation of PHLPP2 by KCTD17, via a Glucagon-Dependent Pathway, Promotes Hepatic Steatosis.

PubMed

Kim, KyeongJin; Ryu, Dongryeol; Dongiovanni, Paola; Ozcan, Lale; Nayak, Shruti; Ueberheide, Beatrix; Valenti, Luca; Auwerx, Johan; Pajvani, Utpal B

2017-12-01

Obesity-induced nonalcoholic fatty liver disease (NAFLD) develops, in part, via excess insulin-stimulated hepatic de novo lipogenesis, which increases, paradoxically, in patients with obesity-induced insulin resistance. Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) terminates insulin signaling by dephosphorylating Akt; levels of PHLPP2 are reduced in livers from obese mice. We investigated whether loss of hepatic PHLPP2 is sufficient to induce fatty liver in mice, mechanisms of PHLPP2 degradation in fatty liver, and expression of genes that regulate PHLPP2 in livers of patients with NAFLD. C57BL/6J mice (controls), obese db/db mice, and mice with liver-specific deletion of PHLPP2 (L-PHLPP2) fed either normal chow or high-fat diet (HFD) were analyzed for metabolic phenotypes, including glucose tolerance and hepatic steatosis. PHLPP2-deficient primary hepatocytes or CRISPR/Cas9-mediated PHLPP2-knockout hepatoma cells were analyzed for insulin signaling and gene expression. We performed mass spectrometry analyses of liver tissues from C57BL/6J mice transduced with Ad-HA-Flag-PHLPP2 to identify posttranslational modifications to PHLPP2 and proteins that interact with PHLPP2. We measured levels of mRNAs by quantitative reverse transcription polymerase chain reaction in liver biopsies from patients with varying degrees of hepatic steatosis. PHLPP2-knockout hepatoma cells and hepatocytes from L-PHLPP2 mice showed normal initiation of insulin signaling, but prolonged insulin action. Chow-fed L-PHLPP2 mice had normal glucose tolerance but hepatic steatosis. In HFD-fed C57BL/6J or db/db obese mice, endogenous PHLPP2 was degraded by glucagon and PKA-dependent phosphorylation of PHLPP2 (at Ser1119 and Ser1210), which led to PHLPP2 binding to potassium channel tetramerization domain containing 17 (KCTD17), a substrate-adaptor for Cul3-RING ubiquitin ligases. Levels of KCTD17 mRNA were increased in livers of HFD-fed C57BL/6J or db/db obese mice and in liver biopsies patients with NAFLD, compared with liver tissues from healthy control mice or patients without steatosis. Knockdown of KCTD17 with small hairpin RNA in primary hepatocytes increased PHLPP2 protein but not Phlpp2 mRNA, indicating that KCTD17 mediates PHLPP2 degradation. KCTD17 knockdown in obese mice prevented PHLPP2 degradation and decreased expression of lipogenic genes. In mouse models of obesity, we found that PHLPP2 degradation induced lipogenesis without affecting gluconeogenesis. KCTD17, which is up-regulated in liver tissues of obese mice and patients with NAFLD, binds to phosphorylated PHLPP2 to target it for ubiquitin-mediated degradation; this increases expression of genes that regulate lipogenesis to promote hepatic steatosis. Inhibitors of this pathway might be developed for treatment of patients with NAFLD. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Dietary Selenium Supplementation Modulates Growth of Brain Metastatic Tumors and Changes the Expression of Adhesion Molecules in Brain Microvessels.

PubMed

Wrobel, Jagoda K; Wolff, Gretchen; Xiao, Rijin; Power, Ronan F; Toborek, Michal

2016-08-01

Various dietary agents can modulate tumor invasiveness. The current study explored whether selenoglycoproteins (SeGPs) extracted from selenium-enriched yeast affect tumor cell homing and growth in the brain. Mice were fed diets enriched with specific SeGPs (SeGP40 or SeGP65, 1 mg/kg Se each), glycoproteins (GP40 or GP65, 0.2-0.3 mg/kg Se each) or a control diet (0.2-0.3 mg/kg Se) for 12 weeks. Then, murine Lewis lung carcinoma cells were infused into the brain circulation. Analyses were performed at early (48 h) and late stages (3 weeks) post tumor cell infusion. Imaging of tumor progression in the brain revealed that mice fed SeGP65-enriched diet displayed diminished metastatic tumor growth, fewer extravasating tumor cells and smaller metastatic lesions. While administration of tumor cells resulted in a significant upregulation of adhesion molecules in the early stage of tumor progression, overexpression of VCAM-1 (vascular call adhesion molecule-1) and ALCAM (activated leukocyte cell adhesion molecule) messenger RNA (mRNA) was diminished in SeGP65 supplemented mice. Additionally, mice fed SeGP65 showed decreased expression of acetylated NF-κB p65, 48 h post tumor cell infusion. The results indicate that tumor progression in the brain can be modulated by specific SeGPs. Selenium-containing compounds were more effective than their glycoprotein controls, implicating selenium as a potential negative regulator of metastatic process.

The influence of dietary fat source on liver and skeletal muscle mitochondrial modifications and lifespan changes in calorie-restricted mice

PubMed Central

Villalba, José Manuel; López-Domínguez, José Alberto; Chen, Yana; Khraiwesh, Husam; González-Reyes, José Antonio; del Río, Lucía Fernández; Gutiérrez-Casado, Elena; del Río, Mercedes; Calvo-Rubio, Miguel; Ariza, Julia; de Cabo, Rafael; López-Lluch, Guillermo; Navas, Plácido; Hagopian, Kevork; Burón, María Isabel; Ramsey, Jon Jay

2015-01-01

The Membrane Theory of Aging proposes that lifespan is inversely related to the level of unsaturation in membrane phospholipids. Calorie restriction (CR) without malnutrition extends lifespan in many model organisms, which may be related to alterations in membrane phospholipids fatty acids. During the last few years our research focused on studying how altering the predominant fat source affects the outcome of CR in mice. We have established four dietary groups: one control group fed 95% of a pre-determined ad libitum intake (in order to prevent obesity), and three CR groups fed 40% less than ad libitum intake. Lipid source for the control and one of the CR groups was soybean oil (high in n-6 PUFA) whereas the two remaining CR groups were fed diets containing fish oil (high in n-3 PUFA), or lard (high in saturated and monounsaturated fatty acids). Dietary intervention periods ranged from 1 to 18 months. We performed a longitudinal lifespan study and a cross-sectional study set up to evaluate several mitochondrial parameters which included fatty acid composition, H+ leak, activities of electron transport chain enzymes, ROS generation, lipid peroxidation, mitochondrial ultrastructure, and mitochondrial apoptotic signaling in liver and skeletal muscle. These approaches applied to different cohorts of mice have independently indicated that lard as a fat source often maximizes the effects of 40% CR on mice. These effects could be due to significant increases of monounsaturated fatty acids levels, in accordance with the Membrane Theory of Aging. PMID:25860863

WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease.

PubMed

Archer, D C; Frkanec, J T; Cromwell, J; Clopton, P; Cunard, R

2007-11-01

Peroxisome proliferator-activated receptor alpha (PPARalpha) ligands are medications used to treat hyperlipidaemia and atherosclerosis. Increasing evidence suggests that these agents are immunosuppressive. In the following studies we demonstrate that WY14,643, a PPARalpha ligand, attenuates expression of anti-glomerular basement membrane disease (AGBMD). C57BL/6 mice were fed 0.05% WY14,643 or control food and immunized with the non-collagenous domain of the alpha3 chain of Type IV collagen [alpha3(IV) NC1] in complete Freund's adjuvant (CFA). WY14,643 reduced proteinuria and greatly improved glomerular and tubulo-interstitial lesions. However, the PPARalpha ligand did not alter the extent of IgG-binding to the GBM. Immunohistochemical studies revealed that the prominent tubulo-interstitial infiltrates in the control-fed mice consisted predominately of F4/80(+) macrophages and WY14,643-feeding decreased significantly the number of renal macrophages. The synthetic PPARalpha ligand also reduced significantly expression of the chemokine, monocyte chemoattractant protein (MCP)-1/CCL2. Sera from mice immunized with AGBMD were also evaluated for antigen-specific IgGs. There was a significant increase in the IgG1 : IgG2c ratio and a decline in the intrarenal and splenocyte interferon (IFN)-gamma mRNA expression in the WY14,643-fed mice, suggesting that the PPARalpha ligand could skew the immune response to a less inflammatory T helper 2-type of response. These studies suggest that PPARalpha ligands may be a novel treatment for inflammatory renal disease.

WY14,643, a PPARα ligand, attenuates expression of anti-glomerular basement membrane disease

PubMed Central

Archer, D C; Frkanec, J T; Cromwell, J; Clopton, P; Cunard, R

2007-01-01

Peroxisome proliferator-activated receptor alpha (PPARα) ligands are medications used to treat hyperlipidaemia and atherosclerosis. Increasing evidence suggests that these agents are immunosuppressive. In the following studies we demonstrate that WY14,643, a PPARα ligand, attenuates expression of anti-glomerular basement membrane disease (AGBMD). C57BL/6 mice were fed 0·05% WY14,643 or control food and immunized with the non-collagenous domain of the α3 chain of Type IV collagen [α3(IV) NC1] in complete Freund's adjuvant (CFA). WY14,643 reduced proteinuria and greatly improved glomerular and tubulo-interstitial lesions. However, the PPARα ligand did not alter the extent of IgG-binding to the GBM. Immunohistochemical studies revealed that the prominent tubulo-interstitial infiltrates in the control-fed mice consisted predominately of F4/80+ macrophages and WY14,643-feeding decreased significantly the number of renal macrophages. The synthetic PPARα ligand also reduced significantly expression of the chemokine, monocyte chemoattractant protein (MCP)-1/CCL2. Sera from mice immunized with AGBMD were also evaluated for antigen-specific IgGs. There was a significant increase in the IgG1 : IgG2c ratio and a decline in the intrarenal and splenocyte interferon (IFN)-γ mRNA expression in the WY14,643-fed mice, suggesting that the PPARα ligand could skew the immune response to a less inflammatory T helper 2-type of response. These studies suggest that PPARα ligands may be a novel treatment for inflammatory renal disease. PMID:17888025

Loss of circadian rhythm of circulating insulin concentration induced by high-fat diet intake is associated with disrupted rhythmic expression of circadian clock genes in the liver.

PubMed

Honma, Kazue; Hikosaka, Maki; Mochizuki, Kazuki; Goda, Toshinao

2016-04-01

Peripheral clock genes show a circadian rhythm is correlated with the timing of feeding in peripheral tissues. It was reported that these clock genes are strongly regulated by insulin action and that a high-fat diet (HFD) intake in C57BL/6J mice for 21days induced insulin secretion during the dark phase and reduced the circadian rhythm of clock genes. In this study, we examined the circadian expression patterns of these clock genes in insulin-resistant animal models with excess secretion of insulin during the day. We examined whether insulin resistance induced by a HFD intake for 80days altered blood parameters (glucose and insulin concentrations) and expression of mRNA and proteins encoded by clock and functional genes in the liver using male ICR mice. Serum insulin concentrations were continuously higher during the day in mice fed a HFD than control mice. Expression of lipogenesis-related genes (Fas and Accβ) and the transcription factor Chrebp peaked at zeitgeber time (ZT)24 in the liver of control mice. A HFD intake reduced the expression of these genes at ZT24 and disrupted the circadian rhythm. Expression of Bmal1 and Clock, transcription factors that compose the core feedback loop, showed circadian variation and were synchronously associated with Fas gene expression in control mice, but not in those fed a HFD. These results indicate that the disruption of the circadian rhythm of insulin secretion by HFD intake is closely associated with the disappearance of circadian expression of lipogenic and clock genes in the liver of mice. Copyright © 2016 Elsevier Inc. All rights reserved.

[Effect of diisobutyl phthalate on learning and memory behavior and apoptosis of hippocampus cells in mice].

PubMed

Ma, Ning; Liu, Shan; Gao, Peng; Cao, Pei; Xu, Haibin

2013-01-01

To give the original research of diisobutyl phthalate (DiBP) on learning and memory behavior, determine whether it can through blood-brain barrier and effect apoptosis of hippocampus cells in mice. Accommodating 60 Kunming mice to the animal house for 3 days, then dividing the mice into 5 groups according to their weights. That is, one control group and four experimental groups (I group, 50 mg/kg BW. II group, 250mg/kg BW. III group, 500 mg/kg BW. IV group, 1000 mg/kg BW). The mice were fed with the corn oil in control group, and the other groups were fed with the related dose of diisobutyl phthalate mixture by gavages last for 8 weeks. At the end of experimental time, passive avoidance response was examined, then all of mice were killed, and choosed the brain tissues to test the DiBP content and apoptosis rate of hippocampal cells and hippocampal ultrastructural alterations on electron microscopy. In the passive avoidance response test, the exposed animals of IV group showed learning impairment as compared to unexposed mice (P < 0.05). DiBP was detected in III group and IV group, the mean content of them were (1.27 +/- 0.56) and (1.96 +/- 0.42) microg/g. The apoptosis rate of hippocampal cells (IV group vs control group) increase significantly (P < 0.05). Hippocampal ultrastructural were damaged in all dose-groups. As a result, in the experiments, exposure to DiBP could exert passive avoidance neurobehavioral effects. DiBP could through blood-brain barrier after oral intake, and disordered the way of apoptosis of hippocampal cells, and morphologic change of mitochondria mybe is the main reason of changes of neuron apoptosis.

Dietary fat and gut microbiota interactions determine diet-induced obesity in mice.

PubMed

Kübeck, Raphaela; Bonet-Ripoll, Catalina; Hoffmann, Christina; Walker, Alesia; Müller, Veronika Maria; Schüppel, Valentina Luise; Lagkouvardos, Ilias; Scholz, Birgit; Engel, Karl-Heinz; Daniel, Hannelore; Schmitt-Kopplin, Philippe; Haller, Dirk; Clavel, Thomas; Klingenspor, Martin

2016-12-01

Gut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice. GF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing. GF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes ) as a characteristic feature of normal SPF mice fed lard. In conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

Differential effects of n-3 polyunsaturated fatty acids on metabolic control and vascular reactivity in the type 2 diabetic ob/ob mouse.

PubMed

Mustad, Vikkie A; Demichele, Stephen; Huang, Yung-Sheng; Mika, Amanda; Lubbers, Nathan; Berthiaume, Nathalie; Polakowski, Jim; Zinker, Brad

2006-10-01

Diets rich in monounsaturated fatty acids (MUFA) are recommended for individuals with type 2 diabetes mellitus (T2DM). The American Heart Association recommends increasing intakes of n-3 polyunsaturated fatty acids (PUFA) to reduce the risk of vascular disease in high-risk individuals; however, the long-term effects of these bioactive fatty acids on glucose metabolism in insulin resistance are controversial. The present studies were conducted to evaluate the effects of diets rich in both MUFA and alpha linolenic acid (C18:3n-3, ALA), eicosapentaenoic acid (C20:5n-3, EPA), or docosahexaenoic acid (C22:6n-3, DHA), on glycemic control and other parameters related to vascular health in a mouse model of T2DM and insulin resistance. Male ob/ob mice (n = 15 per treatment) were fed 1 of 4 lipid-modified formula diets (LFDs) for 4 weeks: (1) MUFA control, (2) ALA blend, (3) EPA blend, and (4) DHA blend. A portion of a MUFA-rich lipid blend in the control LFD was replaced with 11% to 14% energy as n-3 PUFA. After 4 weeks, plasma glucose response to a standard meal (1.5 g carbohydrate/kg body weight) and insulin challenge (2 U/kg body weight, IP) was assessed, and samples were collected for analysis of glucose, insulin, and lipids. Vascular reactivity of isolated aortic rings was assessed in an identical follow-up study. The results showed that insulin-resistant mice fed an LFD with EPA and/or DHA blends had significantly (P < .05) lower triglycerides and free fatty acids, but insulin sensitivity and fasting plasma glucose were not improved. However, mice fed with the ALA blend had significantly improved insulin sensitivity when compared to those fed with other LFD (P < .05). Animals fed an LFD with n-3 PUFA from marine or plant sources showed significantly improved vascular responses as compared with the MUFA-rich LFD (E(max), P < .05) and ob/ob reference mice consuming chow (E(max) and pEC(50), P < .05). In summary, long-term consumption of LFD with n-3 PUFAs improved blood lipids and vascular function in an animal model of insulin resistance and T2DM; however, only MUFA-rich LFD with ALA also improved both insulin sensitivity and glycemic responses. Further studies of MUFA-rich LFD with ALA with individuals who have T2DM are warranted.

Dietary quercetin attenuates oxidant-induced endothelial dysfunction and atherosclerosis in apolipoprotein E knockout mice fed a high-fat diet: a critical role for heme oxygenase-1.

PubMed

Shen, Yu; Ward, Natalie C; Hodgson, Jonathan M; Puddey, Ian B; Wang, Yutang; Zhang, Di; Maghzal, Ghassan J; Stocker, Roland; Croft, Kevin D

2013-12-01

Several lines of evidence indicate that quercetin, a polyphenol derived in the diet from fruit and vegetables, contributes to cardiovascular health. We aimed to investigate the effects of dietary quercetin on endothelial function and atherosclerosis in mice fed a high-fat diet. Wild-type C57BL/6 (WT) and apolipoprotein E gene knockout (ApoE(-/-)) mice were fed: (i) a high-fat diet (HFD) or (ii) a HFD supplemented with 0.05% w/w quercetin (HFD+Q), for 14 weeks. Compared with animals fed HFD, HFD+Q attenuated atherosclerosis in ApoE(-/-) mice. Treatment with the HFD+Q significantly improved endothelium-dependent relaxation of aortic rings isolated from WT but not ApoE(-/-) mice and attenuated hypochlorous acid-induced endothelial dysfunction in aortic rings of both WT and ApoE(-/-) mice. Mechanistic studies revealed that HFD+Q significantly improved plasma F2-isoprostanes, 24h urinary nitrite, and endothelial nitric oxide synthase activity, and increased heme oxygenase-1 (HO-1) protein expression in the aortas of both WT and ApoE(-/-) mice (P<0.05). HFD+Q also resulted in small changes in plasma cholesterol (P<0.05 in WT) and plasma triacylglycerols (P<0.05 in ApoE (-/-)mice). In a separate experiment, quercetin did not protect against hypochlorite-induced endothelial dysfunction in arteries obtained from heterozygous HO-1 gene knockout mice with low expression of HO-1 protein. Quercetin protects mice fed a HFD against oxidant-induced endothelial dysfunction and ApoE(-/-) mice against atherosclerosis. These effects are associated with improvements in nitric oxide bioavailability and are critically related to arterial induction of HO-1. © 2013 Elsevier Inc. All rights reserved.

Hepatic effects of a methionine-choline-deficient diet in hepatocyte RXRalpha-null mice.

PubMed

Gyamfi, Maxwell Afari; Tanaka, Yuji; He, Lin; Klaassen, Curtis D; Wan, Yu-Jui Yvonne

2009-01-15

Retinoid X receptor-alpha (RXRalpha) is an obligate partner for several nuclear hormone receptors that regulate important physiological processes in the liver. In this study the impact of hepatocyte RXRalpha deficiency on methionine and choline deficient (MCD) diet-induced steatosis, oxidative stress, inflammation, and hepatic transporters gene expression were examined. The mRNA of sterol regulatory element-binding protein (SREBP)-regulated genes, important for lipid synthesis, were not altered in wild type (WT) mice, but were increased 2.0- to 5.4-fold in hepatocyte RXRalpha-null (H-RXRalpha-null) mice fed a MCD diet for 14 days. Furthermore, hepatic mRNAs and proteins essential for fatty acid beta-oxidation were not altered in WT mice, but were decreased in the MCD diet-fed H-RXRalpha-null mice, resulting in increased hepatic free fatty acid levels. Cyp2e1 enzyme activity and lipid peroxide levels were induced only in MCD-fed WT mice. In contrast, hepatic mRNA levels of pro-inflammatory factors were increased only in H-RXRalpha-null mice fed the MCD diet. Hepatic uptake transporters Oatp1a1 and Oatp1b2 mRNA levels were decreased in WT mice fed the MCD diet, whereas the efflux transporter Mrp4 was increased. However, in the H-RXRalpha-null mice, the MCD diet only moderately decreased Oatp1a1 and induced both Oatp1a4 and Mrp4 gene expression. Whereas the MCD diet increased serum bile acid levels and alkaline phosphatase activity in both WT and H-RXRalpha-null mice, serum ALT levels were induced (2.9-fold) only in the H-RXRalpha-null mice. In conclusion, these data suggest a critical role for RXRalpha in hepatic fatty acid homeostasis and protection against MCD-induced hepatocyte injury.

Oral or parenteral administration of curcumin does not prevent the growth of high-risk t(4;11) acute lymphoblastic leukemia cells engrafted into a NOD/SCID mouse model

PubMed Central

ZUNINO, SUSAN J.; STORMS, DAVID H.; NEWMAN, JOHN W.; PEDERSEN, THERESA L.; KEEN, CARL L.; DUCORE, JONATHAN M.

2013-01-01

In this study, the efficacy of orally and parenter-ally administered curcumin was evaluated in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice (NOD.CB17-Prkdcscid/J mice) engrafted with the human t(4;11) acute lymphoblastic leukemia line, SEM. SEM cells were injected into the tail vein and engraftment was monitored by flow cytometry. Once engraftment was observed, the chemotherapeutic potential was examined by injecting mice intraperitoneally with curcumin (5 mg/kg body weight) dissolved in dimethylsulfoxide (DMSO) or DMSO alone (control) every other day, or vincristine (0.5 mg/kg body weight) 3 times per week for 4 weeks (n=16 per group). The intraperitoneal administration of curcumin did not inhibit the growth of the leukemia cells. To determine the efficacy of oral curcumin, mice were fed a control diet or a diet containing 0.5% w/w curcumin 3 weeks prior to the injection of the leukemia cells and throughout the experimental period (n=16 per group). To determine whether dietary curcumin can enhance the efficacy of a conventional chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the different diets. Dietary curcumin did not delay the engraftment or growth of leukemia cells, or sensitize the cells to vincristine. Liquid chromatography-tandem mass spectrometry analyses of mouse sera showed that curcumin rapidly metabolized to glucuronidated and sulfated forms within 1 h post-injection and these were the major curcumin metabolites found in the sera of the mice fed the curcumin diet. In contrast to the findings in previous in vitro models, the current data indicate that orally or parenterally administered curcumin is not a potent preventive agent against high-risk t(4;11) acute lymphoblastic leukemia. PMID:23232667

Green tea diet decreases PCB 126-induced oxidative stress in mice by up-regulating antioxidant enzymes.

PubMed

Newsome, Bradley J; Petriello, Michael C; Han, Sung Gu; Murphy, Margaret O; Eske, Katryn E; Sunkara, Manjula; Morris, Andrew J; Hennig, Bernhard

2014-02-01

Superfund chemicals such as polychlorinated biphenyls pose a serious human health risk due to their environmental persistence and link to multiple diseases. Selective bioactive food components such as flavonoids have been shown to ameliorate PCB toxicity, but primarily in an in vitro setting. Here, we show that mice fed a green tea-enriched diet and subsequently exposed to environmentally relevant doses of coplanar PCB exhibit decreased overall oxidative stress primarily due to the up-regulation of a battery of antioxidant enzymes. C57BL/6 mice were fed a low-fat diet supplemented with green tea extract (GTE) for 12 weeks and exposed to 5 μmol PCB 126/kg mouse weight (1.63 mg/kg-day) on weeks 10, 11 and 12 (total body burden: 4.9 mg/kg). F2-isoprostane and its metabolites, established markers of in vivo oxidative stress, measured in plasma via HPLC-MS/MS exhibited fivefold decreased levels in mice supplemented with GTE and subsequently exposed to PCB compared to animals on a control diet exposed to PCB. Livers were collected and harvested for both messenger RNA and protein analyses, and it was determined that many genes transcriptionally controlled by aryl hydrocarbon receptor and nuclear factor (erythroid-derived 2)-like 2 proteins were up-regulated in PCB-exposed mice fed the green tea-supplemented diet. An increased induction of genes such as SOD1, GSR, NQO1 and GST, key antioxidant enzymes, in these mice (green tea plus PCB) may explain the observed decrease in overall oxidative stress. A diet supplemented with green tea allows for an efficient antioxidant response in the presence of PCB 126, which supports the emerging paradigm that healthful nutrition may be able to bolster and buffer a physiological system against the toxicities of environmental pollutants. Copyright © 2014 Elsevier Inc. All rights reserved.

Green tea extracts ameliorate high-fat diet-induced muscle atrophy in senescence-accelerated mouse prone-8 mice.

PubMed

Onishi, Shintaro; Ishino, Mayu; Kitazawa, Hidefumi; Yoto, Ai; Shimba, Yuki; Mochizuki, Yusuke; Unno, Keiko; Meguro, Shinichi; Tokimitsu, Ichiro; Miura, Shinji

2018-01-01

Muscle atrophy (loss of skeletal muscle mass) causes progressive deterioration of skeletal function. Recently, excessive intake of fats was suggested to induce insulin resistance, followed by muscle atrophy. Green tea extracts (GTEs), which contain polyphenols such as epigallocatechin gallate, have beneficial effects on obesity, hyperglycemia, and insulin resistance, but their effects against muscle atrophy are still unclear. Here, we found that GTEs prevented high-fat (HF) diet-induced muscle weight loss in senescence-accelerated mouse prone-8 (SAMP8), a murine model of senescence. SAMP8 mice were fed a control diet, an HF diet, or HF with 0.5% GTEs (HFGT) diet for 4 months. The HF diet induced muscle weight loss with aging (measured as quadriceps muscle weight), whereas GTEs prevented this loss. In HF diet-fed mice, blood glucose and plasma insulin concentrations increased in comparison with the control group, and these mice had insulin resistance as determined by homeostasis model assessment of insulin resistance (HOMA-IR). In these mice, serum concentrations of leukocyte cell-derived chemotaxin 2 (LECT2), which is known to induce insulin resistance in skeletal muscle, were elevated, and insulin signaling in muscle, as determined by the phosphorylation levels of Akt and p70 S6 kinases, tended to be decreased. In HFGT diet-fed mice, these signs of insulin resistance and elevation of serum LECT2 were not observed. Although our study did not directly show the effect of serum LECT2 on muscle weight, insulin resistance examined using HOMA-IR indicated an intervention effect of serum LECT2 on muscle weight, as revealed by partial correlation analysis. Accordingly, GTEs might have beneficial effects on age-related and HF diet-induced muscle weight loss, which correlates with insulin resistance and is accompanied by a change in serum LECT2.

Valsartan Promoting Atherosclerotic Plaque Stabilization by Upregulating Renalase: A Potential-Related Gene of Atherosclerosis.

PubMed

Zhou, Mingxue; Ma, Chao; Liu, Weihong; Liu, Hongxu; Wang, Ning; Kang, Qunfu; Li, Ping

2015-09-01

Renalase is a protein that can regulate sympathetic nerve activity by metabolizing catecholamines, while redundant catecholamines are thought to contribute to atherosclerosis (As). Catecholamine release can be facilitated by angiotensin (Ang) II by binding to Ang II type 1 (AT1) receptors. Valsartan, a special AT1 antagonist, can dilate blood vessels and reduce blood pressure, but it remained unclear whether valsartan can promote the stability of atherosclerotic plaque by affecting renalase. This study examined the tissue distribution of renalase in ApoE(-/-) mice fed with a high-fat diet and the effect of valsartan on expression of renalase. ApoE(-/-) mice were fed with a high-fat diet for 13 or 26 weeks. As a control, 10 C57BL mice were fed with a standard chow diet. After 13 weeks on the high-fat diet, the ApoE(-/-) mice were randomized (10 mice/group) and treated with valsartan, simvastatin, or distilled water (control group) for an additional 13 weeks accompanied by a high-fat diet. Knockout of ApoE caused a dramatic increase in expression of renalase in mice adipose tissue. With the disturbance of lipid metabolism induced by a high-fat diet, renalase expression decreased in the liver. Renalase can be expressed in smooth muscle cells and M2 macrophages in atherosclerotic plaque, and its expression gradually decreases in the fibrous cap during the transition from stable to vulnerable atherosclerotic plaque. Valsartan, an AT1 receptor antagonist, promotes the stabilization of atherosclerotic plaque by increasing the levels of renalase in serum and the expression of renalase in the fibrous cap of atherosclerotic plaque. It also reduces triglyceride levels in serum and increases the expression of renalase in the liver. Renalase may be a potential-related gene of lipid metabolism and As, and it may be the possible molecular target of valsartan to help stabilize atherosclerotic plaque. © The Author(s) 2015.

Chardonnay grape seed flour ameliorates hepatic steatosis and insulin resistance via altered hepatic gene expression for oxidative stress, inflammation, and lipid and ceramide synthesis in diet-induced obese mice

USDA-ARS?s Scientific Manuscript database

Diet-induced obese (DIO) mice were fed high-fat (HF) diets containing either partially defatted flavonoid-rich Chardonnay grape seed flour (ChrSd) or microcrystalline cellulose (MCC, control) for 5 weeks in order to determine whether ChrSd improved insulin resistance and the pathogenesis of hepatic ...

Dietary Green Pea Protects against DSS-Induced Colitis in Mice Challenged with High-Fat Diet.

PubMed

Bibi, Shima; de Sousa Moraes, Luís Fernando; Lebow, Noelle; Zhu, Mei-Jun

2017-05-18

Obesity is a risk factor for developing inflammatory bowel disease. Pea is unique with its high content of dietary fiber, polyphenolics, and glycoproteins, all of which are known to be health beneficial. We aimed to investigate the impact of green pea (GP) supplementation on the susceptibility of high-fat diet (HFD)-fed mice to dextran sulfate sodium (DSS)-induced colitis. Six-week-old C57BL/6J female mice were fed a 45% HFD or HFD supplemented with 10% GP. After 7-week dietary supplementation, colitis was induced by adding 2.5% DSS in drinking water for 7 days followed by a 7-day recovery period. GP supplementation ameliorated the disease activity index score in HFD-fed mice during the recovery stage, and reduced neutrophil infiltration, mRNA expression of monocyte chemoattractant protein-1 (MCP-1) and inflammatory markers interleukin (IL)-6, cyclooxygenase-2 (COX-2), IL-17, interferon-γ (IFN-γ), and inducible nitric oxide synthase (iNOS) in HFD-fed mice. Further, GP supplementation increased mucin 2 content and mRNA expression of goblet cell differentiation markers including Trefoil factor 3 (Tff3), Krüppel-like factor 4 (Klf4), and SAM pointed domain ETS factor 1 (Spdef1) in HFD-fed mice. In addition, GP ameliorated endoplasmic reticulum (ER) stress as indicated by the reduced expression of Activating transcription factor-6 (ATF-6) protein and its target genes chaperone protein glucose-regulated protein 78 (Grp78), the CCAAT-enhancer-binding protein homologous protein (CHOP), the ER degradation-enhancing α-mannosidase-like 1 protein (Edem1), and the X-box binding protein 1 (Xbp1) in HFD-fed mice. In conclusion, GP supplementation ameliorated the severity of DSS-induced colitis in HFD-fed mice, which was associated with the suppression of inflammation, mucin depletion, and ER stress in the colon.

Transition from metabolic adaptation to maladaptation of the heart in obesity: role of apelin.

PubMed

Alfarano, C; Foussal, C; Lairez, O; Calise, D; Attané, C; Anesia, R; Daviaud, D; Wanecq, E; Parini, A; Valet, P; Kunduzova, O

2015-02-01

Impaired energy metabolism is the defining characteristic of obesity-related heart failure. The adipocyte-derived peptide apelin has a role in the regulation of cardiovascular and metabolic homeostasis and may contribute to the link between obesity, energy metabolism and cardiac function. Here we investigate the role of apelin in the transition from metabolic adaptation to maladaptation of the heart in obese state. Adult male C57BL/6J, apelin knock-out (KO) or wild-type mice were fed a high-fat diet (HFD) for 18 weeks. To induce heart failure, mice were subjected to pressure overload after 18 weeks of HFD. Long-term effects of apelin on fatty acid (FA) oxidation, glucose metabolism, cardiac function and mitochondrial changes were evaluated in HFD-fed mice after 4 weeks of pressure overload. Cardiomyocytes from HFD-fed mice were isolated for analysis of metabolic responses. In HFD-fed mice, pressure overload-induced transition from hypertrophy to heart failure is associated with reduced FA utilization (P<0.05), accelerated glucose oxidation (P<0.05) and mitochondrial damage. Treatment of HFD-fed mice with apelin for 4 weeks prevented pressure overload-induced decline in FA metabolism (P<0.05) and mitochondrial defects. Furthermore, apelin treatment lowered fasting plasma glucose (P<0.01), improved glucose tolerance (P<0.05) and preserved cardiac function (P<0.05) in HFD-fed mice subjected to pressure overload. In apelin KO HFD-fed mice, spontaneous cardiac dysfunction is associated with reduced FA oxidation (P<0.001) and increased glucose oxidation (P<0.05). In isolated cardiomyocytes, apelin stimulated FA oxidation in a dose-dependent manner and this effect was prevented by small interfering RNA sirtuin 3 knockdown. These data suggest that obesity-related decline in cardiac function is associated with defective myocardial energy metabolism and mitochondrial abnormalities. Furthermore, our work points for therapeutic potential of apelin to prevent myocardial metabolic abnormalities in heart failure paired with obesity.

Effects of escin mixture from the seeds of Aesculus hippocastanum on obesity in mice fed a high fat diet.

PubMed

Avci, Gülcan; Küçükkurt, Ismail; Küpeli Akkol, Esra; Yeşilada, Erdem

2010-03-01

Escins, a triterpene glycoside mixture obtained from the ethanol extract of Aesculus hippocastanum L. (Hippocastanaceae) seed, was evaluated for its in vivo effects on the plasma levels of some hormones (leptin, insulin, FT(3), FT(4)) and biochemical parameters (glucose, triglyceride, total cholesterol, HDL-C, LDL-C concentrations) in mice fed with a high fat diet for 5 weeks. A high fat diet induced a remarkable increment in the plasma leptin (p <0.01), total cholesterol (p <0.01) and LDL-C (p <0.001) concentrations compared to control group animals. Combined administration of a high-fat diet with escins decreased leptin (31.6%) (p<0.05) and FT(4) (36.0%) (p<0.05) levels, increased HDL-C concentration (17.0%), while remained ineffective on LDL-C concentration in mice. Results have shown that escins may have beneficial effects in the understanding of obesity.

Nicotinamide mononucleotide protects against pro-inflammatory cytokine-mediated impairment of mouse islet function.

PubMed

Caton, P W; Kieswich, J; Yaqoob, M M; Holness, M J; Sugden, M C

2011-12-01

Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD(+) biosynthesis, exists as intracellular NAMPT (iNAMPT) and extracellular NAMPT (eNAMPT). eNAMPT, secreted from adipose tissue, promotes insulin secretion. Administration of nicotinamide mononucleotide (NMN), a product of the eNAMPT reaction, corrects impaired islet function in Nampt ( +/- ) mice. One of its potential targets is the NAD(+)-dependent deacetylase sirtuin 1. We hypothesised that altered NAMPT activity might contribute to the suppression of islet function associated with inflammation, and aimed to determine whether NMN could improve cytokine-mediated islet dysfunction. Acute effects of NMN on cytokine-mediated islet dysfunction were examined in islets incubated with TNFα and IL1β, and in mice fed a fructose-rich diet (FRD) for 16 weeks. Changes in iNAMPT, eNAMPT and inflammation levels were determined in FRD-fed mice. FRD-fed mice displayed markedly lower levels of circulating eNAMPT, with impaired insulin secretion and raised islet expression of Il1b. NMN administration lowered Il1b expression and restored suppressed insulin secretion in FRD-fed mice. NMN also restored insulin secretion in islets cultured with pro-inflammatory cytokines. The changes in islet function corresponded with changes in key markers of islet function and differentiation. The anti-inflammatory effects of NMN were partially blocked by inhibition of sirtuin 1. Chronic fructose feeding causes severe islet dysfunction in mice. Onset of beta cell failure in FRD-fed mice may occur via lowered secretion of eNAMPT, leading to increased islet inflammation and impaired beta cell function. Administration of exogenous NMN to FRD-fed mice corrects inflammation-induced islet dysfunction. Modulation of this pathway may be an attractive target for amelioration of islet dysfunction associated with inflammation.

Effect of Dietary Fibers on Cecal Microbiota and Intestinal Tumorigenesis in Azoxymethane Treated A/J Min/+ Mice

PubMed Central

Måge, Ingrid; Knutsen, Svein Halvor; Rud, Ida; Hetland, Ragna Bogen; Paulsen, Jan Erik

2016-01-01

Foods naturally high in dietary fiber are generally considered to protect against development of colorectal cancer (CRC). However, the intrinsic effect of dietary fiber on intestinal carcinogenesis is unclear. We used azoxymethane (AOM) treated A/J Min/+ mice, which developed a significantly higher tumor load in the colon than in the small intestine, to compare the effects of dietary inulin (IN), cellulose (CE) or brewers spent grain (BSG) on intestinal tumorigenesis and cecal microbiota. Each fiber was tested at two dose levels, 5% and 15% (w/w) content of the AIN-93M diet. The microbiota was investigated by next-generation sequencing of the 16S rRNA gene (V4). We found that mice fed IN had approximately 50% lower colonic tumor load than mice fed CE or BSG (p<0.001). Surprisingly, all three types of fiber caused a dose dependent increase of colonic tumor load (p<0.001). The small intestinal tumor load was not affected by the dietary fiber interventions. Mice fed IN had a lower bacterial diversity than mice fed CE or BSG. The Bacteroidetes/Firmicutes ratio was significantly (p = 0.003) different between the three fiber diets with a higher mean value in IN fed mice compared with BSG and CE. We also found a relation between microbiota and the colonic tumor load, where many of the operational taxonomic units (OTUs) related to low tumor load were significantly enriched in mice fed IN. Among the OTUs related to low tumor load were bacteria affiliated with the Bacteroides genus. These results suggest that type of dietary fiber may play a role in the development of CRC, and that the suppressive effect of IN on colonic tumorigenesis is associated with profound changes in the cecal microbiota profile. PMID:27196124

An integrative transcriptomic approach to identify depot differences in genes and microRNAs in adipose tissues from high fat fed mice.

PubMed

Wijayatunga, Nadeeja N; Pahlavani, Mandana; Kalupahana, Nishan S; Kottapalli, Kameswara Rao; Gunaratne, Preethi H; Coarfa, Cristian; Ramalingam, Latha; Moustaid-Moussa, Naima

2018-02-06

Obesity contributes to metabolic disorders such as diabetes and cardiovascular disease. Characterization of differences between the main adipose tissue depots, white (WAT) [including subcutaneous (SAT) and visceral adipose tissue (VAT)] and brown adipose tissue (BAT) helps to identify their roles in obesity. Thus, we studied depot-specific differences in whole transcriptome and miRNA profiles of SAT, VAT and BAT from high fat diet (HFD/45% of calories from fat) fed mice using RNA sequencing and small RNA-Seq. Using quantitative real-time polymerase chain reaction, we validated depot-specific differences in endoplasmic reticulum (ER) stress related genes and miRNAs using mice fed a HFD vs. low fat diet (LFD/10% of calories from fat). According to the transcriptomic analysis, lipogenesis, adipogenesis, inflammation, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) were higher in VAT compared to BAT, whereas energy expenditure, fatty acid oxidation and oxidative phosphorylation were higher in BAT than in VAT of the HFD fed mice. In contrast to BAT, ER stress marker genes were significantly upregulated in VAT of HFD fed mice than the LFD fed mice. For the first time, we report depot specific differences in ER stress related miRNAs including; downregulation of miR-125b-5p, upregulation miR-143-3p, and miR-222-3p in VAT following HFD and upregulation of miR-30c-2-3p only in BAT following a HFD in mice than the LFD mice. In conclusion, HFD differentially regulates miRNAs and genes in different adipose depots with significant induction of genes related to lipogenesis, adipogenesis, inflammation, ER stress, and UPR in WAT compared to BAT.

Modulation of fear memory by dietary polyunsaturated fatty acids via cannabinoid receptors.

PubMed

Yamada, Daisuke; Takeo, Jiro; Koppensteiner, Peter; Wada, Keiji; Sekiguchi, Masayuki

2014-07-01

Although the underlying mechanism remains unknown, several studies have suggested benefits of n-3 long-chain polyunsaturated fatty acid (PUFA) for patients with anxiety disorders. Elevated fear is thought to contribute to the pathogenesis of particular anxiety disorders. The aim of the present study was to evaluate whether the dietary n-3 to n-6 PUFA (3:6) ratio influences fear memory. For this purpose, the effects of various dietary 3:6 ratios on fear memory were examined in mice using contextual fear conditioning, and the effects of these diets on central synaptic transmission were examined to elucidate the mechanism of action of PUFA. We found that fear memory correlated negatively with dietary, serum, and brain 3:6 ratios in mice. The low fear memory in mice fed a high 3:6 ratio diet was increased by the cannabinoid CB1 receptor antagonist rimonabant, reaching a level seen in mice fed a low 3:6 ratio diet. The agonist sensitivity of CB1 receptor was enhanced in the basolateral nucleus of the amygdala (BLA) of mice fed a high 3:6 ratio diet, compared with that of mice fed a low 3:6 ratio diet. Similar enhancement was induced by pharmacological expulsion of cholesterol in the neuronal membrane of brain slices from mice fed a low 3:6 ratio diet. CB1 receptor-mediated short-term synaptic plasticity was facilitated in pyramidal neurons of the BLA in mice fed a high 3:6 ratio diet. These results suggest that the ratio of n-3 to n-6 PUFA is a factor regulating fear memory via cannabinoid CB1 receptors.

Targeting cholesterol at different levels in the mevalonate pathway protects fatty liver against ischemia-reperfusion injury.

PubMed

Llacuna, Laura; Fernández, Anna; Montfort, Claudia Von; Matías, Núria; Martínez, Laura; Caballero, Francisco; Rimola, Antoni; Elena, Montserrat; Morales, Albert; Fernández-Checa, José C; García-Ruiz, Carmen

2011-05-01

Liver steatosis enhances ischemia/reperfusion (I/R) injury and is considered a primary factor in graft failure after liver transplantation. Although previous reports have shown a role for qualitative steatosis (macrovesicular vs. microvesicular) in hepatic I/R injury, no studies have compared side by side the specific contribution of individual lipids accumulating in fatty liver to I/R damage. We used nutritional and genetic models of micro and macrovesicular fatty livers exhibiting specific lipid profiles to assess their susceptibility to normothermic I/R injury. Unlike choline-deficient (CD) diet-fed mice, characterized by predominant liver triglycerides/free fatty acids (TG/FFA) accumulation, mice fed a cholesterol-enriched (HC) diet, which exhibited enhanced hepatic cholesterol loading in mitochondria, were highly sensitive to I/R-induced liver injury. In vivo two-photon confocal imaging revealed enhanced mitochondrial depolarization and generation of reactive oxygen species following hepatic I/R in HC-fed but not in CD-fed mice, consistent with decreased mitochondrial GSH (mGSH) observed in HC-fed mice. Moreover, ob/ob mice, characterized by increased hepatic TG, FFA, and cholesterol levels, were as sensitive to I/R-mediated liver injury as mice fed the HC diet. Livers from ob/ob mice displayed increased StAR expression and mitochondrial cholesterol accumulation, resulting in mGSH depletion. Interestingly, atorvastatin therapy or squalene synthase inhibition in vivo attenuated StAR overexpression, mitochondrial cholesterol loading, and mGSH depletion, protecting ob/ob mice from I/R-mediated liver injury. Cholesterol accumulation, particularly in mitochondria, sensitizes to hepatic I/R injury, and thus represents a novel target to prevent the enhanced damage of steatotic livers to I/R-mediated damage. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

High dietary fat and sucrose results in an extensive and time-dependent deterioration in health of multiple physiological systems in mice.

PubMed

Burchfield, James G; Kebede, Melkam A; Meoli, Christopher C; Stöckli, Jacqueline; Whitworth, P Tess; Wright, Amanda L; Hoffman, Nolan J; Minard, Annabel Y; Ma, Xiuquan; Krycer, James R; Nelson, Marin E; Tan, Shi-Xiong; Yau, Belinda; Thomas, Kristen C; Wee, Natalie K Y; Khor, Ee-Cheng; Enriquez, Ronaldo F; Vissel, Bryce; Biden, Trevor J; Baldock, Paul A; Hoehn, Kyle L; Cantley, James; Cooney, Gregory J; James, David E; Fazakerley, Daniel J

2018-04-13

Obesity is associated with metabolic dysfunction, including insulin resistance and hyperinsulinemia, and with disorders such as cardiovascular disease, osteoporosis, and neurodegeneration. Typically, these pathologies are examined in discrete model systems and with limited temporal resolution, and whether these disorders co-occur is therefore unclear. To address this question, here we examined multiple physiological systems in male C57BL/6J mice following prolonged exposure to a high-fat/high-sucrose diet (HFHSD). HFHSD-fed mice rapidly exhibited metabolic alterations, including obesity, hyperleptinemia, physical inactivity, glucose intolerance, peripheral insulin resistance, fasting hyperglycemia, ectopic lipid deposition, and bone deterioration. Prolonged exposure to HFHSD resulted in morbid obesity, ectopic triglyceride deposition in liver and muscle, extensive bone loss, sarcopenia, hyperinsulinemia, and impaired short-term memory. Although many of these defects are typically associated with aging, HFHSD did not alter telomere length in white blood cells, indicating that this diet did not generally promote all aspects of aging. Strikingly, glucose homeostasis was highly dynamic. Glucose intolerance was evident in HFHSD-fed mice after 1 week and was maintained for 24 weeks. Beyond 24 weeks, however, glucose tolerance improved in HFHSD-fed mice, and by 60 weeks, it was indistinguishable from that of chow-fed mice. This improvement coincided with adaptive β-cell hyperplasia and hyperinsulinemia, without changes in insulin sensitivity in muscle or adipose tissue. Assessment of insulin secretion in isolated islets revealed that leptin, which inhibited insulin secretion in the chow-fed mice, potentiated glucose-stimulated insulin secretion in the HFHSD-fed mice after 60 weeks. Overall, the excessive calorie intake was accompanied by deteriorating function of numerous physiological systems. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Decreased Arteriolar Tetrahydrobiopterin is Linked to Superoxide Generation from Nitric Oxide Synthase in Mice Fed High Salt

PubMed Central

Nurkiewicz, Timothy R.; Wu, Guoyao; Li, Peng; Boegehold, Matthew A.

2012-01-01

Objective Impaired endothelium-dependent arteriolar dilation in mice fed high salt is due to local oxidation of nitric oxide (NO) by superoxide anion (O2-). We explored the possibility that “uncoupled” endothelial nitric oxide synthase (eNOS) is the source of this O2-. Methods Levels of L-arginine (L-Arg), tetrahydrobiopterin (BH4) and O2- (hydroethidine oxidation) were measured in spinotrapezius muscle arterioles of mice fed normal salt (0.45%, NS) or high salt (4%, HS) diets for 4 weeks, with or without dietary L-Arg supplementation. The contribution of NO to endothelium-dependent dilation was determined from the effect of Nω-nitro-L-arginine methyl ester (L-NAME) on responses to acetylcholine (ACh). Results Arterioles in HS mice had lower [BH4] and higher O2- levels than those in NS mice. ACh further increased arteriolar O2- in HS mice only. L-Arg supplementation prevented the reduction in [BH4] in arterioles of HS mice, and O2- was not elevated in these vessels. Compared to NS mice, arteriolar ACh responses were diminished and insensitive to L-NAME in HS mice, but not in HS mice supplemented with L-Arg. Conclusions These findings suggest that eNOS uncoupling due to low [BH4] is responsible for O2- generation and reduced NO-dependent dilation in arterioles of mice fed a high salt diet. PMID:20163541

FGF21 does not require adipocyte AMP-activated protein kinase (AMPK) or the phosphorylation of acetyl-CoA carboxylase (ACC) to mediate improvements in whole-body glucose homeostasis.

PubMed

Mottillo, Emilio P; Desjardins, Eric M; Fritzen, Andreas M; Zou, Vito Z; Crane, Justin D; Yabut, Julian M; Kiens, Bente; Erion, Derek M; Lanba, Adhiraj; Granneman, James G; Talukdar, Saswata; Steinberg, Gregory R

2017-06-01

Fibroblast growth factor 21 (FGF21) shows great potential for the treatment of obesity and type 2 diabetes, as its long-acting analogue reduces body weight and improves lipid profiles of participants in clinical studies; however, the intracellular mechanisms mediating these effects are poorly understood. AMP-activated protein kinase (AMPK) is an important energy sensor of the cell and a molecular target for anti-diabetic medications. This work examined the role of AMPK in mediating the glucose and lipid-lowering effects of FGF21. Inducible adipocyte AMPK β1β2 knockout mice (iβ1β2AKO) and littermate controls were fed a high fat diet (HFD) and treated with native FGF21 or saline for two weeks. Additionally, HFD-fed mice with knock-in mutations on the AMPK phosphorylation sites of acetyl-CoA carboxylase (ACC)1 and ACC2 (DKI mice) along with wild-type (WT) controls received long-acting FGF21 for two weeks. Consistent with previous studies, FGF21 treatment significantly reduced body weight, adiposity, and liver lipids in HFD fed mice. To add, FGF21 improved circulating lipids, glycemic control, and insulin sensitivity. These effects were independent of adipocyte AMPK and were not associated with changes in browning of white (WAT) and brown adipose tissue (BAT). Lastly, we assessed whether FGF21 exerted its effects through the AMPK/ACC axis, which is critical in the therapeutic benefits of the anti-diabetic medication metformin. ACC DKI mice had improved glucose and insulin tolerance and a reduction in body weight, body fat and hepatic steatosis similar to WT mice in response to FGF21 administration. These data illustrate that the metabolic improvements upon FGF21 administration are independent of adipocyte AMPK, and do not require the inhibitory action of AMPK on ACC. This is in contrast to the anti-diabetic medication metformin and suggests that the treatment of obesity and diabetes with the combination of FGF21 and AMPK activators merits consideration.

Increased atherosclerosis in mice with increased vascular biglycan content.

PubMed

Thompson, Joel C; Tang, Tao; Wilson, Patricia G; Yoder, Meghan H; Tannock, Lisa R

2014-07-01

The response to retention hypothesis of atherogenesis proposes that atherosclerosis is initiated via the retention of atherogenic lipoproteins by vascular proteoglycans. Co-localization studies suggest that of all the vascular proteoglycans, biglycan is the one most closely co-localized with LDL. The goal of this study was to determine if over-expression of biglycan in hyperlipidemic mice would increase atherosclerosis development. Transgenic mice were developed by expressing biglycan under control of the smooth muscle actin promoter, and were crossed to the LDL receptor deficient (C57BL/6 background) atherosclerotic mouse model. Biglycan transgenic and non-transgenic control mice were fed an atherogenic Western diet for 4-12 weeks. LDL receptor deficient mice overexpressing biglycan under control of the smooth muscle alpha actin promoter had increased atherosclerosis development that correlated with vascular biglycan content. Increased vascular biglycan content predisposes to increased lipid retention and increased atherosclerosis development. Published by Elsevier Ireland Ltd.

Suppression of oral tolerance by Lactococcus lactis in mice.

PubMed

Sakai, Tohru; Hirota, Yuko; Nakamoto, Mariko; Shuto, Emi; Hosaka, Toshio; Makino, Seiya; Ikegami, Shuji

2011-01-01

Although oral ovabumin (OVA) administration suppressed the antibody (Ab) response in OVA-immunized mice, Lactococcus lactis increased OVA-specific IgG2a in these mice. L. lactis increased the casein-specific IgG level in NC/Nga mice fed on a casein diet. The percentage of CD4(+)CD25(+) cells was increased in DO11.10 mice orally given OVA, but this increase of CD4(+)CD25(+) cells were suppressed in L. lactis-fed DO11.10 mice.

Metabolic profiles in serum of mouse after chronic exposure to drinking water.

PubMed

Zhang, Yan; Wu, Bing; Zhang, Xuxiang; Li, Aimin; Cheng, Shupei

2011-08-01

The toxicity of Nanjing drinking water on mouse (Mus musculus) was detected by (1)H nuclear magnetic resonance (NMR)-based metabonomic method. Three groups of mice were fed with drinking water (produced by Nanjing BHK Water Plant), 3.8 μg/L benzo(a)pyrene as contrast, and clean water as control, respectively, for 90 days. It was observed that the levels of lactate, alanine, and creatinine in the mice fed with drinking water were increased and that of valine was decreased. The mice of drinking water group were successfully separated from control. The total concentrations of polycyclic aromatic hydrocarbons (PAHs), phthalates (PAEs), and other organic pollutants in the drinking water were 0.23 μg/L, 4.57 μg/L, and 0.34 μg/L, respectively. In this study, Nanjing drinking water was found to induce distinct perturbations of metabolic profiles on mouse including disorders of glucose-alanine cycle, branched-chain amino acid and energy metabolism, and dysfunction of kidney. This study suggests that metabonomic method is feasible and sensitive to evaluate potential toxic effects of drinking water.

Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis.

PubMed

Ye, Jian-Zhong; Li, Ya-Ting; Wu, Wen-Rui; Shi, Ding; Fang, Dai-Qiong; Yang, Li-Ya; Bian, Xiao-Yuan; Wu, Jing-Jing; Wang, Qing; Jiang, Xian-Wan; Peng, Cong-Gao; Ye, Wan-Chun; Xia, Peng-Cheng; Li, Lan-Juan

2018-06-21

To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis (NASH) development in mice fed a methionine-choline-deficient (MCD) diet. Twenty-four male C57BL/6J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk (Control 2w group, n = 6) or 4 wk (Control 4w group, n = 6) or the MCD diet for 2 wk (MCD 2w group, n = 6) or 4 wk (MCD 4w group, n = 6). Liver injury, fibrosis, and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16s rRNA deep sequencing and gas chromatography-mass spectrometry. The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet, however, the mice developed prominent NASH with liver fibrosis, and the intestinal barrier was more impaired. Compared with the control diet, the MCD diet induced gradual gut microbiota dysbiosis, as evidenced by a marked decrease in the abundance of Alistipes and the ( Eubacterium ) coprostanoligenes group ( P < 0.001 and P < 0.05, respectively) and a significant increase in Ruminococcaceae UCG 014 abundance ( P < 0.05) after 2 wk. At 4 wk, the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance ( P < 0.05, and P < 0.01, respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk, arachidic acid, hexadecane, palmitic acid, and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group, and at 4 wk, cholic acid, cholesterol, arachidic acid, tetracosane, and stearic acid were selected. The MCD diet induced persistent alterations in the gut microbiota and metabolome.

Dynamic alterations in the gut microbiota and metabolome during the development of methionine-choline-deficient diet-induced nonalcoholic steatohepatitis

PubMed Central

Ye, Jian-Zhong; Li, Ya-Ting; Wu, Wen-Rui; Shi, Ding; Fang, Dai-Qiong; Yang, Li-Ya; Bian, Xiao-Yuan; Wu, Jing-Jing; Wang, Qing; Jiang, Xian-Wan; Peng, Cong-Gao; Ye, Wan-Chun; Xia, Peng-Cheng; Li, Lan-Juan

2018-01-01

AIM To investigate changes in gut microbiota and metabolism during nonalcoholic steatohepatitis (NASH) development in mice fed a methionine-choline-deficient (MCD) diet. METHODS Twenty-four male C57BL/6J mice were equally divided into four groups and fed a methionine-choline-sufficient diet for 2 wk (Control 2w group, n = 6) or 4 wk (Control 4w group, n = 6) or the MCD diet for 2 wk (MCD 2w group, n = 6) or 4 wk (MCD 4w group, n = 6). Liver injury, fibrosis, and intestinal barrier function were evaluated after 2 and 4 wk of feeding. The fecal microbiome and metabolome were studied using 16s rRNA deep sequencing and gas chromatography-mass spectrometry. RESULTS The mice fed the MCD diet presented with simple hepatic steatosis and slight intestinal barrier deterioration after 2 wk. After 4 wk of feeding with the MCD diet, however, the mice developed prominent NASH with liver fibrosis, and the intestinal barrier was more impaired. Compared with the control diet, the MCD diet induced gradual gut microbiota dysbiosis, as evidenced by a marked decrease in the abundance of Alistipes and the (Eubacterium) coprostanoligenes group (P < 0.001 and P < 0.05, respectively) and a significant increase in Ruminococcaceae UCG 014 abundance (P < 0.05) after 2 wk. At 4 wk, the MCD diet significantly reduced the promising probiotic Bifidobacterium levels and markedly promoted Bacteroides abundance (P < 0.05, and P < 0.01, respectively). The fecal metabolomic profile was also substantially altered by the MCD diet: At 2 wk, arachidic acid, hexadecane, palmitic acid, and tetracosane were selected as potential biomarkers that were significantly different in the corresponding control group, and at 4 wk, cholic acid, cholesterol, arachidic acid, tetracosane, and stearic acid were selected. CONCLUSION The MCD diet induced persistent alterations in the gut microbiota and metabolome. PMID:29930468

Neuron-restrictive silencer factor is not required for the antiepileptic effect of the ketogenic diet.

PubMed

Hu, Xiao-Ling; Cheng, Xuewen; Fei, Jian; Xiong, Zhi-Qi

2011-09-01

The ketogenic diet (KD) has been used as an effective antiepileptic treatment for nearly a century. Inhibition of glycolysis and increased levels of ketone bodies are both known to contribute to the antiepileptic effects of the KD. Neuron-restrictive silencer factor (NRSF), also known as RE-1 silencing transcription factor (REST), is implicated in the antiepileptic effects of the glycolytic inhibitor 2-deoxy-d-glucose (2DG). Glycolytic inhibition is a common feature of the KD and 2DG treatment, leading to the hypothesis that NRSF might also be involved in the antiepileptic effect of the KD. To test this hypothesis, the present study was designed to investigate the role of NRSF in the antiepileptic effect of 2DG, the KD, and acetone in vivo. Kindling was used as a model to test the antiepileptic effects of 2DG, the KD, and acetone on control and NRSF conditional knockout mice (NRSF-cKO; from the intercross of CamKIIα-iCre and NRSF exon 2 floxed mice). After recovery from electrode implantation, adult mice were stimulated twice a day at afterdischarge threshold (ADT) current intensity. In the 2DG- (500 mg/kg) and acetone- (10 mmol/kg) treated groups, drugs were injected intraperitoneally 20 min before each stimulus. In the 2DG group, mice were pretreated with intraperitoneal injections for 3 days in addition to the injections administered before the regular kindling stimulation. In the KD group, mice were fed the KD instead of a control diet until the end of stimulations. Compared with control mice, the antiepileptic effect of 2DG was abolished in NRSF-cKO mice, indicating that NRSF is required for the antiepileptic effect of 2DG. In the KD-fed group, kindling development was retarded in both control and NRSF-cKO mice. In the acetone-treated group, inhibition of kindling-induced epileptogenesis was observed in both control and NRSF-cKO mice, similar to the action of the KD. These findings imply that NRSF repression complex is not essential for the antiepileptic effect of the ketogenic diet. Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.

Secondary poisoning of owls by anticoagulant rodenticides

USGS Publications Warehouse

Mendenhall, Vivian M.; Pank, L.F.

1980-01-01

Anticoagulants-compounds that prevent clotting of the blood-are extensively used for control of small mammal pests. The potential secondary hazards of 6 anticoagulant rodenticides to birds of prey were examined in this study. Whole rats or mice were killed with each anticoagulant and were fed to 1-3 species of owls. Owls died of hemorrhaging after feeding on rats killed with bromadiolone, brodifacoum, or diphacinone; sublethal hemorrhaging occurred in owls fed rats killed with difenacoum. These results demonstrate potential secondary hazards of 4 anticoagulants to avian predators. No abnormalities were observed in owls fed rats killed with fumarin and chlorophacinone

Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response

PubMed Central

Song, Ming; Chen, Theresa; Prough, Russell A.; Cave, Matthew C.; McClain, Craig J.

2017-01-01

Background Obesity and the metabolic syndrome occur in approximately one-third of patients with alcoholic liver disease (ALD). The increased consumption of fructose parallels the increased prevalence of obesity and the metabolic syndrome in the United States and worldwide. In this study, we investigated whether dietary high fructose potentiates chronic alcohol-induced liver injury, and explored potential mechanism(s). Methods Six-week-old male C57BL/6J mice were assigned to 4 groups: control, high fructose, chronic ethanol (EtOH), and high fructose plus chronic alcohol. The mice were fed either control diet or high-fructose diet (60%, w/w) for 18 weeks. Chronic alcohol-fed mice were given 20% (v/v) ethanol (Meadows-Cook model) ad libitum as the only available liquid from the 9th week through the 18th week. Liver injury, steatosis, hepatic inflammatory gene expression, and copper status were assessed. Results High-fructose diet and chronic alcohol consumption alone each induce hepatic fat accumulation and impair copper status. However, the combination of dietary high fructose plus chronic alcohol synergistically induced liver injury as evidenced by robustly increased plasma alanine aminotransferase and aspartate aminotransferase, but the combination did not exacerbate hepatic fat accumulation nor worsen copper status. Moreover, FE-fed mice were characterized by prominent microvesicular steatosis. High-fructose diet and chronic alcohol ingestion together led to a significant up-regulation of Kupffer cell (KC) M1 phenotype gene expression (e.g., tumor necrosis factor-a and monocyte chemoattractant protein-1), as well as Toll-like receptor 4 (TLR4) signaling gene expression, which is also associated with the up-regulation of KCs and activation marker gene expression, including Emr1, CD68, and CD163. Conclusions Our data suggest that dietary high fructose may potentiate chronic alcohol consumption-induced liver injury. The underlying mechanism might be due to the synergistic effect of dietary high fructose and alcohol on the activation of the TLR4 signaling pathway, which in turn leads to KC activation and phenotype switch toward M1 polarization. This study suggests that alcohol–fructose combination contributes to ALD progression. PMID:26858005

Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kanno, Ayumi, E-mail: akanno@med.kobe-u.ac.jp; Asahara, Shun-ichiro, E-mail: asahara@med.kobe-u.ac.jp; Masuda, Katsuhisa, E-mail: katsuhisa.m.0707@gmail.com

A high-fat diet (HF) is associated with obesity, insulin resistance, and hyperglycemia. Animal studies have shown compensatory mechanisms in pancreatic β-cells after high fat load, such as increased pancreatic β-cell mass, enhanced insulin secretion, and exocytosis. However, the effects of high fat intake on insulin synthesis are obscure. Here, we investigated whether insulin synthesis was altered in correlation with an HF diet, for the purpose of obtaining further understanding of the compensatory mechanisms in pancreatic β-cells. Mice fed an HF diet are obese, insulin resistant, hyperinsulinemic, and glucose intolerant. In islets of mice fed an HF diet, more storage ofmore » insulin was identified. We analyzed insulin translation in mouse islets, as well as in INS-1 cells, using non-radioisotope chemicals. We found that insulin translational levels were significantly increased in islets of mice fed an HF diet to meet systemic demand, without altering its transcriptional levels. Our data showed that not only increased pancreatic β-cell mass and insulin secretion but also elevated insulin translation is the major compensatory mechanism of pancreatic β-cells. - Highlights: • More stored insulin was recognized in islets of mice fed a high-fat diet. • Insulin translation was not enhanced by fatty acids, but by insulin demand. • Insulin transcription was not altered in islets of mice fed a high-fat diet. • Insulin translation was markedly enhanced in islets of mice fed a high-fat diet. • Non-radioisotope chemicals were used to measure insulin translation in mouse islets.« less

Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid β-peptide levels, without discernable behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer's disease.

PubMed

Raefsky, Sophia M; Furman, Ran; Milne, Ginger; Pollock, Erik; Axelsen, Paul; Mattson, Mark P; Shchepinov, Mikhail S

2018-06-01

Alzheimer's disease (AD) involves progressive deposition of amyloid β-peptide (Aβ), synapse loss, and neuronal death, which occur in brain regions critical for learning and memory. Considerable evidence suggests that lipid peroxidation contributes to synaptic dysfunction and neuronal degeneration, both upstream and downstream of Aβ pathology. Recent findings suggest that lipid peroxidation can be inhibited by replacement of polyunsaturated fatty acids (PUFA) with isotope-reinforced (deuterated) PUFA (D-PUFA), and that D-PUFA can protect neurons in experimental models of Parkinson's disease. Here, we determined whether dietary D-PUFA would ameliorate Aβ pathology and/or cognitive deficits in a mouse model of AD (amyloid precursor protein/presenilin 1 double mutant transgenic mice). The D-PUFA diet did not ameliorate spatial learning and memory deficits in the AD mice. Compared to mice fed an hydrogenated-PUFA control diet, those fed D-PUFA for 5 months exhibited high levels of incorporation of deuterium into arachidonic acid and docosahexaenoic acid, and reduced concentrations of lipid peroxidation products (F2 isoprostanes and neuroprostanes), in the brain tissues. Concentrations of Aβ40 and Aβ38 in the hippocampus were significantly lower, with a trend to reduced concentrations of Aβ42, in mice fed D-PUFA compared to those fed hydrogenated-PUFA. We conclude that a D-PUFA diet reduces the brain tissue concentrations of both arachidonic acid and docosahexaenoic acid oxidation products, as well as the concentration of Aβs. Published by Elsevier Inc.

Absorption and distribution of cadmium in mice fed diets containing either inorganic or oyster-incorporated cadmium

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sullivan, M.F.; Hardy, J.T.; Miller, B.M.

1984-02-01

To determine the absorption, organ distribution, and retention of organically bound cadmium (Cd) and the effects of dietary zinc (Zn) on Cd metabolism, groups of mice were fed five different diets. The organic Cd used in the diets was in the form of lyophilized oyster (Crassostrea virginica) that had accumulated radiolabeled 109Cd through a plankton food chain. The mice were fed either a standard basal mouse diet (AIN-76) or diets containing five or eight times the Zn concentration of the basal diet. The source of Zn was either oyster tissue or ZnCO3. The concentration of organic and inorganic Cd providedmore » a dose of approximately 0.4 mg/kg. Diets prepared from oyster tissue probably contained all of the Cd and 85% of the Zn in organic form. Diets prepared with inorganic metals contained about the same Cd and Zn concentrations as the diets prepared with oyster. There was very little difference between the retention of Cd by mice that ingested organic (oyster bound) Cd and those fed inorganic Cd (CdCl2). However, when the Cd retained in the intestine was excluded, retention of organic Cd was significantly greater than that of inorganic Cd. The organ distribution of Cd differed significantly according to the chemical form of Cd fed (organic or inorganic) and the Zn level in the diet. The kidneys of mice fed organically bound Cd retained a higher percentage of the metal than the kidneys of those fed inorganic Cd. On the other hand, the livers of animals fed a low-Zn diet retained a higher percentage of the Cd than the livers of those fed a high-Zn diet, regardless of the dietary source of Cd.« less

The effect of organic quail egg supplementation on the blood lipid profile of white mice (Rattus Norvegicus L.) during the lactation period

NASA Astrophysics Data System (ADS)

lestari purba, Sri; Rini Saraswati, Tyas; Isdadiyanto, Sri

2018-05-01

Background: Quail eggs contain a considerable amount of complete nutritional sources such as carbohydrates, proteins, fats, and micronutrients. However, they also have a high cholesterol level, which can potentially cause atherosclerosis and chronic heart diseases. The response of the body to foods containing is influenced by factors such as ethnicity, genetics, and hormonal and nutrient status of the consumer. The cholesterol level of quail eggs can be reduced by manipulating the feed using supplemental organic feed. Organic quail eggs have been believed to correct the lipid profile of white mice during the lactation phase. Purpose: The aim of this study was to analyze the effect of feed containing organic quail eggs on the blood lipid profile of white mice (Rattus norvegicus L.) during the lactation phase. Materials and Methods: This experimental study was conducted using a completely randomized design with four experiments and five repetitions. Experimental mice: T0 mice were used as control; T1 mice were supplemented with quail eggs produced by quails that were fed with standard feed; T2 mice were supplemented with eggs produced by quails fed with standard organic feed; and T3 mice were supplemented with eggs produced by quails fed with organic feed with the addition of cassava leaf flour, mackerel flour, and turmeric powder. Quail egg supplementation was administered to the mice from the early pregnancy period till the end of the lactation phase. The acquired data were analyzed using ANOVA. SPSS version 16.0 software for Windows was used for data analyses. Results and summary: Feeding the white mice with different compositions of organic quail egg supplements had no effect on the consumption of feed and water, body weight, and lipid profile (including total cholesterol, LDL, HDL, and triglyceride) during the lactation phase (P > 0.05).

A ketogenic diet as a potential novel therapeutic intervention in amyotrophic lateral sclerosis.

PubMed

Zhao, Zhong; Lange, Dale J; Voustianiouk, Andrei; MacGrogan, Donal; Ho, Lap; Suh, Jason; Humala, Nelson; Thiyagarajan, Meenakshisundaram; Wang, Jun; Pasinetti, Giulio M

2006-04-03

The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is uncertain but mitochondrial dysfunction may play an important role. Ketones promote mitochondrial energy production and membrane stabilization. SOD1-G93A transgenic ALS mice were fed a ketogenic diet (KD) based on known formulations for humans. Motor performance, longevity, and motor neuron counts were measured in treated and disease controls. Because mitochondrial dysfunction plays a central role in neuronal cell death in ALS, we also studied the effect that the principal ketone body, D-beta-3 hydroxybutyrate (DBH), has on mitochondrial ATP generation and neuroprotection. Blood ketones were > 3.5 times higher in KD fed animals compared to controls. KD fed mice lost 50% of baseline motor performance 25 days later than disease controls. KD animals weighed 4.6 g more than disease control animals at study endpoint; the interaction between diet and change in weight was significant (p = 0.047). In spinal cord sections obtained at the study endpoint, there were more motor neurons in KD fed animals (p = 0.030). DBH prevented rotenone mediated inhibition of mitochondrial complex I but not malonate inhibition of complex II. Rotenone neurotoxicity in SMI-32 immunopositive motor neurons was also inhibited by DBH. This is the first study showing that diet, specifically a KD, alters the progression of the clinical and biological manifestations of the G93A SOD1 transgenic mouse model of ALS. These effects may be due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain.

High-fat diet exacerbates cognitive rigidity and social deficiency in the BTBR mouse model of autism.

PubMed

Zilkha, N; Kuperman, Y; Kimchi, T

2017-03-14

The global increase in rates of obesity has been accompanied by a similar surge in the number of autism diagnoses. Accumulating epidemiological evidence suggest a possible link between overweight and the risk for autism spectrum disorders (ASD), as well as autism severity. In laboratory animals, several studies have shown a connection between various environmental factors, including diet-induced obesity, and the development of autism-related behaviors. However, the effect of high-fat or imbalanced diet on a pre-existing autism-like phenotype is unclear. In this study, we employed the BTBR inbred mouse strain, a well-established mouse model for autism, to assess the impact of inadequate fattening nutrition on the autism-related behavioral phenotype. Male mice were fed by high-fat diet (HFD) or control balanced diet (control) from weaning onward, and tested in a series of behavioral assays as adults. In addition, we measured the hypothalamic expression levels of several genes involved in oxytocin and dopamine signaling, in search of a possible neurobiological underlying mechanism. As an internal control, we also employed similar metabolic and behavioral measures on neurotypical C57 mice. Compared to control-fed mice, BTBR mice fed by HFD showed marked aggravation in autism-related behaviors, manifested in increased cognitive rigidity and diminished preference for social novelty. Moreover, the total autism composite (severity) score was higher in the HFD group, and positively correlated with higher body weight. Finally, we revealed negative correlations associating dopamine signaling factors in the hypothalamus, to autism-related severity and body weight. In contrast, we found no significant effects of HFD on autism-related behaviors of C57 mice, though the metabolic effects of the diet were similar for both strains. Our results indicate a direct causative link between diet-induced obesity and worsening of a pre-existing autism-related behavior and emphasize the need for adequate nutrition in ASD patients. These findings might also implicate the involvement of hypothalamic dopamine in mediating this effect. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice.

PubMed

Zhang, C; McFarlane, C; Lokireddy, S; Masuda, S; Ge, X; Gluckman, P D; Sharma, M; Kambadur, R

2012-01-01

Although myostatin-null (Mstn (-/-)) mice fail to accumulate fat in adipose tissue when fed a high-fat diet (HFD), little is known about the molecular mechanism(s) behind this phenomenon. We therefore sought to identify the signalling pathways through which myostatin regulates accumulation and/or utilisation of fat. Wild-type, Mstn (-/-) and wild-type mice treated with soluble activin type IIB receptor (sActRIIB) were fed a control chow diet or an HFD for 12 weeks. Changes in gene expression were measured by microarray and quantitative PCR. Histological changes in white adipose tissue were assessed together with peripheral tissue fatty acid oxidation and changes in circulating hormones following HFD feeding. Our results demonstrate that inactivation of myostatin results in reduced fat accumulation in mice on an HFD. Molecular analysis revealed that metabolic benefits, due to lack of myostatin, are mediated through at least two independent mechanisms. First, lack of myostatin increased fatty acid oxidation in peripheral tissues through induction of enzymes involved in lipolysis and in fatty acid oxidation in mitochondria. Second, inactivation of myostatin also enhanced brown adipose formation in white adipose tissue of Mstn (-/-) mice. Consistent with the above, treatment of HFD-fed wild-type mice with the myostatin antagonist, sActRIIB, reduced the obesity phenotype. We conclude that absence of myostatin results in enhanced peripheral tissue fatty acid oxidation and increased thermogenesis, culminating in increased fat utilisation and reduced adipose tissue mass. Taken together, our data suggest that anti-myostatin therapeutics could be beneficial in alleviating obesity.

135-Day Interventions of Yam Dioscorin and the Dipeptide Asn-Trp (NW) To Reduce Weight Gains and Improve Impaired Glucose Tolerances in High-Fat Diet-Induced C57BL/6 Mice.

PubMed

Wu, Guang-Cheng; Lin, Shyr-Yi; Liang, Hong-Jen; Hou, Wen-Chi

2018-01-24

The C57BL/6J mice were fed a 135-day normal diet or a high-fat diet (HFD) without, or concurrent with, a single yam dioscorin (80 mg/kg) or dipeptide NW (40 mg/kg) intervention every day. The final body weights (g) of mice were 26.1 ± 1.4, 34.97 ± 2.1, 31.75 ± 2.6, and 31.66 ± 3.1, respectively, for normal diet-fed, HFD-fed, dioscorin-intervened, and NW-intervened group. The mice in both intervened groups showed similar less weight gains and had significant differences (P < 0.05) compared to those in the HFD group under the same cumulative HFD intakes. The blood biochemical index of mice with dioscorin interventions showed significantly lower contents in total cholesterol and low-density lipoprotein, and NW interventions showed significantly lower total triglyceride contents compared to those of the HFD group (P < 0.05). Both intervened mice exhibited similar reductions in total visceral lipid contents and have significant differences compared to those of the HFD group (P < 0.05). The dioscorin intervention was better than NW interventions in lowering blood glucose levels by oral glucose tolerance tests and both showed significant differences (P < 0.05) compared to those in the HFD group. Yam dioscorin or dipeptide NW will potentially be used for preventive functional foods of less body weight gains and impaired glucose tolerance controls, which require further clinical trial investigations.

Choline Supplementation Promotes Hepatic Insulin Resistance in Phosphatidylethanolamine N-Methyltransferase-deficient Mice via Increased Glucagon Action*

PubMed Central

Wu, Gengshu; Zhang, Liyan; Li, Tete; Zuniga, Azeret; Lopaschuk, Gary D.; Li, Liang; Jacobs, René L.; Vance, Dennis E.

2013-01-01

Biosynthesis of hepatic choline via phosphatidylethanolamine N-methyltransferase (PEMT) plays an important role in the development of type 2 diabetes and obesity. We investigated the mechanism(s) by which choline modulates insulin sensitivity. PEMT wild-type (Pemt+/+) and knock-out (Pemt−/−) mice received either a high fat diet (HF; 60% kcal of fat) or a high fat, high choline diet (HFHC; 4 g of choline/kg of HF diet) for 1 week. Hepatic insulin signaling and glucose and lipid homeostasis were investigated. Glucose and insulin intolerance occurred in Pemt−/− mice fed the HFHC diet, but not in their Pemt−/− littermates fed the HF diet. Plasma glucagon was elevated in Pemt−/− mice fed the HFHC diet compared with Pemt−/− mice fed the HF diet, concomitant with increased hepatic expression of glucagon receptor, phosphorylated AMP-activated protein kinase (AMPK), and phosphorylated insulin receptor substrate 1 at serine 307 (IRS1-s307). Gluconeogenesis and mitochondrial oxidative stress were markedly enhanced, whereas glucose oxidation and triacylglycerol biosynthesis were diminished in Pemt−/− mice fed the HFHC diet. A glucagon receptor antagonist (2-aminobenzimidazole) attenuated choline-induced hyperglycemia and insulin intolerance and blunted up-regulation of phosphorylated AMPK and IRS1-s307. Choline induces glucose and insulin intolerance in Pemt−/− mice through modulating plasma glucagon and its action in liver. PMID:23179947

Fish oil concentrate delays sensitivity to thermal nociception in mice

PubMed Central

Veigas, Jyothi M.; Williams, Paul J.; Halade, Ganesh; Rahman, Mizanur M.; Yoneda, Toshiyuki; Fernandes, Gabriel

2011-01-01

Fish oil has been used to alleviate pain associated with inflammatory conditions such as rheumatoid arthritis. The anti-inflammatory property of fish oil is attributed to the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid. Contrarily, vegetable oils such as safflower oil are rich in n-6 fatty acids which are considered to be mediators of inflammation. This study investigates the effect of n-3 and n-6 fatty acids rich oils as dietary supplements on the thermally induced pain sensitivity in healthy mice. C57Bl/6J mice were fed diet containing regular fish oil, concentrated fish oil formulation (CFO) and safflower oil (SO) for 6 months. Pain sensitivity was measured by plantar test and was correlated to the expression of acid sensing ion channels (ASICs), transient receptor potential vanilloid 1 (TRPV1) and c-fos in dorsal root ganglion cells. Significant delay in sensitivity to thermal nociception was observed in mice fed CFO compared to mice fed SO (p<0.05). A significant diminution in expression of ion channels such as ASIC1a (64%), ASIC13 (37%) and TRPV1 (56%) coupled with reduced expression of c-fos, a marker of neuronal activation, was observed in the dorsal root ganglion cells of mice fed CFO compared to that fed SO. In conclusion, we describe here the potential of fish oil supplement in reducing sensitivity to thermal nociception in normal mice. PMID:21345372

Relationship between the effect of dietary fat on swimming endurance and energy metabolism in aged mice.

PubMed

Zhang, Guihua; Shirai, Nobuya; Suzuki, Hiramitsu

2011-10-01

The aim of this study was to investigate the effect of different dietary fats on alterations in endurance, energy metabolism, and plasma levels of interleukin-6 (IL-6) and minerals in mice. Male mice (aged 58 weeks) were fed diets containing 6% safflower oil, fish oil, or lard for 12 weeks. Swimming time to exhaustion, energy metabolism, and plasma IL-6 levels were subsequently determined. Mice fed safflower oil exhibited a marked increase in swimming time compared to the baseline level. Mice fed lard exhibited a significant decrease in swimming time, while mice on a fish oil diet exhibited a small decrease in swimming time. The final swimming time of mice fed safflower oil was significantly longer than that of animals fed lard. This improvement in endurance with dietary safflower oil was accompanied by decreased accumulation of lactate and less glycogen depletion during swimming. In the safflower oil group, muscle carnitine palmitoyltransferase activity increased significantly after swimming, while the plasma non-esterified fatty acid concentration decreased significantly. A trend to increased plasma IL-6 levels was observed in sedentary animals on a safflower oil diet compared to those on a lard diet. These results suggest that dietary safflower oil improves the swimming endurance of aged mice to a greater extent than lard, and that this effect appears to involve glycogen sparing through increased fatty acid utilization. Copyright © 2011 S. Karger AG, Basel.

Breast-feeding regulates immune system development via transforming growth factor-β in mice pups.

PubMed

Sakaguchi, Keita; Koyanagi, Akemi; Kamachi, Fumitaka; Harauma, Akiko; Chiba, Asako; Hisata, Ken; Moriguchi, Toru; Shimizu, Toshiaki; Miyake, Sachiko

2018-03-01

Breast milk contains important nutrients and immunoregulatory factors that are essential for newborn infants. Recently, epidemiological studies suggested that breast-feeding prevents a wide range of infectious diseases and lowers the incidence of infant allergic diseases. To examine the effects of breast milk on immunological development in infancy, we established an artificial rearing system for hand-feeding mice and compared mouse pups fed with either breast milk or milk substitute. All mice were killed at 14 days of age and immune cells in the thymus, spleen, and small intestine were examined on flow cytometry. The number of thymocytes was higher whereas that of total immune cells of peripheral lymphoid tissues was lower in mice fed breast milk compared with milk substitute-fed mice. In peripheral lymphoid tissues, the proportion of B cells was higher and that of CD8 + T cells, macrophages, dendritic cells, and granulocytes was significantly lower in breast milk-fed mice. The same alteration in immune cells of the thymus and peripheral lymphoid tissues in milk substitute-fed mice was also observed in pups reared by mother mice treated with anti-transforming growth factor-β (anti-TGF-β) monoclonal antibody. Breast milk regulates the differentiation and expansion of innate and adaptive immune cells partly due to TGF-β. Hence, TGF-β in breast milk may be a new therapeutic target for innate immune system-mediated diseases of infancy. © 2017 Japan Pediatric Society.

Aliskiren Attenuates Steatohepatitis and Increases Turnover of Hepatic Fat in Mice Fed with a Methionine and Choline Deficient Diet

PubMed Central

Lee, Kuei-Chuan; Chan, Che-Chang; Yang, Ying-Ying; Hsieh, Yun-Cheng; Huang, Yi-Hsiang; Lin, Han-Chieh

2013-01-01

Background & Aims Activation of the renin-angiotensin-system is known to play a role in nonalcoholic steatohepatitis. Renin knockout mice manifest decreased hepatic steatosis. Aliskiren is the first direct renin inhibitor to be approved for clinical use. Our study aims to evaluate the possible therapeutic effects and mechanism of the chronic administration of aliskiren in a dietary steatohepatitis murine model. Methods Male C57BL/6 mice were fed with a methionine and choline-deficient (MCD) diet to induce steatohepatitis. After 8 weeks of feeding, the injured mice were randomly assigned to receive aliskiren (50 mg·kg-1 per day) or vehicle administration for 4 weeks. Normal controls were also administered aliskiren (50 mg·kg-1 per day) or a vehicle for 4 weeks. Results In the MCD mice, aliskiren attenuated hepatic steatosis, inflammation and fibrosis. Aliskiren did not change expression of lipogenic genes but increase turnover of hepatic fat by up-regulating peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a, cytochrome P450-4A14 and phosphorylated AMP-activated protein kinase. Furthermore, aliskiren decreased the hepatic expression of angiotensin II and nuclear factor κB. The levels of oxidative stress, hepatocyte apoptosis, activation of Kupffer cells and hepatic stellate cells, and pro-fibrotic markers were also reduced in the livers of the MCD mice receiving aliskiren. Conclusions Aliskiren attenuates steatohepatitis and fibrosis in mice fed with a MCD diet. Thus, the noted therapeutic effects might come from not only the reduction of angiotensin II but also the up-regulation of fatty acid oxidation-related genes. PMID:24204981

Flaxseed lignans enriched in secoisolariciresinol diglucoside prevent acute asbestos-induced peritoneal inflammation in mice

PubMed Central

Pietrofesa, Ralph A.; Velalopoulou, Anastasia; Arguiri, Evguenia; Menges, Craig W.; Testa, Joseph R.; Hwang, Wei-Ting; Albelda, Steven M.

2016-01-01

Malignant mesothelioma (MM), linked to asbestos exposure, is a highly lethal form of thoracic cancer with a long latency period, high mortality and poor treatment options. Chronic inflammation and oxidative tissue damage caused by asbestos fibers are linked to MM development. Flaxseed lignans, enriched in secoisolariciresinol diglucoside (SDG), have antioxidant, anti-inflammatory and cancer chemopreventive properties. As a prelude to chronic chemoprevention studies for MM development, we tested the ability of flaxseed lignan component (FLC) to prevent acute asbestos-induced inflammation in MM-prone Nf2+/mu mice. Mice (n = 16–17 per group) were placed on control (CTL) or FLC-supplemented diets initiated 7 days prior to a single intraperitoneal bolus of 400 µg of crocidolite asbestos. Three days post asbestos exposure, mice were evaluated for abdominal inflammation, proinflammatory/profibrogenic cytokine release, WBC gene expression changes and oxidative and nitrosative stress in peritoneal lavage fluid (PLF). Asbestos-exposed mice fed CTL diet developed acute inflammation, with significant (P < 0.0001) elevations in WBCs and proinflammatory/profibrogenic cytokines (IL-1ß, IL-6, TNFα, HMGB1 and active TGFß1) relative to baseline (BL) levels. Alternatively, asbestos-exposed FLC-fed mice had a significant (P < 0.0001) decrease in PLF WBCs and proinflammatory/profibrogenic cytokine levels relative to CTL-fed mice. Importantly, PLF WBC gene expression of cytokines (IL-1ß, IL-6, TNFα, HMGB1 and TGFß1) and cytokine receptors (TNFαR1 and TGFßR1) were also downregulated by FLC. FLC also significantly (P < 0.0001) blunted asbestos-induced nitrosative and oxidative stress. FLC reduces acute asbestos-induced peritoneal inflammation, nitrosative and oxidative stress and may thus prove to be a promising agent in the chemoprevention of MM. PMID:26678224

Dietary resveratrol does not delay engraftment, sensitize to vincristine or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice.

PubMed

Zunino, Susan J; Storms, David H; Newman, John W; Pedersen, Theresa L; Keen, Carl L; Ducore, Jonathan M

2012-12-01

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60-85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. To evaluate the efficacy of dietary resveratrol in vivo, 5-week-old NOD.CB17-Prkdcscid/J mice were fed a control diet or a diet containing 0.2% w/w resveratrol. After 3 weeks of dietary treatment, mice were engrafted with the human t(4;11) ALL line SEM by tail vein injection. Engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry. Relative to control diet, dietary resveratrol did not delay the engraftment of the leukemia cells. To determine if dietary resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the control or supplemented diet. Survival curves and monitoring the percentage of human leukemia cells in peripheral blood showed that resveratrol did not inhibit leukemia cell growth or influence the activity of vincristine. Mass spectrometric analysis of mouse serum revealed that the majority of resveratrol was present as glucuronidated and sulfated metabolites. These data do not support the concept that dietary resveratrol has potential as a preventative agent against the growth of high-risk t(4;11) ALL.

Dietary resveratrol does not delay engraftment, sensitize to vincristine or inhibit growth of high-risk acute lymphoblastic leukemia cells in NOD/SCID mice

PubMed Central

ZUNINO, SUSAN J.; STORMS, DAVID H.; NEWMAN, JOHN W.; PEDERSEN, THERESA L.; KEEN, CARL L.; DUCORE, JONATHAN M.

2012-01-01

Acute lymphoblastic leukemia (ALL) with translocation t(4;11) is a high-risk leukemia found in 60–85% of infants with ALL and is often refractory to conventional chemotherapeutics after relapse. To evaluate the efficacy of dietary resveratrol in vivo, 5-week-old NOD.CB17-Prkdcscid/J mice were fed a control diet or a diet containing 0.2% w/w resveratrol. After 3 weeks of dietary treatment, mice were engrafted with the human t(4;11) ALL line SEM by tail vein injection. Engraftment was monitored by evaluating the presence of human CD19+ cells in peripheral blood using flow cytometry. Relative to control diet, dietary resveratrol did not delay the engraftment of the leukemia cells. To determine if dietary resveratrol could increase efficacy of a chemotherapeutic agent, vincristine was injected intraperitoneally into leukemic mice fed the control or supplemented diet. Survival curves and monitoring the percentage of human leukemia cells in peripheral blood showed that resveratrol did not inhibit leukemia cell growth or influence the activity of vincristine. Mass spectrometric analysis of mouse serum revealed that the majority of resveratrol was present as glucuronidated and sulfated metabolites. These data do not support the concept that dietary resveratrol has potential as a preventative agent against the growth of high-risk t(4;11) ALL. PMID:23041950

Consumption of clarified grapefruit juice ameliorates high-fat diet induced insulin resistance and weight gain in mice.

PubMed

Chudnovskiy, Rostislav; Thompson, Airlia; Tharp, Kevin; Hellerstein, Marc; Napoli, Joseph L; Stahl, Andreas

2014-01-01

To determine the metabolic effects of grapefruit juice consumption we established a model in which C57Bl/6 mice drank 25-50% sweetened GFJ, clarified of larger insoluble particles by centrifugation (cGFJ), ad libitum as their sole source of liquid or isocaloric and sweetened water. cGFJ and control groups consumed similar amounts of liquids and calories. Mice fed a high-fat diet and cGFJ experienced a 18.4% decrease in weight, a 13-17% decrease in fasting blood glucose, a three-fold decrease in fasting serum insulin, and a 38% decrease in liver triacylglycerol values, compared to controls. Mice fed a low-fat diet that drank cGFJ experienced a two-fold decrease in fasting insulin, but not the other outcomes observed with the high-fat diet. cGFJ consumption decreased blood glucose to a similar extent as the commonly used anti-diabetic drug metformin. Introduction of cGFJ after onset of diet-induced obesity also reduced weight and blood glucose. A bioactive compound in cGFJ, naringin, reduced blood glucose and improved insulin tolerance, but did not ameliorate weight gain. These data from a well-controlled animal study indicate that GFJ contains more than one health-promoting neutraceutical, and warrant further studies of GFJ effects in the context of obesity and/or the western diet.

The mesencephalic trigeminal sensory nucleus is involved in acquisition of active exploratory behavior induced by changing from a diet of exclusively milk formula to food pellets in mice.

PubMed

Ishii, Toshiaki; Furuoka, Hidefumi; Kitamura, Nobuo; Muroi, Yoshikage; Nishimura, Masakazu

2006-09-21

Post-weaning mice fed exclusively milk display low-frequency exploratory behavior [Ishii, T., Itou, T., and Nishimura, M. (2005) Life Sci. 78, 174-179] compared to mice fed a food pellet diet. This low-frequency exploratory behavior switched to high-frequency exploration after a switch from exclusively milk formula to a food pellet diet. Acquisition of the high-frequency exploratory behavior was irreversible. Recently, we demonstrated that the mesencephalic trigeminal nucleus (Me5) is involved in the control of feeding and exploratory behavior in mice without modulating the emotional state [Ishii, T., Furuoka, H., Itou, T., Kitamura, N., and Nishimura, M. (2005) Brain Res. 1048, 80-86]. We therefore investigated whether the Me5 is involved in acquisition of high-frequency exploratory behavior induced by the switch in diet from an exclusively milk formula to food pellets. Mouse feeding and exploratory behaviors were analyzed using a food search compulsion apparatus, which was designed to distinguish between the two behaviors under standard living conditions. Immunohistochemical analysis of immediate early genes indicated that the Me5, which receives signals from oral proprioceptors, is transiently activated after the diet change. The change from low-frequency to high-frequency exploratory behavior was prevented in milk-fed mice by bilateral lesion of the Me5. These results suggest that the Me5 is activated by signals associated with mastication-induced proprioception and contributes to the acquisition of active exploratory behavior.

Actions of incretin metabolites on locomotor activity, cognitive function and in vivo hippocampal synaptic plasticity in high fat fed mice.

PubMed

Porter, David; Faivre, Emilie; Flatt, Peter R; Hölscher, Christian; Gault, Victor A

2012-05-01

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) improve markers of cognitive function in obesity-diabetes, however, both are rapidly degraded to their major metabolites, GLP-1(9-36)amide and GIP(3-42), respectively. Therefore, the present study investigated effects of GLP-1(9-36)amide and GIP(3-42) on locomotor activity, cognitive function and hippocampal synaptic plasticity in mice with diet-induced obesity and insulin resistance. High-fat fed Swiss TO mice treated with GLP-1(9-36)amide, GIP(3-42) or exendin(9-39)amide (twice-daily for 60 days) did not exhibit any changes in bodyweight, non-fasting plasma glucose and plasma insulin concentrations or glucose tolerance compared with high-fat saline controls. Similarly, locomotor and feeding activity, O(2) consumption, CO(2) production, respiratory exchange ratio and energy expenditure were not altered by chronic treatment with incretin metabolites. Administration of the truncated metabolites did not alter general behavior in an open field test or learning and memory ability as recorded during an object recognition test. High-fat mice exhibited a significant impairment in hippocampal long-term potentiation (LTP) which was not affected by treatment with incretin metabolites. These data indicate that incretin metabolites do not influence locomotor activity, cognitive function and hippocampal synaptic plasticity when administered at pharmacological doses to mice fed a high-fat diet. Copyright © 2012 Elsevier Inc. All rights reserved.

Excess Maternal Fructose Consumption Increases Fetal Loss and Impairs Endometrial Decidualization in Mice

PubMed Central

Saben, Jessica L.; Asghar, Zeenat; Rhee, Julie S.; Drury, Andrea; Scheaffer, Suzanne

2016-01-01

The most significant increase in metabolic syndrome over the previous decade occurred in women of reproductive age, which is alarming given that metabolic syndrome is associated with reproductive problems including subfertility and early pregnancy loss. Individuals with metabolic syndrome often consume excess fructose, and several studies have concluded that excess fructose intake contributes to metabolic syndrome development. Here, we examined the effects of increased fructose consumption on pregnancy outcomes in mice. Female mice fed a high-fructose diet (HFrD) for 6 weeks developed glucose intolerance and mild fatty liver but did not develop other prominent features of metabolic syndrome such as weight gain, hyperglycemia, and hyperinsulinemia. Upon mating, HFrD-exposed mice had lower pregnancy rates and smaller litters at midgestation than chow-fed controls. To explain this phenomenon, we performed artificial decidualization experiments and found that HFrD consumption impaired decidualization. This appeared to be due to decreased circulating progesterone as exogenous progesterone administration rescued decidualization. Furthermore, HFrD intake was associated with decreased bone morphogenetic protein 2 expression and signaling, both of which were restored by exogenous progesterone. Finally, expression of forkhead box O1 and superoxide dismutase 2 [Mn] proteins were decreased in the uteri of HFrD-fed mice, suggesting that HFrD consumption promotes a prooxidative environment in the endometrium. In summary, these data suggest that excess fructose consumption impairs murine fertility by decreasing steroid hormone synthesis and promoting an adverse uterine environment. PMID:26677880

Growth and Progression of TRAMP Prostate Tumors in Relationship to Diet and Obesity

PubMed Central

Bonorden, Melissa J. L.; Grossmann, Michael E.; Ewing, Sarah A.; Rogozina, Olga P.; Ray, Amitabha; Nkhata, Katai J.; Liao, D. Joshua; Grande, Joseph P.; Cleary, Margot P.

2012-01-01

To clarify effects of diet and body weight on prostate cancer development, three studies were undertaken using the TRAMP mouse model of this disease. In the first experiment, obesity was induced by injection of gold thioglucose (GTG). Age of prostate tumor detection (~33 wk) and death (~43 wk) was not significantly different among the groups. In the second study, TRAMP-C2 cells were injected into syngeneic C57BL6 mice and tumor progression was evaluated in mice fed either high-fat or low-fat diets. The high fat fed mice had larger tumors than did the low-fat fed mice. In the third study, tumor development was followed in TRAMP mice fed a high fat diet from 6 weeks of age. There were no significant effects of body weight status or diet on tumor development among the groups. When the tumors were examined for the neuroendocrine marker synaptophysin, there was no correlation with either body weight or diet. However, there was a significant correlation of the expression of synaptophysin with earlier age to tumor detection and death. In summary, TRAMP-C2 cells grew faster when the mice were fed a high-fat diet. Further synaptophysin may be a marker of poor prognosis independent of weight and diet. PMID:23304522

Salt-Sensitive Hypertension and Cardiac Hypertrophy in Transgenic Mice Expressing a Corin Variant Identified in African Americans

PubMed Central

Wang, Wei; Cui, Yujie; Shen, Jianzhong; Jiang, Jingjing; Chen, Shenghan; Peng, Jianhao; Wu, Qingyu

2012-01-01

African Americans represent a high risk population for salt-sensitive hypertension and heart disease but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in African Americans with hypertension and cardiac hypertrophy. In this study, we test the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type or T555I/Q568P variant corin in the heart under the control of α-myosin heavy chain promoter. The mice were crossed into a corin knockout background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of pro-atrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12–14 months of age when fed a normal salt diet or at a younger age when fed a high salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in African Americans who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in African Americans. PMID:22987923

The number of preproghrelin mRNA expressing cells is increased in mice with activity-based anorexia.

PubMed

François, Marie; Barde, Swapnali; Achamrah, Najate; Breton, Jonathan; do Rego, Jean-Claude; Coëffier, Moïse; Hökfelt, Tomas; Déchelotte, Pierre; Fetissov, Sergueï O

2015-06-01

Plasma levels of ghrelin, an orexigenic peptide, are increased during conditions of chronic starvation, such as in patients with anorexia nervosa. However, it is not known whether such increase can be related to the number of preproghrelin mRNA-expressing cells in the stomach, and if chronic starvation may activate a tentative central ghrelin production. In this work, in situ hybridization technique was used to analyze the presence and number of preproghrelin mRNA-expressing cells in the stomach and the hypothalamus of mice with activity-based anorexia (ABA) induced by the combination of running wheel activity with progressive, during 10 days, feeding-time restriction (FTR) and compared with sedentary FTR, ABA pair-fed (PF) and ad libitum-fed control mice. All food-restricted mice lost more than 20% of body weight. Body weight loss was similar in ABA and PF mice, but it was more pronounced than in FTR mice. Food intake was also lower in ABA than in FTR mice. Preproghrelin mRNA-expressing cells in the stomach were increased proportionally to the body weight loss in all food-restricted groups with the highest number in ABA mice. No preproghrelin mRNA-producing cells were detectable in the hypothalamus of either control or food-restricted mice. Thus, the increased number of gastric preproghrelin mRNA-producing cells during chronic starvation proportionally to the body weight loss and reduced food intake may underlie increased plasma ghrelin. Hyperactivity-induced anorexia appears to further increase the number of preproghrelin mRNA-producing cells in the stomach. No evidence was found for ghrelin expression in the hypothalamus, not even in any of the present experimental models. Copyright © 2015 Elsevier Ltd. All rights reserved.

Liver cholesterol concentrations in mice fed diets containing various sources of fat, carbohydrates or fiber.

PubMed

Beynen, A C; Klaasen, H L; Koopman, J P; Fielmich-Bouman, A M; Lemmens, A G

1989-01-01

Liver cholesterol concentrations were measured in mice after feeding for 30 days cholesterol-free, semipurified diets containing various sources of fat, carbohydrates or fiber. Olive oil produced significantly higher liver cholesterol concentrations than tallow, sunflowerseed oil and cocoa fat. In mice fed either fructose or sucrose liver cholesterol was significantly increased when compared with mice fed galactose or lactose. Dietary cellulose, when compared with pectin, did not influence liver cholesterol. The amount of fat in the diet, in the form of either corn oil or coconut fat, had no significant effect on liver cholesterol. It is concluded that the type of carbohydrate and fat in the diet are major determinants of liver cholesterol in mice.

Regulation of mitochondrial trifunctional protein modulates nonalcoholic fatty liver disease in mice

PubMed Central

Nassir, Fatiha; Arndt, Justin J.; Johnson, Sarah A.

2018-01-01

Mitochondrial trifunctional protein (MTP) plays a critical role in the oxidation of long-chain fatty acids. We previously reported that aging mice (>9 months old) heterozygous for an MTP defect (MTP+/−) develop nonalcoholic fatty liver disease (NAFLD). We tested whether a high-fat diet (HFD) accelerates NAFLD in young MTP+/−mice, and whether overexpression of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 3 (SIRT3) deacetylates MTP and improves mitochondrial function and NAFLD. Three-month-old WT and MTP+/− mice were fed HFD (60% cal fat) for 16 weeks and livers were assessed for fatty acid oxidation (FAO) and NAFLD. Compared with WT, MTP+/− mice displayed reduced hepatic SIRT3 levels and reduced FAO, with increased hepatic steatosis and the inflammatory marker CD68. Hepatic overexpression of SIRT3 in HFD-fed MTP+/− mice increased hepatic MTP protein levels at the posttranscriptional level. Immunoprecipitation of MTP from liver mitochondria followed by Western blot with acetyl-lysine antibody showed higher acetylation of MTP in MTP+/− compared with WT mice. Overexpression of SIRT3 in MTP+/− mice significantly reduced the acetylation of MTP compared with β-galactosidase controls, increased mitochondrial FAO, and reduced hepatic steatosis, CD68, and serum ALT levels. Taken together, our data indicate that deacetylation of MTP by SIRT3 improves mitochondrial function and rescues NAFLD in MTP+/− mice. PMID:29581157

Gd-EOB-DTPA-enhanced-MR imaging in the inflammation stage of nonalcoholic steatohepatitis (NASH) in mice.

PubMed

Yamada, Tomomi; Obata, Atsushi; Kashiwagi, Yuto; Rokugawa, Takemi; Matsushima, Shuuichi; Hamada, Tadateru; Watabe, Hiroshi; Abe, Kohji

2016-07-01

The purpose of this study is to investigate the correlation between the liver kinetics of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) and liver histopathology in a mouse model of NASH by using dynamic contrast-enhanced MRI. Twenty male C57/BL6 mice aged 8weeks were fed a methionine-choline-deficient (MCD) diet for 2, 4 and 6weeks (MCD groups: MCD 2w, 4w, or 6w). Gd-EOB-DTPA-enhanced MR imaging of the liver was performed at 2, 4 and 6weeks after the MCD feeding. The signal intensity of the liver was obtained from dynamic MR images and relative enhancement (RE), and the time to maximum RE (Tmax) and half-life of elimination RE (T1/2) were calculated. After MRI scan, histopathological scores of hepatic steatosis and inflammation and blood biochemistry data, such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, were obtained. Plasma AST and ALT levels were significantly increased in mice fed MCD. Histopathological scores indicated that steatohepatitis progressed with the MCD feeding period from 2 to 6weeks, but significant fibrosis was observed only in mice fed MCD for 6weeks. Gd-EOB-DTPA-enhanced MRI showed that Tmax was significantly prolonged in the livers of the 6-week group compared to the control group (control, 4.0±0.7min; MCD 6w, 12.1±1.6min), although there was no alteration in the 2- and 4-week groups. T1/2 was significantly prolonged in mice fed MCD for 4 and 6weeks compared to the control group (control, 19.9±2.0min; MCD 4w, 46.7±8.7min; MCD 6w, 65.4±8.8min). The parameters of Gd-EOB-DTPA kinetics (Tmax and T1/2) in the liver were positively correlated with the liver histopathological score (steatosis vs Tmax, rho=0.69, P=0.0007; inflammation vs Tmax, rho=0.66, P=0.00155; steatosis vs T1/2, rho=0.77, P<0.0001; inflammation vs T1/2, rho=0.73, P=0.0003). The liver kinetics of Gd-EOB-DTPA correlated well with the inflammation score in the mouse model of NASH, suggesting the possibility of detecting the steatohepatitis stage without fibrosis by Gd-EOB-DTPA-enhanced MR imaging. Copyright © 2016 Elsevier Inc. All rights reserved.

Loss of ovarian function in the VCD mouse-model of menopause leads to insulin resistance and a rapid progression into the metabolic syndrome.

PubMed

Romero-Aleshire, Melissa J; Diamond-Stanic, Maggie K; Hasty, Alyssa H; Hoyer, Patricia B; Brooks, Heddwen L

2009-09-01

Factors comprising the metabolic syndrome occur with increased incidence in postmenopausal women. To investigate the effects of ovarian failure on the progression of the metabolic syndrome, female B(6)C(3)F(1) mice were treated with 4-vinylcyclohexene diepoxide (VCD) and fed a high-fat (HF) diet for 16 wk. VCD destroys preantral follicles, causing early ovarian failure and is a well-characterized model for the gradual onset of menopause. After 12 wk on a HF diet, VCD-treated mice had developed an impaired glucose tolerance, whereas cycling controls were unaffected [12 wk AUC HF mice 13,455 +/- 643 vs. HF/VCD 17,378 +/- 1140 mg/dl/min, P < 0.05]. After 16 wk on a HF diet, VCD-treated mice had significantly higher fasting insulin levels (HF 5.4 +/- 1.3 vs. HF/VCD 10.1 +/- 1.4 ng/ml, P < 0.05) and were significantly more insulin resistant (HOMA-IR) than cycling controls on a HF diet (HF 56.2 +/- 16.7 vs. HF/VCD 113.1 +/- 19.6 mg/dl x microU/ml, P < 0.05). All mice on a HF diet gained more weight than mice on a standard diet, and weight gain in HF/VCD mice was significantly increased compared with HF cycling controls. Interestingly, even without a HF diet, progression into VCD-induced menopause caused a significant increase in cholesterol and free fatty acids. Furthermore, in mice fed a standard diet (6% fat), insulin resistance developed 4 mo after VCD-induced ovarian failure. Insulin resistance following ovarian failure (menopause) was prevented by estrogen replacement. Studies here demonstrate that ovarian failure (menopause) accelerates progression into the metabolic syndrome and that estrogen replacement prevents the onset of insulin resistance in VCD-treated mice. Thus, the VCD model of menopause provides a physiologically relevant means of studying how sex hormones influence the progression of the metabolic syndrome.

Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells

PubMed Central

Rezende, Rafael M.; Oliveira, Rafael P.; Medeiros, Samara R.; Gomes-Santos, Ana C.; Alves, Andrea C.; Loli, Flávia G.; Guimarães, Mauro A.F.; Amaral, Sylvia S.; da Cunha, André P.; Weiner, Howard L.; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M.C.

2013-01-01

Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. PMID:22939403

Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells.

PubMed

Rezende, Rafael M; Oliveira, Rafael P; Medeiros, Samara R; Gomes-Santos, Ana C; Alves, Andrea C; Loli, Flávia G; Guimarães, Mauro A F; Amaral, Sylvia S; da Cunha, André P; Weiner, Howard L; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M C

2013-02-01

Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dietary corn fractions reduce atherogenesis in low-density lipoprotein receptor knockout mice.

PubMed

Masisi, Kabo; Le, Khuong; Ghazzawi, Nora; Moghadasian, Mohammed H; Beta, Trust

2017-01-01

Accumulating evidence has suggested that intake of whole grains is a protective factor against pathogenesis of coronary artery disease. The exact mechanisms, however, are still not clearly understood. In this study, we hypothesized that adequate intake of corn fractions (aleurone, endosperm and germ) can modify lipid profiles in relation to atherosclerotic lesion development in low-density lipoprotein receptor knockout (LDLr-KO) mice. The purpose of the present study was to investigate the potential cardiovascular benefits of corn fractions in LDLr-KO mice through a number of biomarkers including lipid profile, and morphologic and morphometrical analysis of atherosclerotic lesions in aortic root. Four groups of male LDLr-KO mice were fed with the experimental diets supplemented with (3 treated) or without (control) 5% (wt/wt) of each of corn fractions for 10 weeks. All diets were supplemented with 0.06% (wt/wt) cholesterol. Compared with mice in the control group, atherosclerotic lesions in the aortic roots were significantly reduced (P=.003) in the mice that were fed diet supplemented with aleurone and germ fractions. This effect was associated with significant reductions in plasma total (P=.02) and LDL (P=.03) cholesterol levels, and an increase in fecal cholesterol excretion (P=.04). Furthermore, abdominal fat mass was significantly reduced by consumption of aleurone (P=.03). In summary, the consumption of aleurone and germ may help attenuate atherosclerosis by reducing plasma total and LDL cholesterol levels. Copyright © 2016 Elsevier Inc. All rights reserved.

Dietary rice component, Oryzanol, inhibits tumor growth in tumor-bearing Mice

USDA-ARS?s Scientific Manuscript database

Scope: We investigated the effects of rice bran and components on tumor growth in mice. Methods and results: Mice fed standard diets supplemented with rice bran, '-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet fo...

A novel mice model of metabolic syndrome: the high-fat-high-fructose diet-fed ICR mice

PubMed Central

Zhuhua, Zhang; Zhiquan, Wang; Zhen, Yang; Yixin, Niu; Weiwei, Zhang; Xiaoyong, Li; Yueming, Liu; Hongmei, Zhang; Li, Qin; Qing, Su

2015-01-01

Currently, the metabolic syndrome (MS) is occurring at growing rates worldwide, raising extensive concerns on the mechanisms and therapeutic interventions for this disorder. Herein, we described a novel method of establishing MS model in rodents. Male Institute of Cancer Research (ICR) mice were fed with high-fat-high-fructose (HFHF) diet or normal chow (NC) respectively for 12 weeks. Metabolic phenotypes were assessed by glucose tolerance test, insulin tolerance test and hyperinsulinemic-euglycemic clamp. Blood pressure was measured by a tail-cuff system. At the end of the experiment, mice were sacrificed, and blood and tissues were harvested for subsequent analysis. Serum insulin levels were measured by ELISA, and lipid profiles were determined biochemically. The HFHF diet-fed ICR mice exhibited obvious characteristics of the components of MS, including obvious obesity, severe insulin resistance, hyperinsulinemia, dislipidemia, significant hypertension and hyperuricemia. Our data suggest that HFHF diet-fed ICR mice may be a robust and efficient animal model that could well mimic the basic pathogenesis of human MS. PMID:26134356

Effects of Two Traditional Chinese Cooking Oils, Canola and Pork, on pH and Cholic Acid Content of Faeces and Colon Tumorigenesis in Kunming Mice.

PubMed

He, Xiao-Qiong; Duan, Jia-Li; Zhou, Jin; Song, Zhong-Yu; Cichello, Simon Angelo

2015-01-01

Faecal pH and cholate are two important factors that can affect colon tumorigenesis, and can be modified by diet. In this study, the effects of two Chinese traditional cooking oils (pork oil and canola/rapeseed oil) on the pH and the cholic acid content in feces, in addition to colon tumorigenesis, were studied in mice. Kunming mice were randomized into various groups; negative control group (NCG), azoxymethane control group (ACG), pork oil group (POG), and canola oil Ggroup (COG). Mice in the ACG were fed a basic rodent chow; mice in POG and COG were given 10% cooking oil rodent chow with the respective oil type. All mice were given four weekly AOM (azoxymethane) i.p. injections (10 mg/kg). The pH and cholic acid of the feces were examined every two weeks. Colon tumors, aberrant crypt foci and organ weights were examined 32 weeks following the final AOM injection. The results showed that canola oil significantly decreased faecal pH in female mice (P<0.05), but had no influence on feces pH in male mice (P>0.05). Pork oil significantly increased the feces pH in both male and female mice (P<0.05). No significant change was found in feces cholic acid content when mice were fed 10% pork oil or canola oil compared with the ACG. Although Kunming mice were not susceptible to AOM-induced tumorigenesis in terms of colon tumor incidence, pork oil significantly increased the ACF number in male mice. Canola oil showed no influence on ACF in either male or female mice. Our results indicate that cooking oil effects faecal pH, but does not affect the faecal cholic acid content and thus AOM-induced colon neoplastic ACF is modified by dietary fat.

Regulatory role for phosphatidylcholine transfer protein/StarD2 in the metabolic response to peroxisome proliferator activated receptor alpha (PPARalpha).

PubMed

Kang, Hye Won; Kanno, Keishi; Scapa, Erez F; Cohen, David E

2010-04-01

Phosphatidylcholine transfer protein (PC-TP, a.k.a. StarD2) is abundantly expressed in liver and is regulated by PPARalpha. When fed the synthetic PPARalpha ligand fenofibrate, Pctp(-/-) mice exhibited altered lipid and glucose metabolism. Microarray profiling of livers from fenofibrate fed wild type and Pctp(-/-) mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. PC-TP expression in cell culture controlled the activities of both PPARalpha and HNF4alpha, suggesting that the mechanism by which it modulates hepatic metabolism is at least in part via activation of transcription factors that govern nutrient homeostasis. 2009 Elsevier B.V. All rights reserved.

Cellular and Physiological Effects of Dietary Supplementation with β-Hydroxy-β-Methylbutyrate (HMB) and β-Alanine in Late Middle-Aged Mice.

PubMed

Vallejo, Julian; Spence, Madoka; Cheng, An-Lin; Brotto, Leticia; Edens, Neile K; Garvey, Sean M; Brotto, Marco

2016-01-01

There is growing evidence that severe decline of skeletal muscle mass and function with age may be mitigated by exercise and dietary supplementation with protein and amino acid ingredient technologies. The purposes of this study were to examine the effects of the leucine catabolite, beta-hydroxy-beta-methylbutyrate (HMB), in C2C12 myoblasts and myotubes, and to investigate the effects of dietary supplementation with HMB, the amino acid β-alanine and the combination thereof, on muscle contractility in a preclinical model of pre-sarcopenia. In C2C12 myotubes, HMB enhanced sarcoplasmic reticulum (SR) calcium release beyond vehicle control in the presence of all SR agonists tested (KCl, P<0.01; caffeine, P = 0.03; ionomycin, P = 0.03). HMB also improved C2C12 myoblast viability (25 μM HMB, P = 0.03) and increased proliferation (25 μM HMB, P = 0.04; 125 μM HMB, P<0.01). Furthermore, an ex vivo muscle contractility study was performed on EDL and soleus muscle from 19 month old, male C57BL/6nTac mice. For 8 weeks, mice were fed control AIN-93M diet, diet with HMB, diet with β-alanine, or diet with HMB and β-alanine. In β-alanine fed mice, EDL muscle showed a 7% increase in maximum absolute force compared to the control diet (202 ± 3vs. 188± 5 mN, P = 0.02). At submaximal frequency of stimulation (20 Hz), EDL from mice fed HMB plus β-alanine showed an 11% increase in absolute force (88.6 ± 2.2 vs. 79.8 ± 2.4 mN, P = 0.025) and a 13% increase in specific force (12.2 ± 0.4 vs. 10.8 ± 0.4 N/cm2, P = 0.021). Also in EDL muscle, β-alanine increased the rate of force development at all frequencies tested (P<0.025), while HMB reduced the time to reach peak contractile force (TTP), with a significant effect at 80 Hz (P = 0.0156). In soleus muscle, all experimental diets were associated with a decrease in TTP, compared to control diet. Our findings highlight beneficial effects of HMB and β-alanine supplementation on skeletal muscle function in aging mice.

Cellular and Physiological Effects of Dietary Supplementation with β-Hydroxy-β-Methylbutyrate (HMB) and β-Alanine in Late Middle-Aged Mice

PubMed Central

Vallejo, Julian; Spence, Madoka; Cheng, An-Lin; Brotto, Leticia; Edens, Neile K.; Garvey, Sean M.; Brotto, Marco

2016-01-01

There is growing evidence that severe decline of skeletal muscle mass and function with age may be mitigated by exercise and dietary supplementation with protein and amino acid ingredient technologies. The purposes of this study were to examine the effects of the leucine catabolite, beta-hydroxy-beta-methylbutyrate (HMB), in C2C12 myoblasts and myotubes, and to investigate the effects of dietary supplementation with HMB, the amino acid β-alanine and the combination thereof, on muscle contractility in a preclinical model of pre-sarcopenia. In C2C12 myotubes, HMB enhanced sarcoplasmic reticulum (SR) calcium release beyond vehicle control in the presence of all SR agonists tested (KCl, P<0.01; caffeine, P = 0.03; ionomycin, P = 0.03). HMB also improved C2C12 myoblast viability (25 μM HMB, P = 0.03) and increased proliferation (25 μM HMB, P = 0.04; 125 μM HMB, P<0.01). Furthermore, an ex vivo muscle contractility study was performed on EDL and soleus muscle from 19 month old, male C57BL/6nTac mice. For 8 weeks, mice were fed control AIN-93M diet, diet with HMB, diet with β-alanine, or diet with HMB and β-alanine. In β-alanine fed mice, EDL muscle showed a 7% increase in maximum absolute force compared to the control diet (202 ± 3vs. 188± 5 mN, P = 0.02). At submaximal frequency of stimulation (20 Hz), EDL from mice fed HMB plus β-alanine showed an 11% increase in absolute force (88.6 ± 2.2 vs. 79.8 ± 2.4 mN, P = 0.025) and a 13% increase in specific force (12.2 ± 0.4 vs. 10.8 ± 0.4 N/cm2, P = 0.021). Also in EDL muscle, β-alanine increased the rate of force development at all frequencies tested (P<0.025), while HMB reduced the time to reach peak contractile force (TTP), with a significant effect at 80 Hz (P = 0.0156). In soleus muscle, all experimental diets were associated with a decrease in TTP, compared to control diet. Our findings highlight beneficial effects of HMB and β-alanine supplementation on skeletal muscle function in aging mice. PMID:26953693

Long-term dietary supplementation with saury oil attenuates metabolic abnormalities in mice fed a high-fat diet: combined beneficial effect of omega-3 fatty acids and long-chain monounsaturated fatty acids.

PubMed

Yang, Zhi-Hong; Inoue, Seika; Taniguchi, Yasuko; Miyahara, Hiroko; Iwasaki, Yusuke; Takeo, Jiro; Sakaue, Hiroshi; Nakaya, Yutaka

2015-12-01

Pacific saury is a common dietary component in East Asia. Saury oil contains considerable levels of n-3 unsaturated fatty acids (PUFA) and long-chain monounsaturated fatty acids (LCMUFA) with aliphatic tails longer than 18 carbons. In our previous study, consumption of saury oil for 4 to 6 wk improved insulin sensitivity and the plasma lipid profile in mice. However, the long-term effects of saury oil on metabolic syndrome (MetS) risk factors remain to be demonstrated. In the current study, we examined the long-term effects of saury oil on mice fed a high-fat diet, and compared the effect of n-3 PUFA EPA and LCMUFA on MetS risk factor in diet-induced obese mice. In Experiment 1, male C57BL/6 J mice were fed either a 32% lard diet (control) or a diet containing 22% lard plus 10% saury oil (saury oil group) for 18 weeks. Although no differences were found in body weight and energy expenditure between the control and saury oil groups, the saury oil diet decreased plasma insulin, non-HDL cholesterol, hepatic steatosis, and adipocyte size, and altered levels of mRNA transcribed from genes involved in insulin signaling and inflammation in adipose tissue. Organ and plasma fatty acid profile analysis revealed that consumption of saury oil increased n-3 PUFA and LCMUFA (especially n-11 LCMUFA) levels in multiple organs, and decreased the fatty acid desaturation index (C16:1/C16:0; C18:1/C18:0) in liver and adipose tissue. In Experiment 2, male C57BL/6 J mice were fed a 32% lard diet (control), a diet containing 28% lard plus 4% EPA (EPA group), or a diet containing 20% lard plus 12% LCMUFA concentrate (LCMUFA group) for 8 weeks. EPA or LCMUFA intake increased organ levels of EPA and LCMUFA, respectively. Consumption of EPA reduced plasma lipid levels and hepatic lipid deposition, and decreased the fatty acid desaturation index in liver and adipose tissue. Consumption of LCMUFA decreased plasma non-HDL cholesterol, improved hyperinsulinemia, and decreased the fatty acid desaturation index in adipose tissue. EPA accumulated mainly in liver, and LCMUFA (especially n-11 LCMUFA) accumulated mainly in white adipose tissue, suggesting their possible individual biological effects for improving MetS. Our results suggest that saury oil-mediated improvement of metabolic syndrome in diet-induced obese mice may possibly be due to a combined effect of n-3 PUFA and LCMUFA.

Diacylglycerol Lipase α Knockout Mice Demonstrate Metabolic and Behavioral Phenotypes Similar to Those of Cannabinoid Receptor 1 Knockout Mice

PubMed Central

Powell, David R.; Gay, Jason P.; Wilganowski, Nathaniel; Doree, Deon; Savelieva, Katerina V.; Lanthorn, Thomas H.; Read, Robert; Vogel, Peter; Hansen, Gwenn M.; Brommage, Robert; Ding, Zhi-Ming; Desai, Urvi; Zambrowicz, Brian

2015-01-01

After creating >4,650 knockouts (KOs) of independent mouse genes, we screened them by high-throughput phenotyping and found that cannabinoid receptor 1 (Cnr1) KO mice had the same lean phenotype published by others. We asked if our KOs of DAG lipase α or β (Dagla or Daglb), which catalyze biosynthesis of the endocannabinoid (EC) 2-arachidonoylglycerol (2-AG), or Napepld, which catalyzes biosynthesis of the EC anandamide, shared the lean phenotype of Cnr1 KO mice. We found that Dagla KO mice, but not Daglb or Napepld KO mice, were among the leanest of 3651 chow-fed KO lines screened. In confirmatory studies, chow- or high fat diet-fed Dagla and Cnr1 KO mice were leaner than wild-type (WT) littermates; when data from multiple cohorts of adult mice were combined, body fat was 47 and 45% lower in Dagla and Cnr1 KO mice, respectively, relative to WT values. By contrast, neither Daglb nor Napepld KO mice were lean. Weanling Dagla KO mice ate less than WT mice and had body weight (BW) similar to pair-fed WT mice, and adult Dagla KO mice had normal activity and VO2 levels, similar to Cnr1 KO mice. Our Dagla and Cnr1 KO mice also had low fasting insulin, triglyceride, and total cholesterol levels, and after glucose challenge had normal glucose but very low insulin levels. Dagla and Cnr1 KO mice also showed similar responses to a battery of behavioral tests. These data suggest: (1) the lean phenotype of young Dagla and Cnr1 KO mice is mainly due to hypophagia; (2) in pathways where ECs signal through Cnr1 to regulate food intake and other metabolic and behavioral phenotypes observed in Cnr1 KO mice, Dagla alone provides the 2-AG that serves as the EC signal; and (3) small molecule Dagla inhibitors with a pharmacokinetic profile similar to that of Cnr1 inverse agonists are likely to mirror the ability of these Cnr1 inverse agonists to lower BW and improve glycemic control in obese patients with type 2 diabetes, but may also induce undesirable neuropsychiatric side-effects. PMID:26082754

Effect of Lactobacillus acidophilus NS1 on plasma cholesterol levels in diet-induced obese mice.

PubMed

Song, M; Park, S; Lee, H; Min, B; Jung, S; Park, S; Kim, E; Oh, S

2015-03-01

We investigated the probiotic properties of Lactobacillus acidophilus NS1, such as acid resistance, bile tolerance, adherence to HT-29 cells, and cholesterol assimilation activity. In an animal study, 7-wk-old male C57BL/6 mice were fed a normal diet, a high-fat diet (HFD), or an HFD with L. acidophilus NS1 (ca. 1.0×10(8) cfu/mL) for 10 wk. Total cholesterol and low-density lipoprotein (LDL) cholesterol levels were significantly lower in mice fed an HFD with L. acidophilus NS1 than in those fed an HFD only, whereas high-density lipoprotein cholesterol levels were similar between these 2 groups. To understand the mechanism of the cholesterol-lowering effect of L. acidophilus NS1 on the HFD-mediated increase in plasma cholesterol levels, we determined mRNA levels of genes involved in cholesterol homeostasis in the liver. Expression of sterol regulatory element-binding protein 2 (Srebp2) and LDL receptor (Ldlr) in the liver was dramatically reduced in mice fed a HFD compared with those fed a normal diet. When L. acidophilus NS1 was administered orally to HFD-fed mice, an HFD-induced suppression of Srebp2 and Ldlr expression in the liver was abolished. These results suggest that the oral administration of L. acidophilus NS1 to mice fed an HFD increased the expression of Srebp2 and Ldlr in the liver, which was inhibited by high fat intake, thus leading to a decrease in plasma cholesterol levels. Lactobacillus acidophilus NS1 could be a useful probiotic microorganism for cholesterol-lowering dairy products and the improvement of hyperlipidemia and hepatic lipid metabolism. Copyright © 2015 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Beneficial effects of apple peel polyphenols on vascular endothelial dysfunction and liver injury in high choline-fed mice.

PubMed

Jia, Mengfan; Ren, Daoyuan; Nie, Yan; Yang, Xingbin

2017-03-22

This study was designed to investigate the preventive effects of Red Fuji apple peel polyphenolic extract (APP) on vascular endothelial dysfunction and liver injury in mice fed a high choline diet. The mice were fed 3% dietary choline in drinking water for 8 weeks and displayed vascular dysfunction and liver damage (p < 0.01). The administration of APP at 600 and 900 mg per kg bw significantly elevated serum NO, HDL and 6-Keto-PGF1a levels and lowered serum TC, TG, LDL, ET-1 and TXB2 levels in the HC-fed mice. Besides, APP also caused the reduction of AST, ALT activities and MDA, CRP, TNF-α levels, and increased the hepatic GSH-Px and SOD activities of the HC-fed mice. Furthermore, the histopathology of the liver by conventional H&E and oil red O staining confirmed the liver steatosis induced by a choline diet and the hepatoprotective effect of APP. The experiment results indicated that the polyphenolic extract from apple peel might be regarded as a preventive and therapeutic product for the amelioration of HC diet-induced vascular dysfunction and hepatic injury.

[Study on early intervention of compound nutrition for cognitive dysfunction in Alzheimer's disease].

PubMed

Wang, Chao; Xie, Wei; Zhu, Jinfeng; Dang, Rui; Wang, Decai

2014-01-01

To observe the early prevention effect of the compound nutrients recipe for cognitive dysfunction of Alzheimer' s disease model-APP-PSN transgenic mouse. 36 APP-PSN transgenic mice aged two months randomly were divided into the intervention group supplied with compound recipe in the diet and the control group fed based feed, the former had high dose and low dose, 12 APP-PSN transgenic negative mice aged two months as the negative control were fed based feed. After 3 months' intervention, four groups' cognitive functions were evaluated using the Morris water maze, active avoidance experiment and jumping stair experiment. There was not statistically different between all the four groups for the weight and food intake. Compared with the control group, Morris water maze's incubation period of the intervention group was lower obviously, and jumping stair experiment's incubation period of the intervention group was higher obviously. In the active avoidance experiment, the high and low dose intervention group' s conditioned response accounted about 46.67% and 45.00% respectively, and the control group's conditioned response accounted about 20.83%. The differences of the three behavioral experiments between control group and intervention group had the statistical significance (P < 0.05), so the same as between control group and negative control group (P < 0.05). And there was no difference between intervention group and negative control group for the three behavioral experiments. The early supplementation with compound nutrition could postpone the occurrence and development of Alzheimer' s disease mice model's cognitive dysfunction.

Beer Is Less Harmful for the Liver than Plain Ethanol: Studies in Male Mice Using a Binge-Drinking Model.

PubMed

Landmann, Marianne; Wagnerberger, Sabine; Kanuri, Giridhar; Ziegenhardt, Doreen; Bergheim, Ina

2015-09-01

Mechanisms involved in the less damaging effects of beer in comparison to hard spirits have not yet been fully understood. The aim of the study was to determine if the effect of beer intake on the liver differs from that of plain ethanol and if so to determine mechanisms involved. Male C57BL/6J mice received either ethanol, beer (ethanol content: 6 g/kg body weight) or iso-caloric maltodextrin solution. Markers of steatosis, lipogenesis, activation of the toll-like receptor-4 signaling cascade and lipid export in liver and tight junction proteins in duodenum were measured 6 and 12 h after acute ethanol or beer intake. Alcohol ingestion resulted in a significant increase of hepatic triglyceride accumulation 6 and 12 h after ingestion, respectively, being markedly lower in mice fed beer. Expression of sterol regulatory element-binding protein-1c mRNA was significantly lower 12 h after alcohol or beer exposure, while fatty acid synthase mRNA expression was induced in livers of ethanol-fed mice and to a lesser extent in mice fed beer 6 h after acute alcohol ingestion. Protein levels of tight junction proteins in the small intestine were similar between groups while expression of myeloid differentiation primary response gene 88 in livers was significantly induced in ethanol- but not in beer-fed mice. Concentrations of 4-hydroxynonenal protein adducts and inducible nitric oxide synthase protein were also only induced in livers of mice fed ethanol. Protein levels of apolipoprotein B were induced in livers of beer-fed mice only. Our data suggest that beer is less harmful on the development of acute alcohol-induced liver damage than plain ethanol in male mice. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

Obesity increases inflammation and impairs lymphatic function in a mouse model of lymphedema.

PubMed

Savetsky, Ira L; Torrisi, Jeremy S; Cuzzone, Daniel A; Ghanta, Swapna; Albano, Nicholas J; Gardenier, Jason C; Joseph, Walter J; Mehrara, Babak J

2014-07-15

Although obesity is a major clinical risk factor for lymphedema, the mechanisms that regulate this effect remain unknown. Recent reports have demonstrated that obesity is associated with acquired lymphatic dysfunction. The purpose of this study was to determine how obesity-induced lymphatic dysfunction modulates the pathological effects of lymphatic injury in a mouse model. We used a diet-induced model of obesity in adult male C57BL/6J mice in which experimental animals were fed a high-fat diet and control animals were fed a normal chow diet for 8-10 wk. We then surgically ablated the superficial and deep lymphatics of the midportion of the tail. Six weeks postoperatively, we analyzed changes in lymphatic function, adipose deposition, inflammation, and fibrosis. We also compared responses to acute inflammatory stimuli in obese and lean mice. Compared with lean control mice, obese mice had baseline decreased lymphatic function. Lymphedema in obese mice further impaired lymphatic function and resulted in increased subcutaneous adipose deposition, increased CD45(+) and CD4(+) cell inflammation (P < 0.01), and increased fibrosis, but caused no change in the number of lymphatic vessels. Interestingly, obese mice had a significantly increased acute inflammatory reaction to croton oil application. In conclusion, obese mice have impaired lymphatic function at baseline that is amplified by lymphatic injury. This effect is associated with increased chronic inflammation, fibrosis, and adipose deposition. These findings suggest that obese patients are at higher risk for lymphedema due to impaired baseline lymphatic clearance and an increased propensity for inflammation in response to injury. Copyright © 2014 the American Physiological Society.

Dietary Aloe QDM Complex Reduces Obesity-Induced Insulin Resistance and Adipogenesis in Obese Mice Fed a High-Fat Diet.

PubMed

Shin, Seulmee; Kim, Seulah; Oh, Hee-Eun; Kong, Hyunseok; Shin, Eunju; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil; Kim, Kyungjae

2012-06-01

Obesity-induced disorders contribute to the development of metabolic diseases such as insulin resistance, fatty liver diseases, and type 2 diabetes (T2D). In this study, we evaluated whether the Aloe QDM complex could improve metabolic disorders related to blood glucose levels and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of Aloe QDM complex or pioglitazone (PGZ) or metformin (Met) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Dietary Aloe QDM complex lowered body weight, fasting blood glucose, plasma insulin, and leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Also, Aloe QDM complex significantly enhanced plasma adiponectin levels and insulin sensitivity via AMPK activity in muscles. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and scavenger receptors in white adipose tissue (WAT). Dietary Aloe QDM complex reduces obesity-induced glucose tolerance not only by suppressing PPARγ/LXRα but also by enhancing AMPK activity in the WAT and muscles, both of which are important peripheral tissues affecting insulin resistance. The Aloe QDM complex could be used as a nutritional intervention against T2D.

Dietary Aloe QDM Complex Reduces Obesity-Induced Insulin Resistance and Adipogenesis in Obese Mice Fed a High-Fat Diet

PubMed Central

Shin, Seulmee; Kim, Seulah; Oh, Hee-Eun; Kong, Hyunseok; Shin, Eunju; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil

2012-01-01

Obesity-induced disorders contribute to the development of metabolic diseases such as insulin resistance, fatty liver diseases, and type 2 diabetes (T2D). In this study, we evaluated whether the Aloe QDM complex could improve metabolic disorders related to blood glucose levels and insulin resistance. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of Aloe QDM complex or pioglitazone (PGZ) or metformin (Met) and were compared with unsupplemented controls (high-fat diet; HFD) or mice fed a regular diet (RD). RT-PCR and western blot analysis were used to quantify the expression of obesity-induced inflammation. Dietary Aloe QDM complex lowered body weight, fasting blood glucose, plasma insulin, and leptin levels, and markedly reduced the impairment of glucose tolerance in obese mice. Also, Aloe QDM complex significantly enhanced plasma adiponectin levels and insulin sensitivity via AMPK activity in muscles. At the same time, Aloe QDM decreased the mRNA and protein of PPARγ/LXRα and scavenger receptors in white adipose tissue (WAT). Dietary Aloe QDM complex reduces obesity-induced glucose tolerance not only by suppressing PPARγ/LXRα but also by enhancing AMPK activity in the WAT and muscles, both of which are important peripheral tissues affecting insulin resistance. The Aloe QDM complex could be used as a nutritional intervention against T2D. PMID:22916045

L-arginine prevents xanthoma development and inhibits atherosclerosis in LDL receptor knockout mice.

PubMed

Aji, W; Ravalli, S; Szabolcs, M; Jiang, X C; Sciacca, R R; Michler, R E; Cannon, P J

1997-01-21

The potential antiatherosclerotic actions of NO were investigated in four groups of mice (n = 10 per group) lacking functional LDL receptor genes, an animal model of familial hypercholesterolemia. Group 1 was fed a regular chow diet. Groups 2 through 4 were fed a 1.25% high-cholesterol diet. In addition, group 3 received supplemental L-arginine and group 4 received L-arginine and N omega-nitro-L-arginine (L-NA), an inhibitor of NO synthase (NOS). Animals were killed at 6 months; aortas were stained with oil red O for planimetry and with antibodies against constitutive and inducible NOSs. Plasma cholesterol was markedly increased in the animals receiving the high-cholesterol diet. Xanthomas appeared in all mice fed the high-cholesterol diet alone but not in those receiving L-arginine. Aortic atherosclerosis was present in all mice on the high-cholesterol diet. The mean atherosclerotic lesion area was reduced significantly (P < .01) in the cholesterol-fed mice given L-arginine compared with those receiving the high-cholesterol diet alone. The mean atherosclerotic lesion area was significantly larger (P < .01) in cholesterol-fed mice receiving L-arginine + L-NA than in those on the high-cholesterol diet alone. Within the atherosclerotic plaques, endothelial cells immunoreacted for endothelial cell NOS; macrophages, foam cells, and smooth muscle cells immunostained strongly for inducible NOS and nitrotyrosine residues. The data indicate that L-arginine prevents xanthoma formation and reduces atherosclerosis in LDL receptor knockout mice fed a high-cholesterol diet. The abrogation of the beneficial effects of L-arginine by L-NA suggests that the antiatherosclerotic actions of L-arginine are mediated by NOS. The data suggest that L-arginine may be beneficial in familial hypercholesterolemia.

Comparison of the Effects of the 1975 Japanese Diet and the Modern Mediterranean Diet on Lipid Metabolism in Mice.

PubMed

Mizowaki, Yui; Sugawara, Saeko; Yamamoto, Kazushi; Sakamoto, Yu; Iwagaki, Yui; Kawakami, Yuki; Igarashi, Miki; Tsuduki, Tsuyoshi

2017-01-01

The Japanese diet and the Mediterranean diet are both known to be good for health, but there had been no direct comparison of their health benefits. In this study, we compared the 1975 Japanese diet, which has been found to have high health benefits, with the 2010 Italian diet, which contributes to the longest life expectancy in Mediterranean countries. Diets were created using one-week menus of the two diets based on FAOSTAT Food Balance Sheets. The diets were prepared, freeze-dried, powdered and fed to mice for 4 weeks to examine their effects on lipid metabolism. In mice fed the Japanese diet, the visceral fat weight was lower, adipocytes were smaller, the liver weight was lower and liver TG tended to be lower than those fed the Italian diet, and little lipid accumulation was observed in hepatocytes of mice fed the Japanese diet. In addition, in mice fed the Japanese diet, the expression levels of genes related to fatty acid synthesis were lower, whereas those of genes related to catabolism of fatty acids and cholesterol were higher than those fed the Italian diet. Therefore, the Japanese diet reduced accumulation of lipids in the white adipose tissue and liver by suppressing fatty acid synthesis and promoting catabolism of fatty acids and cholesterol in the liver, compared to the Italian diet.

Effect of High Sugar Intake on Glucose Transporter and Weight Regulating Hormones in Mice and Humans

PubMed Central

Ritze, Yvonne; Bárdos, Gyöngyi; D’Haese, Jan G.; Ernst, Barbara; Thurnheer, Martin; Schultes, Bernd; Bischoff, Stephan C.

2014-01-01

Objective Sugar consumption has increased dramatically over the last decades in Western societies. Especially the intake of sugar-sweetened beverages seems to be a major risk for the development of obesity. Thus, we compared liquid versus solid high-sugar diets with regard to dietary intake, intestinal uptake and metabolic parameters in mice and partly in humans. Methods Five iso-caloric diets, enriched with liquid (in water 30% vol/vol) or solid (in diet 65% g/g) fructose or sucrose or a control diet were fed for eight weeks to C57bl/6 mice. Sugar, liquid and caloric intake, small intestinal sugar transporters (GLUT2/5) and weight regulating hormone mRNA expression, as well as hepatic fat accumulation were measured. In obese versus lean humans that underwent either bariatric surgery or small bowel resection, we analyzed small intestinal GLUT2, GLUT5, and cholecystokinin expression. Results In mice, the liquid high-sucrose diet caused an enhancement of total caloric intake compared to the solid high-sucrose diet and the control diet. In addition, the liquid high-sucrose diet increased expression of GLUT2, GLUT5, and cholecystokinin expression in the ileum (P<0.001). Enhanced liver triglyceride accumulation was observed in mice being fed the liquid high-sucrose or -fructose, and the solid high-sucrose diet compared to controls. In obese, GLUT2 and GLUT5 mRNA expression was enhanced in comparison to lean individuals. Conclusions We show that the form of sugar intake (liquid versus solid) is presumably more important than the type of sugar, with regard to feeding behavior, intestinal sugar uptake and liver fat accumulation in mice. Interestingly, in obese individuals, an intestinal sugar transporter modulation also occurred when compared to lean individuals. PMID:25010715

Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity.

PubMed

Jacobs, René L; Zhao, Yang; Koonen, Debby P Y; Sletten, Torunn; Su, Brian; Lingrell, Susanne; Cao, Guoqing; Peake, David A; Kuo, Ming-Shang; Proctor, Spencer D; Kennedy, Brian P; Dyck, Jason R B; Vance, Dennis E

2010-07-16

Phosphatidylcholine (PC) is synthesized from choline via the CDP-choline pathway. Liver cells can also synthesize PC via the sequential methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The current study investigates whether or not hepatic PC biosynthesis is linked to diet-induced obesity. Pemt(+/+) mice fed a high fat diet for 10 weeks increased in body mass by 60% and displayed insulin resistance, whereas Pemt(-/-) mice did not. Compared with Pemt(+/+) mice, Pemt(-/-) mice had increased energy expenditure and maintained normal peripheral insulin sensitivity; however, they developed hepatomegaly and steatosis. In contrast, mice with impaired biosynthesis of PC via the CDP-choline pathway in liver became obese when fed a high fat diet. We, therefore, hypothesized that insufficient choline, rather than decreased hepatic phosphatidylcholine, was responsible for the lack of weight gain in Pemt(-/-) mice despite the presence of 1.3 g of choline/kg high fat diet. Supplementation with an additional 2.7 g of choline (but not betaine)/kg of diet normalized energy metabolism, weight gain, and insulin resistance in high fat diet-fed Pemt(-/-) mice. Furthermore, Pemt(+/+) mice that were fed a choline-deficient diet had increased oxygen consumption, had improved glucose tolerance, and gained less weight. Thus, de novo synthesis of choline via PEMT has a previously unappreciated role in regulating whole body energy metabolism.

Prevention of Mycobacterium avium subsp. paratuberculosis Infection in BALB/c Mice by Feeding Lactobacillus acidophilus Strain NP-51

USDA-ARS?s Scientific Manuscript database

The immune responses of 390 BALB/c mice fed the probiotic Lactobacillus acidophilus strain NP51® and infected with Mycobacterium avium subspecies paratuberculosis (MAP) were evaluated in a 6-month trial. Mice were randomized to nine treatment groups fed either viable- or heat-killed NP51 and inocula...

2,4-Dinitrofluorobenzene-induced contact hypersensitivity response in NC/Nga mice fed fructo-oligosaccharide.

PubMed

Fujiwara, Reiko; Sasajima, Naho; Takemura, Naoki; Ozawa, Keisuke; Nagasaka, Yuki; Okubo, Takuma; Sahasakul, Yuraporn; Watanabe, Jun; Sonoyama, Kei

2010-01-01

Strategies to manipulate gut microbiota in infancy have been considered to prevent the development of allergic diseases later in life. We previously demonstrated that maternal dietary supplementation with fructo-oligosaccharide (FOS) during pregnancy and lactation modulated the composition of gut microbiota and diminished the severity of spontaneously developing atopic dermatitis-like skin lesions in the offspring of NC/Nga mice. The present study tested whether dietary FOS affects contact hypersensitivity (CHS), another model for allergic skin disease, in NC/Nga mice. In experiment 1, 5-wk-old female NC/Nga mice were fed diets either with or without FOS supplementation for 3 wk and then received 2,4-dinitrofluorobenzene (DNFB) on the ear auricle 5 times at 7-d intervals. FOS supplementation reduced CHS response as demonstrated by ear swelling. Quantitative RT-PCR analysis showed that mRNA levels for interleukin (IL)-10, IL-12p40, and IL-17 in the lesional ear skin were significantly lower in mice fed FOS. In experiment 2, female NC/Nga mice were fed diets either with or without FOS during pregnancy and lactation. After weaning, offspring were fed the diets supplemented with or without FOS. Three weeks after weaning, offspring received DNFB on the ear auricle 4 times at 7-d intervals. Although FOS supplementation after weaning reduced ear swelling, maternal FOS consumption was ineffective in offspring. The present data suggest that dietary FOS reduces CHS while maternal FOS consumption is ineffective in offspring of DNFB-treated NC/Nga mice.