Expression of genes involved in carbohydrate-lipid metabolism in muscle and fat tissues in the initial stage of adult-age obesity in fed and fasted mice.

PubMed

Bazhan, Nadezhda M; Baklanov, Alexandr V; Piskunova, Julia V; Kazantseva, Antonina J; Makarova, Elena N

2017-10-01

C57Bl mice exhibit impaired glucose metabolism by the late adult age under standard living conditions. The aim of this study was to evaluate white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle expression of genes involved in carbohydrate-lipid metabolism at postpubertal stages preceding the late adult age in C57Bl mice. Muscle mRNA levels of uncoupling protein 3 ( Ucp3 ) and carnitine palmitoyltransferase 1 ( Cpt1 ) (indicators of FFA oxidation), WAT mRNA levels of hormone-sensitive lipase ( Lipe ) and lipoprotein lipase ( Lpl ) (indicators of lipolysis and lipogenesis), muscle and WAT mRNA levels of the type 4 glucose transporter Slc2a4 (indicators of insulin-dependent glucose uptake), and BAT mRNA levels of uncoupling protein 1 ( Ucp1 ) (indicator of thermogenesis) were measured in fed and 16 h-fasted mice in three age groups: 10-week-old (young), 15-week-old (early adult), and 30-week-old (late adult). Weight gain from young to early adult age was not accompanied by changes in WAT and BAT indexes and biochemical blood parameters. Weight gain from early to late adult age was accompanied by increased WAT and BAT indexes and decreased glucose tolerance. Muscle Ucp3 and Cpt1 mRNA levels and WAT Lipe and Slc2a4 mRNA levels increased from young to early adult age and then sharply decreased by the late adult age. Moreover, BAT Ucp1 mRNA level decreased in the late adult age. Fasting failed to increase muscle Cpt1 mRNA levels in late adult mice. These transcriptional changes could contribute to impaired glucose metabolism and the onset of obesity in late adult mice during normal development. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

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

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.

Ursodeoxycholic acid decreases age-related adiposity and inflammation in mice

PubMed Central

Oh, Ah-Reum; Bae, Jin-Sik; Lee, Junghoon; Shin, Eunji; Oh, Byung-Chul; Park, Sang-Chul; Cha, Ji-Young

2016-01-01

Ursodeoxycholic acid (UDCA), a natural, hydrophilic nontoxic bile acid, is clinically effective for treating cholestatic and chronic liver diseases. We investigated the chronic effects of UDCA on age-related lipid homeostasis and underlying molecular mechanisms. Twenty-week-old C57BL/6 male and female mice were fed a diet with or without 0.3% UDCA supplementation for 25 weeks. UDCA significantly reduced weight gain, adiposity, hepatic triglyceride, and hepatic cholesterol without incidental hepatic injury. UDCA-mediated hepatic triglyceride reduction was associated with downregulated hepatic expression of peroxisome proliferator-activated receptor-γ, and of other genes involved in lipogenesis (Chrebp, Acaca, Fasn, Scd1, and Me1) and fatty acid uptake (Ldlr, Cd36). The inflammatory cytokines Tnfa, Ccl2, and Il6 were significantly decreased in liver and/or white adipose tissues of UDCA-fed mice. These data suggest that UDCA exerts beneficial effects on age-related metabolic disorders by lowering the hepatic lipid accumulation, while concurrently reducing hepatocyte and adipocyte susceptibility to inflammatory stimuli. [BMB Reports 2016; 49(2): 105-110] PMID:26350747

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.

Impaired CXCR4 Expression and Cell Engraftment of Bone Marrow-derived Cells from Aged Atherogenic Mice

PubMed Central

Xu, Qiyuan; Wang, Jian’An; He, Jinlin; Zhou, Mingsheng; Adi, Jennipher; Webster, Keith A; Yu, Hong

2011-01-01

Objectives Reduced numbers and activity of circulating progenitor cells are associated with aging and have been linked with coronary artery disease. To determine the impact of aging and atherosclerotic disease on the chemotaxic activity of bone marrow derived cells (BMCs), we examined CXCR4 surface expression on BMCs from aged and atherosclerotic mice. Methods CXCR4 expression and cellular mobility were compared between BMCs of young (6-week old) ApoE null mice (ApoE−/−) and aged ApoE−/− mice that had been fed with a high-fat, high-cholesterol diet for 6-months. Results Age and atherosclerosis correlated with significantly lower surface expression of CXCR4 that was less inducible by calcium. The impaired calcium response was associated with defective calcium influx and was partially recovered by treatment with the calcium ionophore ionomycin. ApoE−/− mice fed high fat diet for 6-months had defective CXCR4 expression and SDF-1 regulation that is equivalent to that of 24-month old wild type mice. BMCs from aged, atherogenic ApoE−/− mice also displayed defective homing to SDF-1, and the animals had lower serum and bone marrow levels of SDF-1. Conclusion Evolution of atherosclerosis in ApoE−/− mice is paralleled by progressive loss of mobility of BMCs with reductions of CXCR4 expression, and reduced levels of SDF-1 in both serum and bone marrow. These changes mute the homing capability of BMCs and may contribute to the progression of atherosclerosis in this model. PMID:21855069

Curcumin suppresses intestinal polyps in APC Min mice fed a high fat diet.

PubMed

Pettan-Brewer, Christina; Morton, John; Mangalindan, Ruby; Ladiges, Warren

2011-01-01

Colorectal cancer (CRC) is a leading cause of cancer deaths in the United States. Various risk factors have been associated with CRC including increasing age and diet. Epidemiological and experimental studies have implicated a diet high in fat as an important risk factor for colon cancer. High fat diets can promote obesity resulting in insulin resistance and inflammation and the development of oxidative stress, increased cell proliferation, and suppression of apoptosis. Because of the high consumption of dietary fats, especially saturated fats, by Western countries, it is of interest to see if non-nutrient food factors might be effective in preventing or delaying CRC in the presence of high saturated fat intake. Curcumin (Curcuma longa), the main yellow pigment in turmeric, was selected to test because of its reported anti-tumor activity. APC Min mice, which develop intestinal polyps and have many molecular features of CRC, were fed a diet containing 35% pork fat, 33% sucrose, and a protein and vitamin mineral mixture (HFD) with or without 0.5% curcumin. These cohorts were compared to APC Min mice receiving standard rodent chow (RC) with 8% fat. APC Min mice fed the HFD for 3 months had a 23% increase in total number of polyps compared to APC Min mice on RC. Curcumin was able to significantly reverse the accelerated polyp development associated with the HFD suggesting it may be effective clinically in helping prevent colon cancer even when ingesting high amounts of fatty foods. The anti-tumor effect of curcumin was shown to be associated with enhanced apoptosis and increased efficiency of DNA repair. Since curcumin prevented the gain in body weight seen in APC Min mice ingesting the HFD, modulation of energy metabolism may also be a factor.

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice.

PubMed

Vermeij, W P; Dollé, M E T; Reiling, E; Jaarsma, D; Payan-Gomez, C; Bombardieri, C R; Wu, H; Roks, A J M; Botter, S M; van der Eerden, B C; Youssef, S A; Kuiper, R V; Nagarajah, B; van Oostrom, C T; Brandt, R M C; Barnhoorn, S; Imholz, S; Pennings, J L A; de Bruin, A; Gyenis, Á; Pothof, J; Vijg, J; van Steeg, H; Hoeijmakers, J H J

2016-09-15

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1 ∆/- ) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg -/- (also known as Ercc5 -/- ) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1 ∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1 ∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1 ∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.

Laminarin favorably modulates gut microbiota in mice fed a high-fat diet.

PubMed

Nguyen, Son G; Kim, Jungman; Guevarra, Robin B; Lee, Ji-Hoon; Kim, Eungpil; Kim, Su-Il; Unno, Tatsuya

2016-10-12

We investigated the anti-obesity effects of the potential prebiotic, laminarin, on mice fed a high-fat diet. A metagenomics approach was applied to characterize the ecological and functional differences of gut microbiota among mice fed a normal diet (CTL), a high-fat diet (HFD), and a laminarin-supplemented high-fat diet (HFL). The HFL mice showed a slower weight gain than the HFD mice during the laminarin-feeding period, but the rate of weight gain increased after the termination of laminarin supplementation. Gut microbial community analysis showed clear differences between the CTL and HFD mice, whereas the HFL mice were between the two. A higher abundance of carbohydrate active enzymes was observed in the HFL mice compared to the HFD mice, with especially notable increases in glycoside hydrolase and polysaccharide lyases. A significant decrease in Firmicutes and an increase in the Bacteroidetes phylum, especially the genus Bacteroides, were observed during laminarin ingestion. Laminarin ingestion altered the gut microbiota at the species level, which was re-shifted after termination of laminarin ingestion. Therefore, supplementing laminarin could reduce the adverse effects of a high-fat diet by shifting the gut microbiota towards a higher energy metabolism. Thus, laminarin could be used to develop anti-obesity functional foods. Our results also suggest that laminarin would need to be consumed regularly in order to prevent or manage obesity.

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.

Aging-associated renal disease in mice is fructokinase dependent.

PubMed

Roncal-Jimenez, Carlos A; Ishimoto, Takuji; Lanaspa, Miguel A; Milagres, Tamara; Hernando, Ana Andres; Jensen, Thomas; Miyazaki, Makoto; Doke, Tomohito; Hayasaki, Takahiro; Nakagawa, Takahiko; Marumaya, Shoichi; Long, David A; Garcia, Gabriela E; Kuwabara, Masanari; Sánchez-Lozada, Laura G; Kang, Duk-Hee; Johnson, Richard J

2016-10-01

Aging-associated kidney disease is usually considered a degenerative process associated with aging. Recently, it has been shown that animals can produce fructose endogenously, and that this can be a mechanism for causing kidney damage in diabetic nephropathy and in association with recurrent dehydration. We therefore hypothesized that low-level metabolism of endogenous fructose might play a role in aging-associated kidney disease. Wild-type and fructokinase knockout mice were fed a normal diet for 2 yr that had minimal (<5%) fructose content. At the end of 2 yr, wild-type mice showed elevations in systolic blood pressure, mild albuminuria, and glomerular changes with mesangial matrix expansion, variable mesangiolysis, and segmental thrombi. The renal injury was amplified by provision of high-salt diet for 3 wk, as noted by the presence of glomerular hypertrophy, mesangial matrix expansion, and alpha smooth muscle actin expression, and with segmental thrombi. Fructokinase knockout mice were protected from renal injury both at baseline and after high salt intake (3 wk) compared with wild-type mice. This was associated with higher levels of active (phosphorylated serine 1177) endothelial nitric oxide synthase in their kidneys. These studies suggest that aging-associated renal disease might be due to activation of specific metabolic pathways that could theoretically be targeted therapeutically, and raise the hypothesis that aging-associated renal injury may represent a disease process as opposed to normal age-related degeneration.

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.

Early Deposition of Ceroid in Kupffer Cells of Mice Fed Hepatic Necrogenic Diets

PubMed Central

Porta, Eduardo A.; Hartroft, W. Stanley

1963-01-01

Experiments were undertaken to study the prenecrotic morphologic changes in liver of mice that were fed diets deficient in vitamin E and selenium. When these diets were fed to male albino mice the accumulation of ceroid pigment in Kupffer cells was observed within seven days of commencing the diets, long before any evidence of necrosis was observed. In later stages of the experiment the ceroid pigment deposited in Kupffer cells was so abundant that it appeared possible that interference with hepatic sinusoidal blood flow and impairment of physiologic activity of the reticuloendothelial system had resulted. ImagesFig. 1Fig. 2 PMID:20327568

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.

Time-restricted feeding reduces adiposity in mice fed a high-fat diet

USDA-ARS?s Scientific Manuscript database

Disruption of the circadian rhythm contributes to obesity. The present study investigated the effects of time-restricted feeding (TRF) of a high-fat diet on adiposity in male C57BL/6 mice. Three-week-old mice were fed a low-fat or high-fat diet (16% or 45% of energy from corn oil) ad libitum (ad l...

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

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

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.

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.

Esculetin prevents non-alcoholic fatty liver in diabetic mice fed high-fat diet.

PubMed

Choi, Ra-Yeong; Ham, Ju Ri; Lee, Mi-Kyung

2016-12-25

This study investigated the effects and mechanism of esculetin (6,7-dihydroxycoumarin) on non-alcoholic fatty liver in diabetic mice fed high-fat diet (HFD). The diabetic mice model was induced by injection of streptozotocin, after which they were fed HFD diet with or without esculetin for 11 weeks. Non-diabetic mice were provided a normal diet. Diabetes induced hepatic hypertrophy, lipid accumulation and droplets; however, esculetin reversed these changes. Esculetin treatment in diabetic mice fed HFD significantly down-regulated expression of lipid synthesis genes (Fasn, Dgat2 and Plpp2) and inflammation genes (Tlr4, Myd88, Nfkb, Tnfα and Il6). Moreover, the activities of hepatic lipid synthesis enzymes (fatty acid synthase and phosphatidate phosphohydrolase) and gluconeogenesis enzyme (glucose-6-phosphatase) in the esculetin group were decreased compared with the diabetic group. In addition, esculetin significantly reduced blood HbA 1c , serum cytokines (TNF-α and IL-6) and chemokine (MCP-1) levels compared with the diabetic group without changing the insulin content in serum and the pancreas. Hepatic SOD activity was lower and lipid peroxidation level was higher in the diabetic group than in the normal group; however, esculetin attenuates these differences. Overall, these results demonstrated that esculetin supplementation could protect against development of non-alcoholic fatty liver in diabetes via regulation of lipids, glucose and inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

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.

Long-term Dietary Macronutrients and Hepatic Gene Expression in Aging Mice.

PubMed

Gokarn, Rahul; Solon-Biet, Samantha M; Cogger, Victoria C; Cooney, Gregory J; Wahl, Devin; McMahon, Aisling C; Mitchell, James R; Mitchell, Sarah J; Hine, Christopher; de Cabo, Rafael; Raubenheimer, David; Simpson, Stephen J; Le Couteur, David G

2018-04-23

Nutrition influences both hepatic function and aging, but mechanisms are poorly understood. Here, the effects of lifelong, ad libitum-fed diets varying in macronutrients and energy on hepatic gene expression were studied. Gene expression was measured using Affymetrix mouse arrays in livers of 46 mice aged 15 months fed one of 25 diets varying in protein, carbohydrates, fat, and energy density from 3 weeks of age. Gene expression was almost entirely influenced by protein intake. Carbohydrate and fat intake had few effects on gene expression compared with protein. Pathways and processes associated with protein intake included those involved with mitochondrial function, metabolic signaling (PI3K-Akt, AMPK, mTOR) and metabolism of protein and amino acids. Protein intake had variable effects on genes associated with regulation of longevity and influenced by caloric restriction. Among the genes of interest with expression that were significantly associated with protein intake are Cth, Gls2, Igf1, and Nnmt, which were increased with higher protein intake, and Igf2bp2, Fgf21, Prkab2, and Mtor, which were increased with lower protein intake. Dietary protein has a powerful impact on hepatic gene expression in older mice, with some overlap with genes previously reported to be involved with regulation of longevity or caloric restriction.

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

Chronic carbon monoxide treatment attenuates development of obesity and remodels adipocytes in mice fed a high-fat diet.

PubMed

Hosick, P A; AlAmodi, A A; Storm, M V; Gousset, M U; Pruett, B E; Gray, W; Stout, J; Stec, D E

2014-01-01

Induction of heme oxygenase-1 (HO-1) has been demonstrated to result in chronic weight loss in several rodent models of obesity. However, the specific contribution of the HO metabolite, carbon monoxide (CO) to this response remains unknown. In this study, we determined the effect of chronic low level administration of a specific CO donor on the progression of obesity and its effects on metabolism and adipocyte biology in mice fed a high-fat diet. Experiments were performed on C57BL/6J mice fed a high-fat diet (60%) from 4 weeks until 30 weeks of age. Mice were administered either the CO donor, carbon monoxide releasing molecules (CORM)-A1 (5 mg kg(-1), intraperitoneally every other day) or the inactive form of the drug (iCORM-A1). Body weights were measured weekly and fasted blood glucose, insulin as well as body composition were measured every 6 weeks. Food intake, O2 consumption, CO2 production, activity and body heat production were measured at 28 weeks after start of the experimental protocol. Chronic CORM-A1 attenuated the development of high fat induced obesity from 18 weeks until the end of the study. Chronic CORM-A1 treatment in mice fed a high-fat diet resulted in significant decreases in fasted blood glucose, insulin and body fat and increased O2 consumption and heat production as compared with mice treated with iCORM-A1. Chronic CORM-A1 treatment also resulted in a significant decrease in adipocyte size and an increase in adipocyte number and in NRF-1, PGC-1α and UCP1 protein levels in epidydmal fat. Our results demonstrate that chronic CO treatment prevents the development of high-fat diet induced obesity via stimulation of metabolism and remodeling of adipocytes.

Meibomian Gland Dysfunction Model in Hairless Mice Fed a Special Diet With Limited Lipid Content.

PubMed

Miyake, Hideki; Oda, Tomoko; Katsuta, Osamu; Seno, Masaharu; Nakamura, Masatsugu

2016-06-01

A novel meibomian gland dysfunction (MGD) model was developed to facilitate understanding of the pathophysiology of MGD and to evaluate treatment with azithromycin ophthalmic solution (azithromycin). MGD was induced in HR-1 hairless mice by feeding them a special diet with limited lipid content (HR-AD). Male HR-1 hairless mice were fed an HR-AD diet for 16 weeks. Development of MGD was assessed by histopathology at 4-week intervals. The lid margin was observed by slit-lamp examination. After cessation of the HR-AD diet, the mice were fed a normal diet to restore normal eye conditions. Expression of cytokeratin 6 was determined by immunostaining. We evaluated the effects of topically applied azithromycin on the plugged orifice in this model. After mice were fed the HR-AD diet, histopathology analysis showed hyperkeratinization of the ductal epithelium in the meibomian gland. Ductal hyperkeratinization resulted in the loss of acini, followed by atrophy of the gland. Slit-lamp examination revealed a markedly plugged orifice, telangiectasia, and a toothpaste-like meibum compared with that of a normal eyelid. Cessation of feeding with HR-AD ameliorated both the MGD signs and the expression of cytokeratin 6, restoring the tissue to a histologically normal state. Azithromycin treatment significantly decreased the number of plugged orifices and ameliorated atrophy, as revealed by histopathologic analysis. We developed a novel model that mimics human MGD signs in HR-1 hairless mice fed an HR-AD diet. Azithromycin treatment led to therapeutic improvement in this model. This MGD model could be useful for the evaluation of drug candidates for MGD.

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

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.

The Ratio of Macronutrients, Not Caloric Intake, Dictates Cardiometabolic Health, Aging, and Longevity in Ad Libitum-Fed Mice

PubMed Central

Solon-Biet, Samantha M.; McMahon, Aisling C.; Ballard, J. William O.; Ruohonen, Kari; Wu, Lindsay E.; Cogger, Victoria C.; Warren, Alessandra; Huang, Xin; Pichaud, Nicolas; Melvin, Richard G.; Gokarn, Rahul; Khalil, Mamdouh; Turner, Nigel; Cooney, Gregory J.; Sinclair, David A.; Raubenheimer, David; Le Couteur, David G.; Simpson, Stephen J.

2016-01-01

Summary The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation. PMID:24606899

The Influence of Macronutrients on Splanchnic and Hepatic Lymphocytes in Aging Mice.

PubMed

Le Couteur, David G; Tay, Szun S; Solon-Biet, Samantha; Bertolino, Patrick; McMahon, Aisling C; Cogger, Victoria C; Colakoglu, Feyza; Warren, Alessandra; Holmes, Andrew J; Pichaud, Nicolas; Horan, Martin; Correa, Carolina; Melvin, Richard G; Turner, Nigel; Ballard, J William O; Ruohonen, Kari; Raubenheimer, David; Simpson, Stephen J

2015-12-01

There is a strong association between aging, diet, and immunity. The effects of macronutrients and energy intake on splanchnic and hepatic lymphocytes were studied in 15 month old mice. The mice were ad-libitum fed 1 of 25 diets varying in the ratios and amounts of protein, carbohydrate, and fat over their lifetime. Lymphocytes in liver, spleen, Peyers patches, mesenteric lymph nodes, and inguinal lymph nodes were evaluated using flow cytometry. Low protein intake reversed aging changes in splenic CD4 and CD8 T cells, CD4:CD8 T cell ratio, memory/effector CD4 T cells and naïve CD4 T cells. A similar influence of total caloric intake in these ad-libitum fed mice was not apparent. Protein intake also influenced hepatic NK cells and B cells, while protein to carbohydrate ratio influenced hepatic NKT cells. Hepatosteatosis was associated with increased energy and fat intake and changes in hepatic Tregs, effector/memory T, and NK cells. Hepatic NK cells were also associated with body fat, glucose tolerance, and leptin levels while hepatic Tregs were associated with hydrogen peroxide production by hepatic mitochondria. Dietary macronutrients, particularly protein, influence splanchnic lymphocytes in old age, with downstream associations with mitochondrial function, liver pathology, and obesity-related phenotype. © The Author 2014. 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.

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.

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.

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

Cancer-Predicting Gene Expression Changes in Colonic Mucosa of Western Diet Fed Mlh1 +/- Mice

PubMed Central

Dermadi Bebek, Denis; Valo, Satu; Reyhani, Nima; Ollila, Saara; Päivärinta, Essi; Peltomäki, Päivi; Mutanen, Marja; Nyström, Minna

2013-01-01

Colorectal cancer (CRC) is the second most common cause of cancer-related deaths in the Western world and interactions between genetic and environmental factors, including diet, are suggested to play a critical role in its etiology. We conducted a long-term feeding experiment in the mouse to address gene expression and methylation changes arising in histologically normal colonic mucosa as putative cancer-predisposing events available for early detection. The expression of 94 growth-regulatory genes previously linked to human CRC was studied at two time points (5 weeks and 12 months of age) in the heterozygote Mlh1 +/- mice, an animal model for human Lynch syndrome (LS), and wild type Mlh1 +/+ littermates, fed by either Western-style (WD) or AIN-93G control diet. In mice fed with WD, proximal colon mucosa, the predominant site of cancer formation in LS, exhibited a significant expression decrease in tumor suppressor genes, Dkk1, Hoxd1, Slc5a8, and Socs1, the latter two only in the Mlh1 +/- mice. Reduced mRNA expression was accompanied by increased promoter methylation of the respective genes. The strongest expression decrease (7.3 fold) together with a significant increase in its promoter methylation was seen in Dkk1, an antagonist of the canonical Wnt signaling pathway. Furthermore, the inactivation of Dkk1 seems to predispose to neoplasias in the proximal colon. This and the fact that Mlh1 which showed only modest methylation was still expressed in both Mlh1 +/- and Mlh1 +/+ mice indicate that the expression decreases and the inactivation of Dkk1 in particular is a prominent early marker for colon oncogenesis. PMID:24204690

Silymarin alleviates hepatic oxidative stress and protects against metabolic disorders in high-fat diet-fed mice.

PubMed

Feng, Bin; Meng, Ran; Huang, Bin; Shen, Shanmei; Bi, Yan; Zhu, Dalong

2016-01-01

Silymarin is a potent antioxidant medicine and has been widely used for the treatment of liver diseases over 30 years. Recent studies suggest that silymarin may benefit patients with glucose intolerance. However, the mechanism underlying the action of silymarin is not clarified. The aim of this work was to assess the impact of silymarin on glucose intolerance in high-fat diet (HFD)-fed mice, and explore the potential therapeutic mechanisms. C57BL/6 mice were fed with HFD for 12 weeks, randomized, and treated orally with vehicle saline or silymarin (30 mg/kg) daily for 30 days. We found that silymarin significantly improved HFD-induced body weight gain, glucose intolerance, and insulin resistance in mice. Silymarin treatment reduced HFD-increased oxidative stress indicators (reactive oxygen species, lipid peroxidation, protein oxidation) and restored HFD-down-regulated activities of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) in the plasma and/or liver of the HFD-fed mice. Furthermore, silymarin decreased HFD-up-regulated hepatic NADPH oxidase expression and NF-κB activation in mice. Additionally, silymarin treatment mitigated HFD-increased plasma IL-1β, TNF-α levels, and HFD-enhanced hepatic NO, TLR4, and iNOS expression in mice. These novel data indicate that silymarin has potent anti-diabetic actions through alleviating oxidative stress and inflammatory response, partially by inhibiting hepatic NADPH oxidase expression and the NF-κB signaling.

Zectran fed orally to mice...cholinesterase levels in blood determined

Treesearch

Jean Marie Lang; Raymond R. Miskus

1967-01-01

Zectran, a carbamate insecticide, is being field-tested against the spruce budworm. Taken in sufficient quantity, it can induce cholinesterase (ChE) inhibition in mammals. In laboratory experiments, Zectran was fed orally to mice. Results indicated that maximum ChE inhibition occurred 15 to 30 minutes after ingestion of Zectran, and that a ChE test is unreliable in the...

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.

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.

[Development of Rhodnius pictipes Stal, 1872 fed on mice and through a silicone membrane (Hemiptera, Reduviidae, Triatominae)].

PubMed

Rocha, D da S; da Fonseca, A H; Costa, F A; Jurberg, J; Galvão, C

1997-01-01

Rhodnius pictipes (Hemiptera, Reduviidae) from Serra Norte, State of Pará, Brazil, acclimatized in an insectary at the Laboratório Nacional e Internacional de Referência em Taxonomia de Triatomíneos, Departamento de Entomologia, Instituto Oswaldo Cruz, were fed through a silicone membrane. In order to know the viability and the efficiency of this membrane compared with insects fed on mice, the number of bloodmeals taken, period of development of the five nymphal instars, longevity of adults, average amount of blood intake in each meal and percent of mortality were observed. A total of 310 insects, were used, comprising 50 nymphs of each instar, as well as 30 male and 30 female adults. Insects fed artificially had reduced minimal and maximal periods of development than the group fed on mice. The largest relative increase of body weight was observed in the 2nd instar followed by the 1st, and the amount of blood ingested increased during the development, to the 5th instar for both groups. There were no significant differences between the groups fed artificially and in vivo according to Tukey's test for p > 0.05. The percent of mortality in the 1st instar was 18% for artificially fed and 16% for the group fed on mice; these percentages decreased as insects developed until the 4th instar, without mortality, returning to increase in the 5th instar. R. pictipes was shown to be easily adaptable to artificial feeding, and could be considered as an important and viable experimental model.

Utility and reliability of non-invasive muscle function tests in high-fat-fed mice.

PubMed

Martinez-Huenchullan, Sergio F; McLennan, Susan V; Ban, Linda A; Morsch, Marco; Twigg, Stephen M; Tam, Charmaine S

2017-07-01

What is the central question of this study? Non-invasive muscle function tests have not been validated for use in the study of muscle performance in high-fat-fed mice. What is the main finding and its importance? This study shows that grip strength, hang wire and four-limb hanging tests are able to discriminate the muscle performance between chow-fed and high-fat-fed mice at different time points, with grip strength being reliable after 5, 10 and 20 weeks of dietary intervention. Non-invasive tests are commonly used for assessing muscle function in animal models. The value of these tests in obesity, a condition where muscle strength is reduced, is unclear. We investigated the utility of three non-invasive muscle function tests, namely grip strength (GS), hang wire (HW) and four-limb hanging (FLH), in C57BL/6 mice fed chow (chow group, n = 48) or a high-fat diet (HFD group, n = 48) for 20 weeks. Muscle function tests were performed at 5, 10 and 20 weeks. After 10 and 20 weeks, HFD mice had significantly reduced GS (in newtons; mean ± SD: 10 weeks chow, 1.89 ± 0.1 and HFD, 1.79 ± 0.1; 20 weeks chow, 1.99 ± 0.1 and HFD, 1.75 ± 0.1), FLH [in seconds per gram body weight; median (interquartile range): 10 weeks chow, 2552 (1337-4964) and HFD, 1230 (749-1994); 20 weeks chow, 2048 (765-3864) and HFD, 1036 (717-1855)] and HW reaches [n; median (interquartile range): 10 weeks chow, 4 (2-5) and HFD, 2 (1-3); 20 weeks chow, 3 (1-5) and HFD, 1 (0-2)] and higher falls [n; median (interquartile range): 10 weeks chow, 0 (0-2) and HFD, 3 (1-7); 20 weeks chow, 1 (0-4) and HFD, 8 (5-10)]. Grip strength was reliable in both dietary groups [intraclass correlation coefficient (ICC) = 0.5-0.8; P < 0.05], whereas FLH showed good reliability in chow (ICC = 0.7; P < 0.05) but not in HFD mice after 10 weeks (ICC < 0.5). Our data demonstrate that non-invasive muscle function tests are valuable and reliable tools for assessment of muscle strength and

The effects of Momordica charantia on obesity and lipid profiles of mice fed a high-fat diet.

PubMed

Wang, Jun; Ryu, Ho Kyung

2015-10-01

The present study was conducted to investigate the effects of dried Momordica charantia aqueous extracts (MCA) and ethanol extracts (MCE) on obesity and lipid profiles in mice fed a high-fat diet. Forty two ICR mice were randomly divided into six groups. The normal group was fed a basal diet, and other groups were fed a 45% high-fat diet (HFD) for 7 weeks. The normal and HFD groups were also orally administered distilled water each day for 7 weeks. The remaining groups received Momordica charantia extract (0.5 or 1.0 g/kg/day MCA, and 0.5 or 1.0 g/kg/day MCE). In order to measure the anti-obesity and lipid profile improvement effects, body and visceral tissue weight, lipid profiles, plasma insulin levels, hepatic malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured. Both MCA and MCE significantly decreased body and visceral tissue weight relative to those of the HFD group (P < 0.05). Additionally high doses of MCE and MCA significantly reduced the plasmatic insulin levels compared to the HFD groups (P < 0.05) to concentrations comparable to those found in the normal group. MCA and MCE supplementation also significantly modulated the lipid profiles in plasma, liver, and feces compared to mice fed the HFD (P < 0.05). Furthermore MCA and MCE significantly increased hepatic SOD activity, and reduced MDA generation in the liver of the HFD mice (P < 0.05). Results from the present study suggest that Momordica charantia extracts have anti-obesity effects and the ability to modulate lipid prolife of mice fed a HFD by suppressing body weight gain, visceral tissue weight, plasma and hepatic lipid concentrations, and lipid peroxidation along with increasing lipid metabolism.

The effects of Momordica charantia on obesity and lipid profiles of mice fed a high-fat diet

PubMed Central

Wang, Jun

2015-01-01

BACKGROUND/OBJECTIVES The present study was conducted to investigate the effects of dried Momordica charantia aqueous extracts (MCA) and ethanol extracts (MCE) on obesity and lipid profiles in mice fed a high-fat diet. MATERIALS/METHODS Forty two ICR mice were randomly divided into six groups. The normal group was fed a basal diet, and other groups were fed a 45% high-fat diet (HFD) for 7 weeks. The normal and HFD groups were also orally administered distilled water each day for 7 weeks. The remaining groups received Momordica charantia extract (0.5 or 1.0 g/kg/day MCA, and 0.5 or 1.0 g/kg/day MCE). In order to measure the anti-obesity and lipid profile improvement effects, body and visceral tissue weight, lipid profiles, plasma insulin levels, hepatic malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity were measured. RESULTS Both MCA and MCE significantly decreased body and visceral tissue weight relative to those of the HFD group (P < 0.05). Additionally high doses of MCE and MCA significantly reduced the plasmatic insulin levels compared to the HFD groups (P < 0.05) to concentrations comparable to those found in the normal group. MCA and MCE supplementation also significantly modulated the lipid profiles in plasma, liver, and feces compared to mice fed the HFD (P < 0.05). Furthermore MCA and MCE significantly increased hepatic SOD activity, and reduced MDA generation in the liver of the HFD mice (P < 0.05). CONCLUSIONS Results from the present study suggest that Momordica charantia extracts have anti-obesity effects and the ability to modulate lipid prolife of mice fed a HFD by suppressing body weight gain, visceral tissue weight, plasma and hepatic lipid concentrations, and lipid peroxidation along with increasing lipid metabolism. PMID:26425278

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.

Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice.

PubMed

Newman, John C; Covarrubias, Anthony J; Zhao, Minghao; Yu, Xinxing; Gut, Philipp; Ng, Che-Ping; Huang, Yu; Haldar, Saptarsi; Verdin, Eric

2017-09-05

Ketogenic diets recapitulate certain metabolic aspects of dietary restriction such as reliance on fatty acid metabolism and production of ketone bodies. We investigated whether an isoprotein ketogenic diet (KD) might, like dietary restriction, affect longevity and healthspan in C57BL/6 male mice. We find that Cyclic KD, KD alternated weekly with the Control diet to prevent obesity, reduces midlife mortality but does not affect maximum lifespan. A non-ketogenic high-fat diet (HF) fed similarly may have an intermediate effect on mortality. Cyclic KD improves memory performance in old age, while modestly improving composite healthspan measures. Gene expression analysis identifies downregulation of insulin, protein synthesis, and fatty acid synthesis pathways as mechanisms common to KD and HF. However, upregulation of PPARα target genes is unique to KD, consistent across tissues, and preserved in old age. In all, we show that a non-obesogenic ketogenic diet improves survival, memory, and healthspan in aging mice. Published by Elsevier Inc.

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

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 ...

Deficiency of CB2 cannabinoid receptor in mice improves insulin sensitivity but increases food intake and obesity with age.

PubMed

Agudo, J; Martin, M; Roca, C; Molas, M; Bura, A S; Zimmer, A; Bosch, F; Maldonado, R

2010-12-01

The endocannabinoid system has a key role in energy storage and metabolic disorders. The endocannabinoid receptor 2 (CB2R), which was first detected in immune cells, is present in the main peripheral organs responsible for metabolic control. During obesity, CB2R is involved in the development of adipose tissue inflammation and fatty liver. We examined the long-term effects of CB2R deficiency in glucose metabolism. Mice deficient in CB2R (Cb2 ( -/- ) [also known as Cnr2]) were studied at different ages (2-12 months). Two-month-old Cb2 (-/-) and wild-type mice were treated with a selective CB2R antagonist or fed a high-fat diet. The lack of CB2R in Cb2 (-/-) mice led to greater increases in food intake and body weight with age than in Cb2 (+/+) mice. However, 12-month-old obese Cb2 (-/-) mice did not develop insulin resistance and showed enhanced insulin-stimulated glucose uptake in skeletal muscle. In agreement, adipose tissue hypertrophy was not associated with inflammation. Similarly, treatment of wild-type mice with CB2R antagonist resulted in improved insulin sensitivity. Moreover, when 2-month-old Cb2 (-/-) mice were fed a high-fat diet, reduced body weight gain and normal insulin sensitivity were observed. These results indicate that the lack of CB2R-mediated responses protected mice from both age-related and diet-induced insulin resistance, suggesting that these receptors may be a potential therapeutic target in obesity and insulin resistance.

Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE)

PubMed Central

Baba, Shahid P.; Hellmann, Jason; Srivastava, Sanjay; Bhatnagar, Aruni

2011-01-01

Diabetes results in enhanced chemical modification of proteins by advanced lipoxidation end products (ALEs) and advanced glycation end products (AGEs) precursors. These modifications have been linked to the development of several secondary diabetic complications. Our previous studies showed that aldose reductase (AR; AKR1B3) catalyzes the reduction of ALEs and AGEs precursors; however, the in vivo significance of this metabolic pathway during diabetes and obesity has not been fully assessed. Therefore we examined the role of AR in regulating ALEs and AGEs formation in murine models of diet-induced obesity and streptozotocin-induced diabetes. In comparison with wild-type (WT) and AR-null mice fed normal chow, mice fed a high-fat (HF) diet (42% kcal fat) showed increased accumulation of AGEs and protein–acrolein adducts in the plasma. AGEs and acrolein adducts were also increased in the epididymal fat of WT and AR-null mice fed a HF diet. Deletion of AR increased the accumulation of 4-hydroxy-trans-2-nonenal (HNE) protein adduct in the plasma and increased the expression of the AGE receptor (RAGE) in HF fed mice. No change in AGEs formation was observed in the kidneys of HF-fed mice. In comparison, renal tissue from AR-null mice treated with streptozotocin showed greater AGE accumulation than streptozotocin-treated WT mice. These data indicated that AR regulated the accumulation of lipid peroxidation derived aldehydes and AGEs under conditions of severe, but not mild, hyperglycemia and that deletion of AR increased RAGE-induction via mechanisms that were independent of AGEs accumulation. PMID:21276777

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

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.

Bardoxolone methyl prevents insulin resistance and the development of hepatic steatosis in mice fed a high-fat diet.

PubMed

Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Dinh, Chi H L; Wang, Hongqin; Cheng, Licai; Huang, Xu-Feng

2015-09-05

High-fat (HF) diet-induced obesity is a major risk factor for the development of insulin resistance and hepatic steatosis. We examined the hypothesis that bardoxolone methyl (BM) would prevent the development of insulin resistance and hepatic steatosis in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC), HF (40% fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Glucose metabolism was assessed using a glucose tolerance test (GTT) and insulin sensitivity test (IST). Signalling molecules involved in insulin resistance, inflammation, and lipid metabolism were examined in liver tissue via western blotting and RT-PCR. BM prevented HF diet-induced insulin resistance and alterations in the protein levels of protein tyrosine phosphatase 1B (PTP1B), forkhead box protein O1 (FOXO1) and BDNF, and expression of the insulin receptor (IR), IRS-1 and glucose-6-phosphatase (G6Pase) genes. Furthermore, BM prevented fat accumulation in the liver and decreases in the β-oxidation gene, peroxisomal acyl-coenzyme A oxidase 1 (ACOX) in mice fed a HF diet. In the livers of HF fed mice, BM administration prevented HF diet-induced macrophage infiltration, inflammation as indicated by reduced IL-6 and signal transducer and activator of transcription 3 (STAT3) protein levels and TNFα mRNA expression, and increased nuclear factor-like 2 (Nrf2) mRNA expression and nuclear protein levels. These findings suggest that BM prevents HF diet induced insulin resistance and the development of hepatic steatosis in mice fed a chronic HF diet through modulation of molecules involved in insulin signalling, lipid metabolism and inflammation in the liver. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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, ...

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

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.

Every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice.

PubMed

Xie, Kan; Neff, Frauke; Markert, Astrid; Rozman, Jan; Aguilar-Pimentel, Juan Antonio; Amarie, Oana Veronica; Becker, Lore; Brommage, Robert; Garrett, Lillian; Henzel, Kristin S; Hölter, Sabine M; Janik, Dirk; Lehmann, Isabelle; Moreth, Kristin; Pearson, Brandon L; Racz, Ildiko; Rathkolb, Birgit; Ryan, Devon P; Schröder, Susanne; Treise, Irina; Bekeredjian, Raffi; Busch, Dirk H; Graw, Jochen; Ehninger, Gerhard; Klingenspor, Martin; Klopstock, Thomas; Ollert, Markus; Sandholzer, Michael; Schmidt-Weber, Carsten; Weiergräber, Marco; Wolf, Eckhard; Wurst, Wolfgang; Zimmer, Andreas; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabě de Angelis, Martin; Ehninger, Dan

2017-07-24

Dietary restriction regimes extend lifespan in various animal models. Here we show that longevity in male C57BL/6J mice subjected to every-other-day feeding is associated with a delayed onset of neoplastic disease that naturally limits lifespan in these animals. We compare more than 200 phenotypes in over 20 tissues in aged animals fed with a lifelong every-other-day feeding or ad libitum access to food diet to determine whether molecular, cellular, physiological and histopathological aging features develop more slowly in every-other-day feeding mice than in controls. We also analyze the effects of every-other-day feeding on young mice on shorter-term every-other-day feeding or ad libitum to account for possible aging-independent restriction effects. Our large-scale analysis reveals overall only limited evidence for a retardation of the aging rate in every-other-day feeding mice. The data indicate that every-other-day feeding-induced longevity is sufficiently explained by delays in life-limiting neoplastic disorders and is not associated with a more general slowing of the aging process in mice.Dietary restriction can extend the life of various model organisms. Here, Xie et al. show that intermittent periods of fasting achieved through every-other-day feeding protect mice against neoplastic disease but do not broadly delay organismal aging in animals.

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.

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.

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

A Polyphenol-Rich Fraction Obtained from Table Grapes Decreases Adiposity, Insulin Resistance, and Markers of Inflammation and Impacts Gut Microbiota in High-Fat Fed Mice

PubMed Central

Collins, Brian; Hoffman, Jessie; Martinez, Kristina; Grace, Mary; Lila, Mary Ann; Cockrell, Chase; Nadimpalli, Anuradha; Chang, Eugene; Chuang, Chia-Chi; Zhong, Wei; Mackert, Jessica; Shen, Wan; Cooney, Paula; Hopkins, Robin; McIntosh, Michael

2016-01-01

The objective of this study was to determine if consuming an extractable or non-extractable fraction of table grapes reduced the metabolic consequences of consuming a high-fat, American-type diet. Male C57BL/6J mice were fed a low fat (LF) diet, a high fat (HF) diet, or a HF diet containing whole table grape powder (5% w/w), an extractable, polyphenol-rich (HF-EP) fraction, a non-extractable, polyphenol-poor (HF-NEP) fraction, or equal combinations of both fractions (HF-EP+NEP) from grape powder for 16 weeks. Mice fed the HF-EP and HF-EP+NEP diets had lower percentages of body fat and amounts of white adipose tissue (WAT) and improved glucose tolerance compared to the HF-fed controls. Mice fed the HF-EP+NEP diet had lower liver weights and triglyceride (TG) levels compared to the HF-fed controls. Mice fed the HF-EP+NEP diets had higher hepatic mRNA levels of hormone sensitive lipase and adipose TG lipase, and decreased expression of c-reactive protein compared to the HF-fed controls. In epididymal (visceral) WAT, the expression levels of several inflammatory genes were lower in mice fed the HF-EP and HF-EP+NEP diets compared to the HF-fed controls. Mice fed the HF diets had increased myeloperoxidase activity and impaired localization of the tight junction protein zonula occludens-1 in ileal mucosa compared to the HF-EP and HF-NEP diets. Several of these treatment effects were associated with alterations in gut bacterial community structure. Collectively, these data demonstrate that the polyphenol-rich, EP fraction from table grapes attenuated many of the adverse health consequences associated with consuming a HF diet. PMID:27133434

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.

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.

Anti-Inflammatory Properties of Brazilian Green Propolis Encapsulated in a γ-Cyclodextrin Complex in Mice Fed a Western-Type Diet.

PubMed

Rimbach, Gerald; Fischer, Alexandra; Schloesser, Anke; Jerz, Gerold; Ikuta, Naoko; Ishida, Yoshiyuki; Matsuzawa, Ryota; Matsugo, Seiichi; Huebbe, Patricia; Terao, Keiji

2017-05-26

Ageing is often accompanied by chronic inflammation. A fat- and sugar-rich Western-type diet (WTD) may accelerate the ageing phenotype. Cell culture studies have indicated that artepillin C-containing Brazilian green propolis exhibits anti-inflammatory properties. However, little is known regarding its anti-inflammatory potential in mouse liver in vivo. In this study, female C57BL/6NRj wild-type mice were fed a WTD, a WTD supplemented with Brazilian green propolis supercritical extract (GPSE) encapsulated in γ-cyclodextrin (γCD) or a WTD plus γCD for 10 weeks. GPSE-γCD did not affect the food intake, body weight or body composition of the mice. However, mRNA levels of the tumour necrosis factor α were significantly downregulated ( p < 0.05) in these mice compared to those in the WTD-fed controls. Furthermore, the gene expression levels of other pro-inflammatory markers, including serum amyloid P, were significantly ( p < 0.001) decreased following GPSE-γCD treatment. GPSE-γCD significantly induced hepatic ferritin gene expression ( p < 0.01), which may contribute to its anti-inflammatory properties. Conversely, GPSE-γCD did not affect the biomarkers of endogenous antioxidant defence, including catalase, glutathione peroxidase-4, paraoxonase-1, glutamate cysteine ligase and nuclear factor erythroid 2-related factor-2 (Nrf2). Overall, the present data suggest that dietary GPSE-γCD exhibits anti-inflammatory, but not antioxidant activity in mouse liver in vivo. Thus, GPSE-γCD has the potential to serve as a natural hepatoprotective bioactive compound for dietary-mediated strategies against chronic inflammation.

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

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.

Chronic exercise reduces hypothalamic transforming growth factor-β1 in middle-aged obese mice.

PubMed

Silva, Vagner R R; Katashima, Carlos K; Lenhare, Luciene; Silva, Carla G B; Morari, Joseane; Camargo, Rafael L; Velloso, Licio A; Saad, Mario A; da Silva, Adelino S R; Pauli, Jose Rodrigo; Ropelle, Eduardo Rochete

2017-08-28

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging.

Chronic exercise reduces hypothalamic transforming growth factor-β1 in middle-aged obese mice

PubMed Central

Silva, Vagner R. R.; Katashima, Carlos K.; Lenhare, Luciene; Silva, Carla G. B.; Morari, Joseane; Camargo, Rafael L.; Velloso, Licio A.; Saad, Mario A.; da Silva, Adelino S. R.; Pauli, Jose Rodrigo; Ropelle, Eduardo Rochete

2017-01-01

Obesity and aging are associated with hypothalamic inflammation, hyperphagia and abnormalities in the thermogenesis control. It has been demonstrated that the association between aging and obesity induces hypothalamic inflammation and metabolic disorders, at least in part, through the atypical hypothalamic transforming growth factor-β (TGF-β1). Physical exercise has been used to modulate several metabolic parameters. Thus, the aim of this study was to evaluate the impact of chronic exercise on TGF-β1 expression in the hypothalamus of Middle-Aged mice submitted to a one year of high-fat diet (HFD) treatment. We observed that long-term of HFD-feeding induced hypothalamic TGF-β1 accumulation, potentiated the hypothalamic inflammation, body weight gain and defective thermogenesis of Middle-Aged mice when compared to Middle-Aged animals fed on chow diet. As expected, chronic exercise induced negative energy balance, reduced food consumption and increasing the energy expenditure, which promotes body weight loss. Interestingly, exercise training reduced the TGF-β1 expression and IkB-α ser32 phosphorylation in the hypothalamus of Middle-Aged obese mice. Taken together our study demonstrated that chronic exercise suppressed the TGF-β1/IkB-α axis in the hypothalamus and improved the energy homeostasis in an animal model of obesity-associated to aging. PMID:28854149

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

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

Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness behavior.

PubMed

Townsend, Brigitte E; Chen, Yung-Ju; Jeffery, Elizabeth H; Johnson, Rodney W

2014-11-01

Aging is associated with oxidative stress and heightened inflammatory response to infection. Dietary interventions to reduce these changes are therefore desirable. Broccoli contains glucoraphanin, which is converted to sulforaphane (SFN) by plant myrosinase during cooking preparation or digestion. Sulforaphane increases antioxidant enzymes including NAD(P)H quinone oxidoreductase and heme oxygenase I and inhibits inflammatory cytokines. We hypothesized that dietary broccoli would support an antioxidant response in brain and periphery of aged mice and inhibit lipopolysaccharide (LPS)-induced inflammation and sickness. Young adult and aged mice were fed control or 10% broccoli diet for 28 days before an intraperitoneal LPS injection. Social interactions were assessed 2, 4, 8, and 24 hours after LPS, and mRNA was quantified in liver and brain at 24 hours. Dietary broccoli did not ameliorate LPS-induced decrease in social interactions in young or aged mice. Interleukin-1β (IL-1β) expression was unaffected by broccoli consumption but was induced by LPS in brain and liver of adult and aged mice. In addition, IL-1β was elevated in brain of aged mice without LPS. Broccoli consumption decreased age-elevated cytochrome b-245 β, an oxidative stress marker, and reduced glial activation markers in aged mice. Collectively, these data suggest that 10% broccoli diet provides a modest reduction in age-related oxidative stress and glial reactivity, but is insufficient to inhibit LPS-induced inflammation. Thus, it is likely that SFN would need to be provided in supplement form to control the inflammatory response to LPS. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Dietary broccoli mildly improves neuroinflammation in aged mice but does not reduce lipopolysaccharide-induced sickness behavior

PubMed Central

Townsend, Brigitte E.; Chen, Yung-Ju; Jeffery, Elizabeth H.; Johnson, Rodney W.

2015-01-01

Aging is associated with oxidative stress and heightened inflammatory response to infection. Dietary interventions to reduce these changes are therefore desirable. Broccoli contains glucoraphanin, which is converted to sulforaphane (SFN) by plant myrosinase during cooking preparation or digestion. SFN increases antioxidant enzymes including NAD(P)H quinone oxidoreductase (NQO1) and heme oxygenase I (HMOX1) and inhibits inflammatory cytokines. We hypothesized that dietary broccoli would support an antioxidant response in brain and periphery of aged mice and inhibit lipopolysaccharide-induced inflammation and sickness. Young adult and aged mice were fed control or 10% broccoli diet for 28 days prior to an intraperitoneal LPS injection. Social interactions were assessed 2, 4, 8, and 24 h following LPS, and mRNA quantified in liver and brain at 24 h. Dietary broccoli did not ameliorate LPS-induced decrease in social interactions in young or aged mice. Interleukin (IL)-1β expression was unaffected by broccoli consumption but was induced by LPS in brain and liver of adult and aged mice. Additionally, IL-1β was elevated in brain of aged mice without LPS. Broccoli consumption decreased age-elevated cytochrome b-245 β, an oxidative stress marker, and reduced glial activation markers in aged mice. Collectively, these data suggest that 10% broccoli diet provides a modest reduction in age-related oxidative stress and glial reactivity, but is insufficient to inhibit LPS-induced inflammation. Thus, it is likely that SFN would need to be provided in supplement form to control the inflammatory response to LPS. PMID:25439028

Protective Effects of Flax Seed (Linum Usitatissimum) Hydroalcoholic Extract on Fetus Brain in Aged and Young Mice.

PubMed

Kamali, Mahsa; Bahmanpour, Soghra

2016-05-01

One of the major problems of the aged women or older than 35 is getting pregnant in the late fertility life. Fertility rates begin to decline gradually at the age of 30, more so at 35, and markedly at 40. Even with fertility treatments such as in vitro fertilization, women have more difficulty in getting pregnant or may deliver abnormal fetus. The purpose of this study was to assess the effects of flax seed hydroalcoholic extract on the fetal brain of aged mice and its comparison with young mice. In this experimental study, 32 aged and 32 young mice were divided into 4 groups. Controls received no special treatment. The experimental mice groups, 3 weeks before mating, were fed with flax seed hydroalcoholic extract by oral gavages. After giving birth, the brains of the fetus were removed. Data analysis was performed by statistical test ANOVA using SPSS version 18 (P<0.05). The mean fetus brain weight of aged mother groups compared to the control group was increased significantly (P<0.05). This study showed that flax seed hydroalcoholic extract could improve fetal brain weights in the aged groups.

Bardoxolone methyl prevents the development and progression of cardiac and renal pathophysiologies in mice fed a high-fat diet.

PubMed

Camer, Danielle; Yu, Yinghua; Szabo, Alexander; Wang, Hongqin; Dinh, Chi H L; Huang, Xu-Feng

2016-01-05

Obesity caused by the consumption of a high-fat (HF) diet is a major risk factor for the development of associated complications, such as heart and kidney failure. A semi-synthetic triterpenoid, bardoxolone methyl (BM) was administrated to mice fed a HF diet for 21 weeks to determine if it would prevent the development of obesity-associated cardiac and renal pathophysiologies. Twelve week old male C57BL/6J mice were fed a lab chow (LC), HF (40% fat), or a HF diet supplemented with 10 mg/kg/day BM in drinking water. After 21 weeks, the left ventricles of hearts and cortex of kidneys of mice were collected for analysis. Histological analysis revealed that BM prevented HF diet-induced development of structural changes in the heart and kidneys. BM prevented HF diet-induced decreases in myocyte number in cardiac tissue, although this treatment also elevated cardiac endothelin signalling molecules. In the kidneys, BM administration prevented HF diet-induced renal corpuscle hypertrophy and attenuated endothelin signalling. Furthermore, in both the hearts and kidneys of mice fed a HF diet, BM administration prevented HF diet-induced increases in fat accumulation, macrophage infiltration and tumour necrosis factor alpha (TNFα) gene expression. These findings suggest that BM prevents HF diet-induced developments of cardiac and renal pathophysiologies in mice fed a chronic HF diet by preventing inflammation. Moreover, these results suggest that BM has the potential as a therapeutic for preventing obesity-induced cardiac and renal pathophysiologies. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Breast-feeding at 12 months of age and dietary habits among breast-fed and non-breast-fed infants.

PubMed

Lande, Britt; Andersen, Lene Frost; Veierød, Marit B; Baerug, Anne; Johansson, Lars; Trygg, Kerstin U; Bjørneboe, Gunn-Elin Aa

2004-06-01

To analyse factors associated with breast-feeding and use of sweetened drinks at 12 months, and to compare dietary habits among breast-fed and non-breast-fed infants. Data were collected by a semi-quantitative food-frequency questionnaire filled in by the parents. National dietary survey in Norway. In total, 1932 12-month-old infants were included. At 12 months, 36% of the infants were breast-fed. The odds of breast-feeding at this age were more than doubled both for mothers > or =35 years compared with mothers <25 years and for mothers in the highest educational group compared with mothers in the lowest. A negative association was found for maternal smoking, and the odds of breast-feeding were 40% lower for mothers who smoked than for non-smokers. Some dietary differences were observed between breast-fed and non-breast-fed infants apart from intake of milk. In particular, breast-fed infants had a significantly lower daily intake of sweetened drinks than non-breast-fed infants and a 16% lower mean daily intake of added sugars (P<0.001). Furthermore, breast-fed infants had 30% higher odds of not receiving sweetened drinks daily, compared with non-breast-fed infants. Maternal age, education and smoking status were important factors for breast-feeding at 12 months. Breast-fed infants had lower intakes of sweetened drinks and added sugars than non-breast-fed infants. From a public health perspective, continued promotion of breast-feeding is needed to reduce inequalities in breast-feeding. Moreover, prevention of high intakes of sweetened drinks and added sugars should start in infancy.

Reducing endoplasmic reticulum stress does not improve steatohepatitis in mice fed a methionine- and choline-deficient diet.

PubMed

Henkel, Anne S; Dewey, Amanda M; Anderson, Kristy A; Olivares, Shantel; Green, Richard M

2012-07-01

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of nonalcoholic steatohepatitis. The ER stress response is activated in the livers of mice fed a methionine- and choline-deficient (MCD) diet, yet the role of ER stress in the pathogenesis of MCD diet-induced steatohepatitis is unknown. Using chemical chaperones on hepatic steatosis and markers of inflammation and fibrosis in mice fed a MCD diet, we aim to determine the effects of reducing ER stress. C57BL/6J mice were fed a MCD diet with or without the ER chemical chaperones 4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) for 2 wk. TUDCA and PBA effectively attenuated the ER stress response in MCD diet-fed mice, as evidenced by reduced protein levels of phosphorylated eukaryotic initiation factor 2α and phosphorylated JNK and suppression of mRNA levels of CCAAT/enhancer binding protein homologous protein, glucose-regulated protein 78 kDa, and X-box binding protein 1. However, PBA and TUDCA did not decrease MCD diet-induced hepatic steatosis. MCD diet-induced hepatic inflammation, as evidenced by increased plasma alanine aminotransferase and induction of hepatic TNFα expression, was also not reduced by PBA or TUDCA. PBA and TUDCA did not attenuate MCD diet-induced upregulation of the fibrosis-associated genes tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9. ER chemical chaperones reduce MCD diet-induced ER stress, yet they do not improve MCD diet-induced hepatic steatosis, inflammation, or activation of genes associated with fibrosis. These data suggest that although the ER stress response is activated by the MCD diet, it does not have a primary role in the pathogenesis of MCD diet-induced steatohepatitis.

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.

Effects of Gliadin consumption on the Intestinal Microbiota and Metabolic Homeostasis in Mice Fed a High-fat Diet

PubMed Central

Zhang, Li; Andersen, Daniel; Roager, Henrik Munch; Bahl, Martin Iain; Hansen, Camilla Hartmann Friis; Danneskiold-Samsøe, Niels Banhos; Kristiansen, Karsten; Radulescu, Ilinca Daria; Sina, Christian; Frandsen, Henrik Lauritz; Hansen, Axel Kornerup; Brix, Susanne; Hellgren, Lars I.; Licht, Tine Rask

2017-01-01

Dietary gluten causes severe disorders like celiac disease in gluten-intolerant humans. However, currently understanding of its impact in tolerant individuals is limited. Our objective was to test whether gliadin, one of the detrimental parts of gluten, would impact the metabolic effects of an obesogenic diet. Mice were fed either a defined high-fat diet (HFD) containing 4% gliadin (n = 20), or a gliadin-free, isocaloric HFD (n = 20) for 23 weeks. Combined analysis of several parameters including insulin resistance, histology of liver and adipose tissue, intestinal microbiota in three gut compartments, gut barrier function, gene expression, urinary metabolites and immune profiles in intestinal, lymphoid, liver and adipose tissues was performed. Mice fed the gliadin-containing HFD displayed higher glycated hemoglobin and higher insulin resistance as evaluated by the homeostasis model assessment, more hepatic lipid accumulation and smaller adipocytes than mice fed the gliadin-free HFD. This was accompanied by alterations in the composition and activity of the gut microbiota, gut barrier function, urine metabolome, and immune phenotypes within liver and adipose tissue. Our results reveal that gliadin disturbs the intestinal environment and affects metabolic homeostasis in obese mice, suggesting a detrimental effect of gluten intake in gluten-tolerant subjects consuming a high-fat diet. PMID:28300220

Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent.

PubMed

Tetri, Laura H; Basaranoglu, Metin; Brunt, Elizabeth M; Yerian, Lisa M; Neuschwander-Tetri, Brent A

2008-11-01

The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1-16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-alpha and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation.

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.

Effects of dietary heme iron and exercise training on abdominal fat accumulation and lipid metabolism in high-fat diet-fed mice.

PubMed

Katsumura, Masanori; Takagi, Shoko; Oya, Hana; Tamura, Shohei; Saneyasu, Takaoki; Honda, Kazuhisa; Kamisoyama, Hiroshi

2017-08-01

Animal by-products can be recycled and used as sources of essential nutrients. Water-soluble heme iron (WSHI), a functional food additive for supplementing iron, is produced by processing animal blood. In this study, we investigated the effects of dietary supplementation of 3% WSHI and exercise training for 4 weeks on the accumulation of abdominal fat and lipid metabolism in mice fed high-fat diet. Exercise-trained mice had significantly less perirenal adipose tissue, whereas WSHI-fed mice tended to have less epididymal adipose tissue. In addition, total weight of abdominal adipose tissues was significantly decreased in the Exercise + WSHI group. Dietary WSHI significantly increased the messenger RNA (mRNA) levels of lipoprotein lipase and hormone-sensitive lipase. WSHI-fed mice also tended to show increased mRNA levels of adipose triglyceride lipase in their epididymal adipose tissue. Dietary WSHI also significantly decreased the mRNA levels of fatty acid oxidation-related enzymes in the liver, but did not influence levels in the Gastrocnemius muscle. Exercise training did not influence the mRNA levels of lipid metabolism-related enzymes in the epididymal adipose tissue, liver or the Gastrocnemius muscle. These findings suggest that the accumulation of abdominal fat can be efficiently decreased by the combination of dietary WSHI and exercise training in mice fed high-fat diet. © 2016 Japanese Society of Animal Science.

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.

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...

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.

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

The effect of calorie restriction on the presence of apoptotic ovarian cells in normal wild type mice and low-plasma-IGF-1 Laron dwarf mice

PubMed Central

2013-01-01

Background It is known that caloric restriction extends lifespan and can minimize age-related dysfunction of the reproductive system. We became interested in how caloric restriction influences apoptosis, which is a crucial process that maintains ovarian cell homeostasis. Methods We examined ovarian cells in: 2.5-year-old wild type mice on caloric restriction (CR) or fed ad libitum (AL) and Laron dwarf mice (GHR-KO) at the same ages on CR or fed AL. Apoptosis was assessed by histochemical analysis on paraffin sections of ovarian tissue. Results Morphological and histochemical analysis revealed that CR improved reproductive potential in 2.5-year-old WT littermates and GHR-KO female mice, as indicated by the increased number of ovarian follicles. The level of apoptosis in ovarian tissue was higher in WT mice on a CR diet compared with WT mice on the AL diet. In GHR-KO mice, the level of apoptosis in ovaries was similar for mice on CR and on AL diets and bigger than in WT mice on CR. Conclusions Morphological and histochemical analysis revealed a younger biological age of the ovaries in 2-year-old WT littermates and GHR-KO female mice on CR compared with animals fed AL. PMID:24063422

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

Rice bran enzymatic extract reduces atherosclerotic plaque development and steatosis in high-fat fed ApoE-/- mice.

PubMed

Perez-Ternero, Cristina; Claro, Carmen; Parrado, Juan; Herrera, Maria Dolores; Alvarez de Sotomayor, Maria

2017-05-01

Rice bran is a by-product of rice milling and is rich in bioactive molecules such as γ-oryzanol, phytosterols, and tocotrienols. The rice bran enzymatic extract (RBEE) previously showed vessel remodeling prevention and lipid-lowering, antioxidant, anti-inflammatory, and antiapoptotic activities. The aim of this study was to identify RBEE hypolipidemic mechanisms and to study the effects of RBEE on the progression of atherosclerosis disease and linked vascular dysfunction and liver steatosis in apolipoprotein E-knockout (ApoE-/-) mice fed low- or high-fat (LFD, HFD, respectively) and cholesterol diets. ApoE-/- mice were fed LFD (13% kcal) or HFD (42% kcal) supplemented or not supplemented with 1 or 5% RBEE (w/w) for 23 wk. Then, serum, aorta, liver, and feces were collected and flash frozen for further analysis. RBEE supplementation of HFD improved serum values by augmenting high-density lipoprotein cholesterol and preventing total cholesterol and aspartate aminotransferase increase. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity was attenuated (1 and 5% RBEE) and cholesterol excretion increased (5% RBEE). Diet supplementation with 5% RBEE reduced plaque development regardless of the diet. In HFD-fed mice, both doses of RBEE reduced lipid deposition and macrophage infiltration in the aortic sinus and downregulated intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. None of these effects was observed in mice fed LFD. Liver steatosis was reduced by RBEE supplementation of LFD (1% RBEE) and HFD (1 and 5% RBEE) and nuclear peroxisome proliferator-activated receptor-α expression upregulated in the HDF 5% RBEE group. Regular consumption of RBEE-supplemented HFD reduced plaque development and liver steatosis by decreasing inflammation and hyperlipidemia through an HMG-CoA reductase activity and lipid excretion-related mechanism. Copyright © 2016 Elsevier Inc. All rights reserved.

Dietary pomegranate extract and inulin affect gut microbiome differentially in mice fed an obesogenic diet.

PubMed

Zhang, Song; Yang, Jieping; Henning, Susanne M; Lee, Rupo; Hsu, Mark; Grojean, Emma; Pisegna, Rita; Ly, Austin; Heber, David; Li, Zhaoping

2017-12-01

Growing evidence suggests that dysbiosis of gut microbiota is associated with pathogenesis of a variety of human diseases. Using dietary intervention to shape the composition and metabolism of the gut microbiota is increasingly recognized. In the present study, we investigated the effects of polysaccharide inulin and polyphenol-rich pomegranate extract (PomX) alone or in combination on the cecal microbiota composition and function in a diet induced obesity mouse model. Male C57BL/6 mice were randomly divided into four experimental groups and consumed either high-fat/high-sucrose [HF/HS (32% energy from fat, 25% energy from sucrose, 17% energy from protein)] diet, HF/HS diet supplemented with PomX (0.25%), or inulin (9%) or PomX and inulin in combination for 4 weeks. In mice fed the PomX-diet the proportion of Turicibacteraceae and Ruminococcaceae was significantly increased compared to the control HF/HS diet. Supplementation with inulin alone and inulin + PomX combination significantly increased the proportion of Verrucomicrobiaceae (A. muciniphila) and decreased Clostridiaceae. Only mice fed the inulin diet experienced an increase in serum lipopolysaccharide (LPS) and monocyte chemoattractant protein 1 (MCP-1), which was reversed when feeding the inulin + PomX diet. Feeding the inulin + PomX diet was associated with a significant increase in Bifidobacteriaceae and Rikenellaceae, which may have contributed to the reduction of endotoxemia markers. Inulin supplementation showed lower species richness of gut microbiota compared to mice fed with HF/HS or HF/HS/PomX, and the reduction was reversed by the addition of PomX. Inulin alone and in combination with PomX had distinct microbial clusters determined by both weighted and unweighted UniFrac Beta-Diversity principle coordinate analysis. A total of 19 KEGG biological pathways were significantly regulated in the gut microbiota with PomX and inulin alone or combined treatment. Inulin significantly enhanced KEGG

Exercise Increases and Browns Muscle Lipid in High-Fat Diet-Fed Mice.

PubMed

Morton, Tiffany L; Galior, Kornelia; McGrath, Cody; Wu, Xin; Uzer, Gunes; Uzer, Guniz Bas; Sen, Buer; Xie, Zhihui; Tyson, David; Rubin, Janet; Styner, Maya

2016-01-01

Muscle lipid increases with high-fat feeding and diabetes. In trained athletes, increased muscle lipid is not associated with insulin resistance, a phenomenon known as the athlete's paradox. To understand if exercise altered the phenotype of muscle lipid, female C57BL/6 mice fed CTL or high-fat diet (HFD for 6 or 18 weeks) were further divided into sedentary or exercising groups (CTL-E or HFD-E) with voluntary access to running wheels for the last 6 weeks of experiments, running 6 h/night. Diet did not affect running time or distance. HFD mice weighed more than CTL after 18 weeks (p < 0.01). Quadriceps muscle TG was increased in running animals and in sedentary mice fed HFD for 18 weeks (p < 0.05). In exercised animals, markers of fat, Plin1, aP2, FSP27, and Fasn, were increased significantly in HFD groups. Ucp1 and Pgc1a, markers for brown fat, increased with exercise in the setting of high fat feeding. Fndc5, which encodes irisin, and CytC were sensitive to exercise regardless of diet. Plin5 was increased with HFD and unaffected by exercise; the respiratory exchange ratio was 15% lower in the 18-week HFD group compared with CTL (p < 0.001) and 10% lower in 18 weeks HFD-E compared with CTL-E (p < 0.001). Increased Ucp1 and Pgc1a in exercised muscle of running mice suggests that a beige/brown fat phenotype develops, which differs from the fat phenotype that induces insulin resistance in high fat feeding. This suggests that increased muscle lipid may develop a "brown" phenotype in the setting of endurance exercise training, a shift that is further promoted by HFD.

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

Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent

PubMed Central

Tetri, Laura H.; Basaranoglu, Metin; Brunt, Elizabeth M.; Yerian, Lisa M.; Neuschwander-Tetri, Brent A.

2008-01-01

The aims of this study were to determine whether combining features of a western lifestyle in mice with trans fats in a high-fat diet, high-fructose corn syrup in the water, and interventions designed to promote sedentary behavior would cause the hepatic histopathological and metabolic abnormalities that characterize nonalcoholic steatohepatitis (NASH). Male C57BL/6 mice fed ad libitum high-fat chow containing trans fats (partially hydrogenated vegetable oil) and relevant amounts of a high-fructose corn syrup (HFCS) equivalent for 1–16 wk were compared with mice fed standard chow or mice with trans fats or HFCS omitted. Cage racks were removed from western diet mice to promote sedentary behavior. By 16 wk, trans fat-fed mice became obese and developed severe hepatic steatosis with associated necroinflammatory changes. Plasma alanine aminotransferase levels increased, as did liver TNF-α and procollagen mRNA, indicating an inflammatory and profibrogenic response to injury. Glucose intolerance and impaired fasting glucose developed within 2 and 4 wk, respectively. Plasma insulin, resistin, and leptin levels increased in a profile similar to that seen in patients with NASH. The individual components of this diet contributed to the phenotype independently; isocaloric replacement of trans fats with lard established that trans fats played a major role in promoting hepatic steatosis and injury, whereas inclusion of HFCS promoted food consumption, obesity, and impaired insulin sensitivity. Combining risk factors for the metabolic syndrome by feeding mice trans fats and HFCS induced histological features of NASH in the context of a metabolic profile similar to patients with this disease. Because dietary trans fats promoted liver steatosis and injury, their role in the epidemic of NASH needs further evaluation. PMID:18772365

Probiotic Dahi containing Lactobacillus acidophilus and Bifidobacterium bifidum alleviates age-inflicted oxidative stress and improves expression of biomarkers of ageing in mice.

PubMed

Kaushal, Deepti; Kansal, Vinod K

2012-02-01

The potential benefiting effects of probiotic Dahi on age-inflicted accumulation of oxidation products, antioxidant enzymes and expression of biomarkers of ageing were evaluated in mice. Probiotic Dahi were prepared by co-culturing in buffalo milk (3% fat) Dahi bacteria (Lactococcus lactis ssp. cremoris NCDC-86 and Lactococcus lactis ssp. lactis biovar diacetylactis NCDC-60) along with selected strain of Lactobacillus acidophilus LaVK2 (La-Dahi) or combined L. acidophilus and Bifidobacterium bifidum BbVK3 (LaBb-Dahi). Four groups of 12 months old mice (6 each) were fed for 4 months supplements (5 g/day) of buffalo milk (3% fat), Dahi, La-Dahi and LaBb-Dahi, respectively, with basal diet. The activities of catalase (CAT) and glutathione peroxidase (GPx) declined and the contents of oxidation products, thiobarbituric acid reactive substances (TBARS) and protein carbonyls, increased in red blood corpuscles (RBCs), liver, kidney and heart tissues and superoxide dismutase (SOD) activity increased in RBCs and hepatic tissues during ageing of mice. Feeding ageing mice with La-Dahi or LaBb-Dahi increased CAT activity in all the four tissues, and GPx activity in RBCs and hepatic tissue, and a significant decline in TBARS in plasma, kidney and hepatic tissues and protein carbonyls in plasma. Feeding mice with probiotic Dahi also reversed age related decline in expression of biomarkers of ageing, peroxisome proliferators activated receptor-α, senescence marker protein-30 (SMP-30) and klotho in hepatic and kidney tissues. The present study suggests that probiotic Dahi containing selected strains of bacteria can be used as a potential nutraceutical intervention to combat oxidative stress and molecular alterations associated with ageing.

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.

Men and mice: Relating their ages.

PubMed

Dutta, Sulagna; Sengupta, Pallav

2016-05-01

Since the late 18th century, the murine model has been widely used in biomedical research (about 59% of total animals used) as it is compact, cost-effective, and easily available, conserving almost 99% of human genes and physiologically resembling humans. Despite the similarities, mice have a diminutive lifespan compared to humans. In this study, we found that one human year is equivalent to nine mice days, although this is not the case when comparing the lifespan of mice versus humans taking the entire life at the same time without considering each phase separately. Therefore, the precise correlation of age at every point in their lifespan must be determined. Determining the age relation between mice and humans is necessary for setting up experimental murine models more analogous in age to humans. Thus, more accuracy can be obtained in the research outcome for humans of a specific age group, although current outcomes are based on mice of an approximate age. To fill this gap between approximation and accuracy, this review article is the first to establish a precise relation between mice age and human age, following our previous article, which explained the relation in ages of laboratory rats with humans in detail. Copyright © 2015 Elsevier Inc. All rights reserved.

Lipoprotein(A) with An Intact Lysine Binding Site Protects the Retina From an Age-Related Macular Degeneration Phenotype in Mice (An American Ophthalmological Society Thesis)

PubMed Central

Handa, James T.; Tagami, Mizuki; Ebrahimi, Katayoon; Leibundgut, Gregor; Janiak, Anna; Witztum, Joseph L.; Tsimikas, Sotirios

2015-01-01

Purpose: To test the hypothesis that the accumulation of oxidized phospholipids (OxPL) in the macula is toxic to the retina unless neutralized by a variety of mechanisms, including binding by lipoprotein(a) [Lp(a)], which is composed of apolipoprotein(a) [apo(a)] and apolipoprotein B-100 (apoB). Methods: Human maculas and eyes from two Lp(a) transgenic murine models were subjected to morphologic, ultrastructural, and immunohistochemical analysis. “Wild-type Lp(a)” mice, which express human apoB-100 and apo(a) that contains oxidized phospholipid, and “mutant LBS− Lp(a)” mice with a defective apo(a) lysine binding site (LBS) for oxidized phospholipid binding, were fed a chow or high-fat diet for 2 to 12 months. Oxidized phospholipid–containing lipoproteins were detected by immunoreactivity to E06, a murine monoclonal antibody binding to the phosphocholine headgroup of oxidized, but not native, phospholipids. Results: Oxidized phospholipids, apo(a), and apoB accumulate in maculas, including drusen, of age-related macular degeneration (AMD) samples and age-matched controls. Lp(a) mice fed a high-fat diet developed age-related changes. However, mutant LBS− Lp(a) mice fed a high-fat diet developed retinal pigment epithelial cell degeneration and drusen. These changes were associated with increased OxPL, decreased antioxidant defenses, increased complement, and decreased complement regulators. Conclusions: Human maculas accumulate Lp(a) and OxPL. Mutant LBS− Lp(a) mice, lacking the ability to bind E06-detectable oxidized phospholipid, develop AMD-like changes. The ability of Lp(a) to bind E06-detectable OxPL may play a protective role in AMD. PMID:26538774

Glucagon-like peptide-2 treatment improves glucose dysmetabolism in mice fed a high-fat diet.

PubMed

Baldassano, Sara; Amato, Antonella; Caldara, Gaetano Felice; Mulè, Flavia

2016-12-01

Previous studies suggested that endogenous glucagon-like peptide 2 (GLP-2) is dispensable for the regulation of glucose homeostasis under normal conditions, while it can play a beneficial role in obesity conditions. The purpose of the present study was to investigate whether chronic treatment with Gly 2 -GLP-2, a stable analogue of GLP-2, can have an impact on glycaemic and lipid control in mice fed a high-fat diet (HFD), an animal model of human obesity and insulin resistance. HFD mice were treated once a day with Gly 2 -GLP-2 for 4 weeks. Body weight, food intake, fasting glucose, intraperitoneal glucose tolerance, insulin-induced glucose clearance, glucose-stimulated insulin secretion, β-cell mass, plasma lipid metabolic profile, and lipid deposition in the liver were examined. In untreated HFD mice, fasting glucose levels, glucose tolerance, glucose-stimulated plasma insulin and sensibility to exogenous insulin were deteriorating with time and β-cell mass increased. In Gly 2 -GLP-2-treated mice, we found significant increase in glucose tolerance and exogenous insulin sensitivity, reduction in glucose-stimulated plasma insulin and in the increase in β-cell mass in comparison with pair-aged HFD untreated animals. The chronic treatment with the peptide was not associated with remarkable improvements of dyslipidemia and it did not prevent liver fat accumulation and the presence of microvesicular steatosis. In conclusion, the results of the present study suggest, for the first time, that Gly 2 -GLP-2 may produce glucose metabolic benefits in mice with diet-induced obesity. The mechanisms underlying the beneficial impact of GLP-2 on glucose metabolism remain to be established.

Practical pathology of aging mice

PubMed Central

Pettan-Brewer, Christina; Treuting, Piper M.

2011-01-01

Old mice will have a subset of lesions as part of the progressive decline in organ function that defines aging. External and palpable lesions will be noted by the research, husbandry, or veterinary staff during testing, cage changing, or physical exams. While these readily observable lesions may cause alarm, not all cause undue distress or are life-threatening. In aging research, mice are maintained until near end of life that, depending on strain and genetic manipulation, can be upwards of 33 months. Aging research has unique welfare issues related to age-related decline, debilitation, fragility, and associated pain of chronic diseases. An effective aging research program includes the collaboration and education of the research, husbandry, and veterinary staff, and of the members of the institution animal care and use committee. This collaborative effort is critical to humanely maintaining older mice and preventing excessive censorship due to non-lethal diseases. Part of the educational process is becoming familiar with how old mice appear clinically, at necropsy and histopathologically. This baseline knowledge is important in making the determination of humane end points, defining health span, contributing causes of death and effects of interventions. The goal of this paper is to introduce investigators to age-associated diseases and lesion patterns in mice from clinical presentation to pathologic assessment. To do so, we present and illustrate the common clinical appearances, necropsy and histopathological lesions seen in subsets of the aging colonies maintained at the University of Washington. PMID:22953032

Assessment the levels of tartrate-resistant acid phosphatase (TRAP) on mice fed with eggshell calcium citrate malate.

PubMed

Yu, Yiding; Zhang, Mingdi; Lin, Songyi; Wang, Liyan; Liu, Jingbo; Jones, Gregory; Huang, Hsiang-Chi

2013-07-01

Optimized conditions were obtained by one-factor-at-a-time test (OFAT) and ternary quadratic regression orthogonal composite design (TQROCD) respectively. By pulse electric fields (PEF) technology, the process of eggshell calcium citrate malate (ESCCM), eggshell calcium citrate (ESCC) and eggshells calcium malate (ESCM) were comprehensive compared. The levels of tartrate-resistant acid phosphatase (TRAP) and the bioavailability on mice fed with eggshell calcium citrate malate (ESCCM) treated by pulsed electric field (PEF) were evaluated. Results showed that the rates of calcium dissolution of the different acids studied can be arranged as ESCCM (7.90 mg/mL)>ESCC (7.12 mg/mL)>ESCM (7.08 mg/mL) from highest to lowest rate of dissolution. At the same dose 133.0 mg kg(-1) d(-1), the levels of TRAP in the ESCCM treatment groups were significantly lower than those in ESCM and ESCC (P<0.05). Bone calcium content in the mice fed with ESCCM was generally higher than fed with ESCM and ESCC. Copyright © 2013 Elsevier B.V. All rights reserved.

Anti-obesity and anti-hyperglycemic effects of the dietary citrus limonoid nomilin in mice fed a high-fat diet.

PubMed

Ono, Eri; Inoue, Jun; Hashidume, Tsutomu; Shimizu, Makoto; Sato, Ryuichiro

2011-07-08

TGR5 is a member of the G protein-coupled receptor family and is activated by bile acids (BAs). TGR5 is thought to be a promising drug target for metabolic diseases because the activation of TGR5 prevents obesity and hyperglycemia in mice fed a high-fat diet (HFD). In the present study, we identified a naturally occurring limonoid, nomilin, as an activator of TGR5. Unlike BAs, nomilin did not exhibit the farnesoid X receptor ligand activity. Although the nomilin derivative obacunone was capable of activating TGR5, limonin (the most abundant limonoid in citrus seeds) was not a TGR5 activator. When male C57BL/6J mice fed a HFD for 9 weeks were further fed a HFD either alone or supplemented with 0.2%w/w nomilin for 77 days, nomilin-treated mice had lower body weight, serum glucose, serum insulin, and enhanced glucose tolerance. Our results suggest a novel biological function of nomilin as an agent having anti-obesity and anti-hyperglycemic effects that are likely to be mediated through the activation of TGR5. Copyright © 2011 Elsevier Inc. All rights reserved.

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.

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.

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

Differences in betaine-homocysteine methyltransferase expression, ER stress response and liver injury between alcohol-fed mice and rats

PubMed Central

Shinohara, Masao; Ji, Cheng; Kaplowitz, Neil

2009-01-01

Chronic ethanol infusion resulted in greater serum ALT elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperhomocysteinemia but no increase was seen in rats. Similarly, a high methionine low folate diet (HMLF) induced less steatosis, serum ALT increase, and hyperhomocysteinemia in rats than in mice. Western blot analysis of betaine homocysteine methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression which did not occur in mice. Nuclear NFκB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous homocysteine exposure. Mice fed ethanol i.g. exhibited an increase in GRP78 and IRE1 which was not seen in the rat and SREBP-1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol induced steatosis, ER stress and hyperhomocysteinemia and this correlates with induction of BHMT in rats. These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperhomocysteinemia, ER stress and liver injury. PMID:20069651

Lipid Emulsion Administered Intravenously or Orally Attenuates Triglyceride Accumulation and Expression of Inflammatory Markers in the Liver of Nonobese Mice Fed Parenteral Nutrition Formula123

PubMed Central

Ito, Kyoko; Hao, Lei; Wray, Amanda E.; Ross, A. Catharine

2013-01-01

The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4–5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 μg/g orally), LE (200 μL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy. PMID:23325918

Effect of a mitochondrial-targeted coenzyme Q analog on pancreatic β-cell function and energetics in high fat fed obese mice.

PubMed

Imai, Yumi; Fink, Brian D; Promes, Joseph A; Kulkarni, Chaitanya A; Kerns, Robert J; Sivitz, William I

2018-06-01

We recently reported that mitoquinone (mitoQ, 500 μmol/L) added to drinking water of C57BL/6J mice attenuated weight gain and reduced oxidative stress when administered to high-fat (HF) fed mice. Here, we examined the effects of mitoQ administered to HF fed mice on pancreatic islet morphology, dynamics of insulin secretion, and islet mitochondrial metabolism. C57BL/6J mice were fed HF for 130 days while we administered vehicle (cyclodextrin [CD]) or mitoQ added to the drinking water at up to 500 μmol/L. MitoQ-treated mice vs vehicle gained significantly less weight, expended significantly more energy as determined by indirect calorimetry, and trended to consume less (nonsignificant) food. As we and others reported before, mitoQ-treated mice drank less water but showed no difference in percent body fluid by nuclear magnetic resonance. Circulating insulin and glucose-stimulated insulin secretion by isolated islets were decreased in mitoQ-treated mice while insulin sensitivity (plasma insulin x glucose) was greater. Islet respiration as basal oxygen consumption (OCR), OCR directed at ATP synthesis, and maximal uncoupled OCR were also reduced in mitoQ-treated mice. Quantitative morphologic studies revealed that islet size was reduced in the mitoQ-treated mice while visual inspection of histochemically stained sections suggested that mitoQ reduced islet lipid peroxides. MitoQ markedly improved liver function as determined by plasma alanine aminotransferase. In summary, mitoQ treatment reduced the demand for insulin and reduced islet size, likely consequent to the action of mitoQ to mitigate weight gain and improve liver function. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Fibroblast Growth Factor 21 (Fgf21) Gene Expression Is Elevated in the Liver of Mice Fed a High-Carbohydrate Liquid Diet and Attenuated by a Lipid Emulsion but Is Not Upregulated in the Liver of Mice Fed a High-Fat Obesogenic Diet.

PubMed

Hao, Lei; Huang, Kuan-Hsun; Ito, Kyoko; Sae-Tan, Sudathip; Lambert, Joshua D; Ross, A Catharine

2016-02-01

Fibroblast growth factor 21 (FGF21) is a regulator of carbohydrate and lipid metabolism; however, the regulation of Fgf21 gene expression by diet remains incompletely understood. We investigated the effect of a high-carbohydrate (HC) liquid diet, with and without supplementation with a lipid emulsion (LE), and of a high-fat diet (HFD) compared with a low-fat diet (LFD) on the regulation of Fgf21 gene expression in the liver of intact mice. C57BL/6 male mice were fed standard feed pellets (SFPs), a purified HC liquid diet (adequate in calories and protein), or an HC liquid diet containing an LE at either 4% or 13.5% of energy for 5 wk (Expt. 1) or 1 wk (Expt. 2). In Expt. 3, mice were fed a purified LFD (∼10% fat) or HFD (∼60% fat) or were fed an HFD and given access to a running wheel for voluntary exercise for 16 wk. Fgf21 mRNA in liver and FGF21 protein in plasma were increased by 3.5- to 7-fold in HC mice compared with SFP mice (P < 0.001), whereas the LE dose-dependently attenuated the induction of Fgf21 expression (P < 0.05). After 16 wk, hepatic Fgf21 mRNA did not differ between LFD and HFD mice but was dramatically reduced in the HFD+exercise group to <20% of the level in the HFD group (P < 0.0001). In mice, hepatic Fgf21 expression was upregulated by 1 and 5 wk of feeding a lipogenic HC diet but not by 16 wk of feeding an obesogenic HFD, whereas the addition of fat as an LE to the HC formula significantly reduced Fgf21 gene expression and the plasma FGF21 protein concentration. Our results support a strong and reversible response of hepatic Fgf21 expression to shifts in dietary glucose intake. © 2016 American Society for Nutrition.

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.

Diet Replenishment for Ad-libitum–fed Mice Housed in Social Groups is Compatible with Shelf Life

PubMed Central

Huerkamp, Michael J; Dowdy, Minida R

2008-01-01

Regulatory guidelines and best practices in the care of research animals allow diets milled for laboratory animals to be used within 180 d of formulation but otherwise permit latitude and professional judgment in how and when feed is offered. As such, practices at some research institutions allow for the replenishment (‘topping up’) of fresh chow over that existing in the cage food hopper, rather than complete replacement of the diet on a regular basis. To determine the depletion rate of a pelleted diet as fed from a conventional overhead food hopper, the consumption of full hoppers of food was measured for breeding pairs of mice in production and gender-specific groups of weanlings and juvenile mice kept in ventilated cages at 71.9 ± 0.2 °F (approximately 22.6 °C) and 40% ± 5% relative humidity. Breeding pairs of mice depleted 97% of a 250-g ration within 44 d of offering and consumed diet at a rate of 4.7 ± 0.5 g per mouse daily. Gender-grouped weanling and juvenile mice housed 5 to 6 per cage exhausted more than 99% of a 500-g ration of diet in 24 d and consumed chow at a rate of 3.4 ± 0.3 g per animal daily. These findings suggest that breeding pairs and groups of mice kept 5 to 6 per cage deplete feed at such a rate that diets can be fed by using replenishment provided diet is offered within 5 mo of the milling date. PMID:18459713

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.

Chronic administration of Angelica sinensis polysaccharide effectively improves fatty liver and glucose homeostasis in high-fat diet-fed mice.

PubMed

Wang, Kaiping; Cao, Peng; Wang, Hanxiang; Tang, Zhuohong; Wang, Na; Wang, Jinglin; Zhang, Yu

2016-05-18

This study aimed to investigate the therapeutic effects of Angelica sinensis polysaccharide (ASP), an active component derived from a water extract of Angelica sinensis, in high-fat diet (HFD)-fed BALB/c mice. The potential mechanisms underlying the activity of this compound were also considered. Specifically, serum and hepatic biochemical parameters were evaluated, and key proteins involved in the lipid/glucose metabolism were analyzed. Long-term feeding with a HFD induced severe fatty liver and hyperglycemia. Histological examination clearly showed that ASP reduced lipid accumulation in the liver and attenuated hepatic steatosis in HFD-fed mice. In addition, ASP markedly alleviated serum and liver lipid disorders and fatty liver via the upregulation of PPARγ expression and the activation of adiponectin-SIRT1-AMPK signaling. Furthermore, ASP also significantly relieved severe oxidative stress, demonstrating that ASP might attenuate nonalcoholic fatty liver disease via a "two-hit" mechanism. In addition, ASP reduced blood glucose levels and ameliorated insulin resistance via the regulation of related metabolic enzymes and by activating the PI3K/Akt pathway in HFD-fed mice. Our findings revealed that ASP might be used as an alternative dietary supplement or health care product to ameliorate metabolic syndrome in populations that consistently consume HFDs.

Postprandial fatty acid uptake and adipocyte remodeling in angiotensin type 2 receptor-deficient mice fed a high-fat/high-fructose diet

PubMed Central

Noll, Christophe; Labbé, Sébastien M.; Pinard, Sandra; Shum, Michael; Bilodeau, Lyne; Chouinard, Lucie; Phoenix, Serge; Lecomte, Roger; Carpentier, André C.; Gallo-Payet, Nicole

2016-01-01

ABSTRACT The role of the angiotensin type-2 receptor in adipose physiology remains controversial. The aim of the present study was to demonstrate whether genetic angiotensin type-2 receptor-deficiency prevents or worsens metabolic and adipose tissue morphometric changes observed following a 6-week high-fat/high-fructose diet with injection of a small dose of streptozotocin. We compared tissue uptake of nonesterified fatty acid and dietary fatty acid in wild-type and angiotensin type-2 receptor-deficient mice by using the radiotracer 14(R,S)-[18F]-fluoro-6-thia-heptadecanoic acid in mice fed a standard or high-fat diet. Postprandial fatty acid uptake in the heart, liver, skeletal muscle, kidney and adipose tissue was increased in wild-type mice after a high-fat diet and in angiotensin type-2 receptor-deficient mice on both standard and high-fat diets. Compared to the wild-type mice, angiotensin type-2 receptor-deficient mice had a lower body weight, an increase in fasting blood glucose and a decrease in plasma insulin and leptin levels. Mice fed a high-fat diet exhibited increased adipocyte size that was prevented by angiotensin type-2 receptor-deficiency. Angiotensin type-2 receptor-deficiency abolished the early hypertrophic adipocyte remodeling induced by a high-fat diet. The small size of adipocytes in the angiotensin type-2 receptor-deficient mice reflects their inability to store lipids and explains the increase in fatty acid uptake in non-adipose tissues. In conclusion, a genetic deletion of the angiotensin type-2 receptor is associated with metabolic dysfunction of white adipose depots, and indicates that adipocyte remodeling occurs before the onset of insulin resistance in the high-fat fed mouse model. PMID:27144096

Aging Exacerbates Obesity-induced Cerebromicrovascular Rarefaction, Neurovascular Uncoupling, and Cognitive Decline in Mice

PubMed Central

Tucsek, Zsuzsanna; Toth, Peter; Tarantini, Stefano; Sosnowska, Danuta; Gautam, Tripti; Warrington, Junie P.; Giles, Cory B.; Wren, Jonathan D.; Koller, Akos; Ballabh, Praveen; Sonntag, William E.; Csiszar, Anna

2014-01-01

Epidemiological studies show that obesity has deleterious effects on the brain and cognitive function in the elderly population. However, the specific mechanisms through which aging and obesity interact to promote cognitive decline remain unclear. To test the hypothesis that aging exacerbates obesity-induced cerebromicrovascular impairment, we compared young (7 months) and aged (24 months) high-fat diet–fed obese C57BL/6 mice. We found that aging exacerbates the obesity-induced decline in microvascular density both in the hippocampus and in the cortex. The extent of hippocampal microvascular rarefaction and the extent of impairment of hippocampal-dependent cognitive function positively correlate. Aging exacerbates obesity-induced loss of pericyte coverage on cerebral microvessels and alters hippocampal angiogenic gene expression signature, which likely contributes to microvascular rarefaction. Aging also exacerbates obesity-induced oxidative stress and induction of NADPH oxidase and impairs cerebral blood flow responses to whisker stimulation. Collectively, obesity exerts deleterious cerebrovascular effects in aged mice, promoting cerebromicrovascular rarefaction and neurovascular uncoupling. The morphological and functional impairment of the cerebral microvasculature in association with increased blood–brain barrier disruption and neuroinflammation (Tucsek Z, Toth P, Sosnowsk D, et al. Obesity in aging exacerbates blood–brain barrier disruption, neuroinflammation and oxidative stress in the mouse hippocampus: effects on expression of genes involved in beta-amyloid generation and Alzheimer’s disease. J Gerontol Biol Med Sci. 2013. In press, PMID: 24269929) likely contribute to obesity-induced cognitive decline in aging. PMID:24895269

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.

Whey Protein Reduces Early Life Weight Gain in Mice Fed a High-Fat Diet

PubMed Central

Tranberg, Britt; Hellgren, Lars I.; Lykkesfeldt, Jens; Sejrsen, Kristen; Jeamet, Aymeric; Rune, Ida; Ellekilde, Merete; Nielsen, Dennis S.; Hansen, Axel Kornerup

2013-01-01

An increasing number of studies indicate that dairy products, including whey protein, alleviate several disorders of the metabolic syndrome. Here, we investigated the effects of whey protein isolate (whey) in mice fed a high-fat diet hypothesising that the metabolic effects of whey would be associated with changes in the gut microbiota composition. Five-week-old male C57BL/6 mice were fed a high-fat diet ad libitum for 14 weeks with the protein source being either whey or casein. Faeces were collected at week 0, 7, and 13 and the fecal microbiota was analysed by denaturing gradient gel electrophoresis analyses of PCR-derived 16S rRNA gene (V3-region) amplicons. At the end of the study, plasma samples were collected and assayed for glucose, insulin and lipids. Whey significantly reduced body weight gain during the first four weeks of the study compared with casein (P<0.001–0.05). Hereafter weight gain was similar resulting in a 15% lower final body weight in the whey group relative to casein (34.0±1.0 g vs. 40.2±1.3 g, P<0.001). Food intake was unaffected by protein source throughout the study period. Fasting insulin was lower in the whey group (P<0.01) and glucose clearance was improved after an oral glucose challenge (P<0.05). Plasma cholesterol was lowered by whey compared to casein (P<0.001). The composition of the fecal microbiota differed between high- and low-fat groups at 13 weeks (P<0.05) whereas no difference was seen between whey and casein. In conclusion, whey initially reduced weight gain in young C57BL/6 mice fed a high-fat diet compared to casein. Although the effect on weight gain ceased, whey alleviated glucose intolerance, improved insulin sensitivity and reduced plasma cholesterol. These findings could not be explained by changes in food intake or gut microbiota composition. Further studies are needed to clarify the mechanisms behind the metabolic effects of whey. PMID:23940754

Soy protein isolate inhibits hepatic tumor promotion in mice fed a high-fat liquid diet.

PubMed

Mercer, Kelly E; Pulliam, Casey F; Pedersen, Kim B; Hennings, Leah; Ronis, Martin Jj

2017-03-01

Alcoholic and nonalcoholic fatty liver diseases are risk factors for development of hepatocellular carcinoma, but the underlying mechanisms are poorly understood. On the other hand, ingestion of soy-containing diets may oppose the development of certain cancers. We previously reported that replacing casein with a soy protein isolate reduced tumor promotion in the livers of mice with alcoholic liver disease after feeding a high fat ethanol liquid diet following initiation with diethylnitrosamine. Feeding soy protein isolate inhibited processes that may contribute to tumor promotion including inflammation, sphingolipid signaling, and Wnt/β-catenin signaling. We have extended these studies to characterize liver tumor promotion in a model of nonalcoholic fatty liver disease produced by chronic feeding of high-fat liquid diets in the absence of ethanol. Mice treated with diethylnitrosamine on postnatal day 14 were fed a high-fat liquid diet made with casein or SPI as the sole protein source for 16 weeks in adulthood. Relative to mice fed normal chow, a high fat/casein diet led to increased tumor promotion, hepatocyte proliferation, steatosis, and inflammation. Replacing casein with soy protein isolate counteracted these effects. The high fat diets also resulted in a general increase in transcripts for Wnt/β-catenin pathway components, which may be an important mechanism, whereby hepatic tumorigenesis is promoted. However, soy protein isolate did not block Wnt signaling in this nonalcoholic fatty liver disease model. We conclude that replacing casein with soy protein isolate blocks development of steatosis, inflammation, and tumor promotion in diethylnitrosamine-treated mice fed high fat diets. Impact statement The impact of dietary components on cancer is a topic of great interest for both the general public and the scientific community. Liver cancer is currently the second leading form of cancer deaths worldwide. Our study has addressed the effect of the protein

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.

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

Metabolomic and genomic profiling of n-3 polyunsaturated fatty acid effects on muscle metabolism in mice fed a high fat diet

USDA-ARS?s Scientific Manuscript database

We previously reported that feeding mice high-fat (HF) diets enriched with eicosapentaenoic acid (EPA) decreased inflammation, adiposity and insulin resistance. In the current study, we used skeletal muscle from mice fed HF or HF-EPA for 11 weeks to further dissect mechanisms mediating EPA effects o...

Histochemical Examination on Periodontal Tissues of Klotho-Deficient Mice Fed With Phosphate-Insufficient Diet

PubMed Central

Hikone, Kumiko; Hasegawa, Tomoka; Tsuchiya, Erika; Hongo, Hiromi; Sasaki, Muneteru; Yamamoto, Tomomaya; Kudo, Ai; Oda, Kimimitsu; Haraguchi, Mai; de Freitas, Paulo Henrique Luiz; Li, Minqi; Iida, Junichiro; Amizuka, Norio

2017-01-01

To elucidate which of elevated serum concentration of inorganic phosphate (Pi) or disrupted signaling linked to αklotho/fibroblast growth factor 23 (FGF23) is a predominant regulator for senescence-related degeneration seen in αKlotho-deficient mice, we have examined histological alteration of the periodontal tissues in the mandibular interalveolar septum of αKlotho-deficient mice fed with Pi-insufficient diet. We prepared six groups of mice: wild-type, kl/kl, and αKlotho−/− mice with normal diet or low-Pi diet. As a consequence, kl/klnorPi and αKlotho−/−norPi mice showed the same abnormalities in periodontal tissues: intensely stained areas with hematoxylin in the interalveolar septum, dispersed localization of alkaline phosphatase–positive osteoblasts and tartrate-resistant acid phosphatase–reactive osteoclasts, and accumulation of dentin matrix protein 1 in the osteocytic lacunae. Although kl/kllowPi mice improved these histological abnormalities, αKlotho−/− lowPi mice failed to normalize those. Gene expression of αKlotho was shown to be increased in kl/kl lowPi specimens. It seems likely that histological abnormalities of kl/kl mice have been improved by the rescued expression of αKlotho, rather than low concentration of serum Pi. Thus, the histological malformation in periodontal tissues in αKlotho-deficient mice appears to be due to not only increased concentration of Pi but also disrupted αklotho/FGF23 signaling. PMID:28122194

Medium-chain triglycerides promote macrophage reverse cholesterol transport and improve atherosclerosis in ApoE-deficient mice fed a high-fat diet.

PubMed

Zhang, Xinsheng; Zhang, Yong; Liu, Yinghua; Wang, Jin; Xu, Qing; Yu, Xiaoming; Yang, Xueyan; Liu, Zhao; Xue, Changyong

2016-09-01

We previously observed that medium-chain triglycerides (MCTs) could reduce body fat mass and improve the metabolism of cholesterol. We hypothesized that MCTs can improve atherosclerosis by promoting the reverse cholesterol transport (RCT) process. Therefore, the objective of this study was to investigate the roles of MCTs in macrophage RCT and the progression of atherosclerosis. To test this hypothesis, 30 4-week-old ApoE-deficient (ApoE(-/-)) mice were randomly divided into 2 groups and fed a diet of 2% MCTs or long-chain triglycerides (LCTs) for 16 weeks. Ten age- and sex-matched C57BL/6J mice were fed a diet of 2% LCTs as the control. Macrophage-to-feces RCT was assessed in vivo by intraperitoneal injection of RAW 264.7 macrophages containing (3)H-labeled cholesterol, and atherosclerotic plaques were measured. The mRNA and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. There was a greater decrease in body fat mass, atherosclerotic plaques, and an improvement in serum lipid profiles. In addition, the MCT mice group showed an increase in (3)H-tracer in the feces and a decrease in the liver. Significantly higher levels of mRNA and protein expression of hepatic ATP-binding cassette transporter A1, ATP-binding cassette transporter G5, cholesterol 7α-hydroxylase, and intestinal ATP-binding cassette transporter G8, as well as lower levels of expression of intestinal Niemann-Pick C1-like 1, were found in the MCT group. These results suggest that MCTs could obviously promote macrophage RCT and improve atherosclerosis in ApoE(-/-) mice, indicating that MCTs have the potential to prevent cardiovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Proteomic analysis of mice fed methionine and choline deficient diet reveals marker proteins associated with steatohepatitis.

PubMed

Lee, Su Jin; Kang, Jeong Han; Iqbal, Waqas; Kwon, Oh-Shin

2015-01-01

The mechanisms underlying the progression of simple steatosis to steatohepatitis are yet to be elucidated. To identify the proteins involved in the development of liver tissue inflammation, we performed comparative proteomic analysis of non-alcoholic steatohepatitis (NASH). Mice fed a methionine and choline deficient diet (MCD) developed hepatic steatosis characterized by increased free fatty acid (FFA) and triglyceride levels as well as alpha-SMA. Two-dimensional proteomic analysis revealed that the change from the normal diet to the MCD diet affected the expressions of 50 proteins. The most-pronounced changes were observed in the expression of proteins involved in Met metabolism and oxidative stress, most of which were significantly downregulated in NASH model animals. Peroxiredoxin (Prx) is the most interesting among the modulated proteins identified in this study. In particular, cross-regulated Prx1 and Prx6 are likely to participate in cellular defense against the development of hepatitis. Thus, these Prx isoforms may be a useful new marker for early stage steatohepatitis. Moreover, curcumin treatment results in alleviation of the severity of hepatic inflammation in steatohepatitis. Notably, curcumin administration in MCD-fed mice dramatically reduced CYP2E1 as well as Prx1 expression, while upregulating Prx6 expression. These findings suggest that curcumin may have a protective role against MCD fed-induced oxidative stress.

Expression of aquaporins in the efferent ductules, sperm counts, and sperm motility in estrogen receptor-alpha deficient mice fed lab chow versus casein.

PubMed

Ruz, Ricardo; Gregory, Mary; Smith, Charles E; Cyr, Daniel G; Lubahn, Dennis B; Hess, Rex A; Hermo, Louis

2006-02-01

Estrogens play an important role in the male reproductive tract, and this is especially so for the efferent ductules, where alpha-estrogen receptors (ERalpha) have been localized. Mice deficient in ERalpha (alphaERKO mice) are infertile, and the effect appears to be due in part to retention of water at the level of the efferent ductules. In the present study, we examined the consequences of ERalpha deletion on the distribution of certain aquaporins (AQPs), water protein channels, in the efferent ductules and on sperm numbers and motility. In addition, the effects of feeding mice a regular lab chow diet, which contains phytoestrogens, known to affect male reproductive tract functions, and a casein diet, which lacks phytoestrogens, were also assessed. Light microscope immunolocalizations of AQP-1 and AQP-9 revealed dramatic reduction and patchier staining in alphaERKO mice with distal areas of the efferent ductules being more affected than proximal areas. No other changes in immunolocalizations were noted as a consequence of diet. Computer-assisted sperm analyses demonstrated a 62% reduction in cauda epididymal sperm/ml in alphaERKO mice fed lab chow, whereas 87% fewer sperm/ml were observed in alphaERKO mice fed casein, suggesting an enhanced role for sperm production and concentration in a diet containing phytoestrogens. All sperm motility parameters were altered to some degree in alphaERKO mice fed lab chow. Alterations in sperm motility parameters were also detected, but were less dramatic in alphaERKO mice fed casein. These data suggest that the decrease in AQP expression in the efferent ductules of alphaERKO mice contributes in part to water retention in this tissue, eventually leading to backflow of water into the testis, with subsequent decreases in sperm concentration and motility. The data also suggest that phytoestrogens, which are present in regular lab chow, can influence the male reproductive tract with and without the presence of ERalpha, promoting

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

Testosterone and Dihydrotestosterone Differentially Improve Cognition in Aged Female Mice

ERIC Educational Resources Information Center

Benice, Ted S.; Raber, Jacob

2009-01-01

Compared with age-matched male mice, female mice experience a more severe age-related cognitive decline (ACD). Since androgens are less abundant in aged female mice compared with aged male mice, androgen supplementation may enhance cognition in aged female mice. To test this, we assessed behavioral performance on a variety of tasks in 22- to…

Glucosamine enhances body weight gain and reduces insulin response in mice fed chow diet but mitigates obesity, insulin resistance and impaired glucose tolerance in mice high-fat diet.

PubMed

Hwang, Ji-Sun; Park, Ji-Won; Nam, Moon-Suk; Cho, Hyeongjin; Han, Inn-Oc

2015-03-01

This study investigated the potential of glucosamine (GlcN) to affect body weight gain and insulin sensitivity in mice normal and at risk for developing diabetes. Male C57BL/6J mice were fed either chow diet (CD) or a high fat diet (HFD) and the half of mice from CD and HFD provided with a solution of 10% (w/v) GlcN. Total cholesterol and nonesterified free fatty acid levels were determined. Glucose tolerance test and insulin tolerance test were performed. HepG2 human hepatoma cells or differentiated 3T3-L1 adipocytes were stimulated with insulin under normal (5 mM) or high glucose (25 mM) conditions. Effect of GlcN on 2-deoxyglucose (2-DG) uptake was determined. JNK and Akt phosphorylation and nucleocytoplasmic protein O-GlcNAcylation were assayed by Western blotting. GlcN administration stimulated body weight gain (6.58±0.82 g vs. 11.1±0.42 g), increased white adipose tissue fat mass (percentage of bodyweight, 3.7±0.32 g vs. 5.61±0.34 g), and impaired the insulin response in livers of mice fed CD. However, GlcN treatment in mice fed HFD led to reduction of body weight gain (18.02±0.66 g vs. 16.22±0.96 g) and liver weight (2.27±0.1 vs. 1.85±0.12 g). Furthermore, obesity-induced insulin resistance and impaired Akt insulin signaling in the liver were alleviated by GlcN administration. GlcN inhibited the insulin response under low (5 mM) glucose conditions, whereas it restored the insulin response for Akt phosphorylation under high (25 mM) glucose conditions in HepG2 and 3T3-L1 cells. Uptake of 2-DG increased upon GlcN treatment under 5 mM glucose compared to control, whereas insulin-stimulated 2-DG uptake decreased under 5 mM and increased under 25 mM glucose in differentiated 3T3-L1 cells. Our results show that GlcN increased body weight gain and reduced the insulin response for glucose maintenance when fed to normal CD mice, whereas it alleviated body weight gain and insulin resistance in HFD mice. Therefore, the current data support the integrative

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

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.

Effects of aging and dietary antler supplementation on the calcium-regulating hormones and bone status in ovariectomized SAMP8 mice.

PubMed

Chen, Chun-Chi; Liu, Mei-Hui; Wang, Ming-Fu; Chen, Cheng-Chin

2007-12-31

This study was conducted to investigate the effects of aging and long-term dietary antler supplementation on the calcium-regulating hormones and bone status in ovariectomized (Ovx) SAMP8 mice. The female SAMP8 mice were divided into four groups (in each group n = 6), Ovx or sham operated at the age of 2 months, and fed with 0.2% antler containing diet or control diet from the age of 2.5 months. The samples were collected at the age of 3, 6, 9, 12, and 15 months, respectively, for physicochemical analyses, biochemical analyses, and the determination of hormones by radioimmunoassay. The results showed that plasma calcium (Ca) concentrations were maintained in a narrow range in all groups throughout the whole experimental period. With aging and/or ovariectomy, plasma parathyroid hormone (PTH) and 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3) levels increased, and plasma phosphorus (P) and calcitonin (CT) levels decreased, and the femoral bone densities and Ca contents increased during the earlier stage, and then decreased gradually in all groups. Plasma PTH and 1,25-(OH)2-D3 levels in the Ovx mice were significantly higher than those in the intact mice, and plasma P concentrations, plasma CT levels, femoral bone densities, and femoral Ca contents in the Ovx mice were significantly lower than those in the intact mice. In addition, the decreases of plasma P levels, plasma CT levels, femoral bone densities, and femoral Ca contents, and the increases of plasma PTH levels were moderated by antler administration in both Ovx and intact mice. However, there was no effect of the dietary antler supplementation on the plasma 1,25-(OH)2-D3 levels in the female mice. It is concluded that prolonged dietary antler supplementation has important positive effects on bone loss with age and/ or ovarian function deficiency.

IL-8 signaling is up regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present

PubMed Central

Liu, Hui; French, Barbara A.; Nelson, Tyler J.; Li, Jun; Tillman, Brittany; French, Samuel W.

2015-01-01

Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up regulation in AH livers and a 26-fold up regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Over expression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH. PMID:26260904

IL-8 signaling is up-regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present.

PubMed

Liu, Hui; French, Barbara A; Nelson, Tyler J; Li, Jun; Tillman, Brittany; French, Samuel W

2015-10-01

Chemokines and their receptors are involved in oncogenesis and in tumor progression, invasion, and metastasis. Various chemokines also promote cell proliferation and resistance to apoptosis of stressed cells. The chemokine CXCL8, also known as interleukin-8 (IL-8), is a proinflammatory molecule that has functions within the tumor microenvironment. Deregulation of IL-8 signaling is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of IL-8 signaling by RNA sequencing (RNA-Seq) analyses. Real-time PCR analysis of CXCR2 further shows a 6-fold up-regulation in AH livers and a 26-fold up-regulation in the livers of DDC re-fed mice. IL-8 mRNA was also significantly up-regulated in AH livers and DDC re-fed mice livers. This indicates that CXCR2 and IL-8 may be crucial for liver MDB formation. MDB containing balloon hepatocytes in AH livers had increased intensity of staining of the cytoplasm for both CXCR2 and IL-8. Overexpression of IL-8 leads to an increase of the mitogen activated protein kinase (MAPK) cascade and exacerbates the inflammatory cycle. These observations constitute a demonstration of the altered regulation of IL-8 signaling in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by IL-8 signaling in AH. Copyright © 2015 Elsevier Inc. All rights reserved.

Gene expression profile of high-fat diet-fed C57BL/6J mice: in search of potential role of azelaic acid.

PubMed

Muthulakshmi, Shanmugam; Chakrabarti, Alok K; Mukherjee, Sanjay

2015-03-01

High-fat diet (HFD) elevates circulatory fatty acids and influences glucose and fat metabolism. Azelaic acid (AzA), a naturally occurring α,ω-dicarboxylic acid in wheat, rye, barley, oat seeds and sorghum, has been reported to exert antidiabetic effects in HFD-induced type 2 diabetes mellitus (T2DM) C57BL/6J mice. The present study was undertaken to identify the genes that are differentially modulated by treatment with AzA in HFD-fed mice. Mice were fed HFD for 10 weeks and subjected to intragastric administration of 80 mg/kg body weight (BW) of AzA daily along with HFD from 11 to 15 weeks. Lipid profile, adipokines and cytokines were examined in the plasma/liver of mice. Whole genome profiling was performed in the liver of mice using microarray and validated by qRT-PCR, Western blot and immunohistochemical analyses. HFD intake resulted in significantly elevated lipids (except high-density lipoproteins), resistin, tumour necrosis factor alpha and interleukin-6 with marked reduction in adiponectin. Administration of AzA to HFD-fed mice significantly restored the lipids, adipokines and cytokines to near normal. Transcript profiling revealed that HFD intake activated the genes involved in stress response, cell cycle regulation and apoptosis. Treatment with AzA caused increased expression of genes involved in reactive oxygen species (ROS) scavenging, receptor-mediated signalling, transcription, protein modification and insulin signal transduction. AzA activates insulin signal molecules leading to insulin sensitivity. The ability of AzA to modulate the expression of these genes supports the notion that AzA is a promising drug candidate for the treatment of insulin resistance associated with T2DM.

Altered regulation of miR-34a and miR-483-3p in alcoholic hepatitis and DDC fed mice.

PubMed

Liu, Hui; French, Barbara A; Li, Jun; Tillman, Brittany; French, Samuel W

2015-12-01

MicroRNAs are small noncoding RNAs that negatively regulate gene expression by binding to the untranslated regions of their target mRNAs. Deregulation of miRNAs is shown to play pivotal roles in tumorigenesis and progression. Mallory-Denk Bodies (MDBs) are prevalent in various liver diseases including alcoholic hepatitis (AH) and are formed in mice livers by feeding DDC. By comparing AH livers where MDBs had formed with normal livers, there were significant changes of miR-34a and miR-483-3p by RNA sequencing (RNA-Seq) analyses. Real-time PCR further shows a 3- and 6-fold upregulation (respectively) of miR-34a in the AH livers and in the livers of DDC re-fed mice, while miR-483-3p was significantly downregulated in AH and DDC re-fed mice livers. This indicates that miR-34a and miR-483-3p may be crucial for liver MDB formation. P53 mRNA was found to be significantly downregulated both in the AH livers and in the livers of DDC re-fed mice, indicating that the upregulation of miR-34a is permitted by the decrease of p53 in AH since miR-34a is a main target of p53. Overexpression of miR-34a leads to an increase of p53 targets such as p27, which inhibits the cell cycle leading to cell cycle arrest. Importantly, BRCA1 is a target gene of miR-483-3p by RNA-Seq analyses and the downregulation of miR-483-3p may be the mechanism for liver MDB formation since the BRCA1 signal was markedly upregulated in AH livers. These results constitute a demonstration of the altered regulation of miR-34a and miR-483-3p in the livers of AH and mice fed DDC where MDBs formed, providing further insight into the mechanism of MDB formation mediated by miR-34a and miR-483-3p in AH. Copyright © 2015 Elsevier Inc. All rights reserved.

Mechanisms for the anti-obesity actions of bofutsushosan in high-fat diet-fed obese mice.

PubMed

Kobayashi, Shinjiro; Kawasaki, Yuki; Takahashi, Tatsuo; Maeno, Hironori; Nomura, Masaaki

2017-01-01

The Kampo medicine bofutsushosan (BTS; Pulvis ledebouriellae compositae ; Fang Feng Tong Sheng San ) has been used as an anti-obesity treatment in overweight patients. In this study, we assessed the underlying physiological changes induced by BTS in obese mice maintained on a high-fat diet. Male ICR mice were fed a 60% kcal fat diet for 5 weeks starting at 4 weeks of age and then fed the same diet with administration of water (control) or aqueous BTS extract (1.0-2.0 g/kg) for 25 days. Body weight, wet weight of isolated white adipose tissue, and obesity-related serum parameters (glucose, lipids, leptin, adiponectin) were measured after treatment. The mRNA expression levels of leptin, adiponectin, and UCP1 in the adipose tissues were determined by quantitative real-time polymerase chain reaction after the first 5 days of treatment. Bofutsushosan (1.5-2.0 g/kg) significantly decreased total body weight and total wet weight of white adipose tissue isolated from subcutaneous (retroperitoneal) and visceral regions (epididymal, mesenteric, and perirenal). At 2.0 g/kg, BTS also decreased total fat mass, visceral fat mass, and ratio of fat mass to body weight as measured by computed tomography, and significantly decreased epididymal adipocyte size after 14 and 25 days' treatment. Twenty-five days' treatment lowered serum glucose, insulin, leptin, and triglycerides, and reduced homeostasis model assessment-insulin resistance. Alternatively, 2.0 g/kg BTS significantly increased mRNA levels of adiponectin, leptin, and UCP1 in interscapular brown adipose tissue but not epididymal white adipose tissue after 5 days' administration. In the early administration period, BTS increased mRNA expression levels of leptin, adiponectin, and UCP1 in brown adipose tissues. With longer administration, BTS improved insulin resistance, and subsequently reduced serum levels of leptin and triglyceride in parallel with decreased visceral white adipose tissue volume and adipocyte size.

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

Sexually dimorphic brain fatty acid composition in low and high fat diet-fed mice.

PubMed

Rodriguez-Navas, Carlos; Morselli, Eugenia; Clegg, Deborah J

2016-08-01

In this study, we analyzed the fatty acid profile of brains and plasma from male and female mice fed chow or a western-style high fat diet (WD) for 16 weeks to determine if males and females process fatty acids differently. Based on the differences in fatty acids observed in vivo, we performed in vitro experiments on N43 hypothalamic neuronal cells to begin to elucidate how the fatty acid milieu may impact brain inflammation. Using a comprehensive mass spectrometry fatty acid analysis, which includes a profile for 52 different fatty acid isomers, we assayed the plasma and brain fatty acid composition of age-matched male and female mice maintained on chow or a WD. Additionally, using the same techniques, we determined the fatty acid composition of N43 hypothalamic cells following exposure to palmitic and linoleic acid, alone or in combination. Our data demonstrate there is a sexual dimorphism in brain fatty acid content both following the consumption of the chow diet, as well as the WD, with males having an increased percentage of saturated fatty acids and reductions in ω6-polyunsaturated fatty acids when compared to females. Interestingly, we did not observe a sexual dimorphism in fatty acid content in the plasma of the same mice. Furthermore, exposure of N43 cells to the ω6-PUFA linoleic acid, which is higher in female brains when compared to males, reduces palmitic acid-induced inflammation. Our data suggest male and female brains, and not plasma, differ in their fatty acid profile. This is the first time, to our knowledge, lipidomic analyses has been used to directly test the hypothesis there is a sexual dimorphism in brain and plasma fatty acid composition following consumption of the chow diet, as well as following exposure to the WD.

Curcumin may impair iron status when fed to mice for six months

PubMed Central

Chin, Dawn; Huebbe, Patricia; Frank, Jan; Rimbach, Gerald; Pallauf, Kathrin

2014-01-01

Curcumin has been shown to have many potentially health beneficial properties in vitro and in animal models with clinical studies on the toxicity of curcumin reporting no major side effects. However, curcumin may chelate dietary trace elements and could thus potentially exert adverse effects. Here, we investigated the effects of a 6 month dietary supplementation with 0.2% curcumin on iron, zinc, and copper status in C57BL/6J mice. Compared to non-supplemented control mice, we observed a significant reduction in iron, but not zinc and copper stores, in the liver and the spleen, as well as strongly suppressed liver hepcidin and ferritin expression in the curcumin-supplemented mice. The expression of the iron-importing transport proteins divalent metal transporter 1 and transferrin receptor 1 was induced, while hepatic and splenic inflammatory markers were not affected in the curcumin-fed mice. The mRNA expression of other putative target genes of curcumin, including the nuclear factor (erythroid-derived 2)-like 2 and haem oxygenase 1 did not differ between the groups. Most of the published animal trials with curcumin-feeding have not reported adverse effects on iron status or the spleen. However, it is possible that long-term curcumin supplementation and a Western-type diet may aggravate iron deficiency. Therefore, our findings show that further studies are needed to evaluate the effect of curcumin supplementation on iron status. PMID:24634837

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

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.

Plasticity of lifelong calorie-restricted C57BL/6J mice in adapting to a medium-fat diet intervention at old age.

PubMed

Rusli, Fenni; Boekschoten, Mark V; Borelli, Vincenzo; Sun, Chen; Lute, Carolien; Menke, Aswin L; van den Heuvel, Joost; Salvioli, Stefano; Franceschi, Claudio; Müller, Michael; Steegenga, Wilma T

2018-04-01

Calorie restriction (CR) is a dietary regimen that supports healthy aging. In this study, we investigated the systemic and liver-specific responses caused by a diet switch to a medium-fat (MF) diet in 24-month-old lifelong, CR-exposed mice. This study aimed to increase the knowledge base on dietary alterations of gerontological relevance. Nine-week-old C57BL/6J mice were exposed either to a control, CR, or MF diet. At the age of 24 months, a subset of mice of the CR group was transferred to ad libitumMF feeding (CR-MF). The mice were sacrificed at the age of 28 months, and then, biochemical and molecular analyses were performed. Our results showed that, despite the long-term exposure to the CR regimen, mice in the CR-MF group displayed hyperphagia, rapid weight gain, and hepatic steatosis. However, no hepatic fibrosis/injury or alteration in CR-improved survival was observed in the diet switch group. The liver transcriptomic profile of CR-MF mice largely shifted to a profile similar to the MF-fed animals but leaving ~22% of the 1,578 differentially regulated genes between the CR and MF diet groups comparable with the expression of the lifelong CR group. Therefore, although the diet switch was performed at an old age, the CR-MF-exposed mice showed plasticity in coping with the challenge of a MF diet without developing severe liver pathologies. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation.

PubMed

Melo, Arine M; Benatti, Rafaela O; Ignacio-Souza, Leticia M; Okino, Caroline; Torsoni, Adriana S; Milanski, Marciane; Velloso, Licio A; Torsoni, Marcio Alberto

2014-05-01

The goal of this study was to determine the presence early of markers of endoplasmic reticulum stress (ERS) and insulin resistance in the offspring from dams fed HFD (HFD-O) or standard chow diet (SC-O) during pregnancy and lactation. To address this question, we evaluated the hypothalamic and hepatic tissues in recently weaned mice (d28) and the hypothalamus of newborn mice (d0) from dams fed HFD or SC during pregnancy and lactation. Body weight, adipose tissue mass, and food intake were more accentuated in HFD-O mice than in SC-O mice. In addition, intolerance to glucose and insulin was higher in HFD-O mice than in SC-O mice. Compared with SC-O mice, levels of hypothalamic IL1-β mRNA, NFκB protein, and p-JNK were increased in HFD-O mice. Furthermore, compared with SC-O mice, hypothalamic AKT phosphorylation after insulin challenge was reduced, while markers of ERS (p-PERK, p-eIF2α, XBP1s, GRP78, and GRP94) and p-AMPK were increased in the hypothalamic tissue of HFD-O at d28 but not at d0. These damages to hypothalamic signaling were accompanied by increased triglyceride deposits, activation of NFκB, p-JNK, p-PERK and p-eIF2α. These point out lactation period as maternal trigger for metabolic changes in the offspring. These changes may occur early and quietly contribute to obesity and associated pathologies in adulthood. Although in rodents the establishment of ARC neuronal projections occurs during the lactation period, in humans it occurs during the third trimester. Gestational diabetes and obesity in this period may contribute to impairment of energy homeostasis. Copyright © 2014 Elsevier Inc. All rights reserved.

Reduced mitochondrial mass and function add to age-related susceptibility toward diet-induced fatty liver in C57BL/6J mice.

PubMed

Lohr, Kerstin; Pachl, Fiona; Moghaddas Gholami, Amin; Geillinger, Kerstin E; Daniel, Hannelore; Kuster, Bernhard; Klingenspor, Martin

2016-10-01

Nonalcoholic fatty liver disease (NAFLD) is a major health burden in the aging society with an urging medical need for a better understanding of the underlying mechanisms. Mitochondrial fatty acid oxidation and mitochondrial-derived reactive oxygen species (ROS) are considered critical in the development of hepatic steatosis, the hallmark of NAFLD. Our study addressed in C57BL/6J mice the effect of high fat diet feeding and age on liver mitochondria at an early stage of NAFLD development. We therefore analyzed functional characteristics of hepatic mitochondria and associated alterations in the mitochondrial proteome in response to high fat feeding in adolescent, young adult, and middle-aged mice. Susceptibility to diet-induced obesity increased with age. Young adult and middle-aged mice developed fatty liver, but not adolescent mice. Fat accumulation was negatively correlated with an age-related reduction in mitochondrial mass and aggravated by a reduced capacity of fatty acid oxidation in high fat-fed mice. Irrespective of age, high fat diet increased ROS production in hepatic mitochondria associated with a balanced nuclear factor erythroid-derived 2 like 2 (NFE2L2) dependent antioxidative response, most likely triggered by reduced tethering of NFE2L2 to mitochondrial phosphoglycerate mutase 5. Age indirectly influenced mitochondrial function by reducing mitochondrial mass, thus exacerbating diet-induced fat accumulation. Therefore, consideration of age in metabolic studies must be emphasized. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

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.

[Anti-aging action of the total lactones of ginkgo on aging mice].

PubMed

Dong, Liu-yi; Fan, Li; Li, Gui-fang; Guo, Yan; Pan, Jian; Chen, Zhi-wu

2004-03-01

To investigate the effects of total lactones of ginkgo on aging by using D-galactose induced aging mice and natural aging mice. By using D-galactose induced aging mice, to detect the LF content in heart and liver, the Hyp content in liver, the MAO, GSH-Px activities and the NO content in cerebrum. The apoptosis of cerebral cell was determined by terminal deoxy-nucleotidyl transforase-mediated dUTP-digoxigenin nick end-labeling (Tunel) in natural aging mice. TLG was shown to increase the GSH-Px activities, reduce the NO content and decrease the MAO activity in cerebrum. Meanwhile, TLG was found to reduce the LF content in liver and heart and raise the Hyp content in liver. TLG was shown to inhibit apoptosis of cerebral cell and decrease the number of apoptotic cells in the brain. TLG possesses effect on antiaging via attenuating lipid peroxidation and NO and apoptosis of cerebral cells.

Exposure to excess insulin (glargine) induces type 2 diabetes mellitus in mice fed on a chow diet.

PubMed

Yang, Xuefeng; Mei, Shuang; Gu, Haihua; Guo, Huailan; Zha, Longying; Cai, Junwei; Li, Xuefeng; Liu, Zhenqi; Cao, Wenhong

2014-06-01

We have previously shown that insulin plays an important role in the nutrient-induced insulin resistance. In this study, we tested the hypothesis that chronic exposure to excess long-acting insulin (glargine) can cause typical type 2 diabetes mellitus (T2DM) in normal mice fed on a chow diet. C57BL/6 mice were treated with glargine once a day for 8 weeks, followed by evaluations of food intake, body weight, blood levels of glucose, insulin, lipids, and cytokines, insulin signaling, histology of pancreas, ectopic fat accumulation, oxidative stress level, and cholesterol content in mitochondria in tissues. Cholesterol content in mitochondria and its association with oxidative stress in cultured hepatocytes and β-cells were also examined. Results show that chronic exposure to glargine caused insulin resistance, hyperinsulinemia, and relative insulin deficiency (T2DM). Treatment with excess glargine led to loss of pancreatic islets, ectopic fat accumulation in liver, oxidative stress in liver and pancreas, and increased cholesterol content in mitochondria of liver and pancreas. Prolonged exposure of cultured primary hepatocytes and HIT-TI5 β-cells to insulin induced oxidative stress in a cholesterol synthesis-dependent manner. Together, our results show that chronic exposure to excess insulin can induce typical T2DM in normal mice fed on a chow diet. © 2014 The authors.

Proteins Differentially Expressed in the Pancreas of Hepatic Alcohol Dehydrogenase-Deficient Deer Mice Fed Ethanol For 3 Months.

PubMed

Bhopale, Kamlesh K; Amer, Samir M; Kaphalia, Lata; Soman, Kizhake V; Wiktorowicz, John E; Shakeel Ansari, Ghulam A; Kaphalia, Bhupendra S

2017-07-01

The aim of this study was to identify differentially expressed proteins in the pancreatic tissue of hepatic alcohol dehydrogenase-deficient deer mice fed ethanol to understand metabolic basis and mechanism of alcoholic chronic pancreatitis. Mice were fed liquid diet containing 3.5 g% ethanol daily for 3 months, and differentially expressed pancreatic proteins were identified by protein separation using 2-dimensional gel electrophoresis and identification by mass spectrometry. Nineteen differentially expressed proteins were identified by applying criteria established for protein identification in proteomics. An increased abundance was found for ribosome-binding protein 1, 60S ribosomal protein L31-like isoform 1, histone 4, calcium, and adenosine triphosphate (ATP) binding proteins and the proteins involved in antiapoptotic processes and endoplasmic reticulum function, stress, and/or homeostasis. Low abundance was found for endoA cytokeratin, 40S ribosomal protein SA, amylase 2b isoform precursor, serum albumin, and ATP synthase subunit β and the proteins involved in cell motility, structure, and conformation. Chronic ethanol feeding in alcohol dehydrogenase-deficient deer mice differentially expresses pancreatic functional and structural proteins, which can be used to develop biomarker(s) of alcoholic chronic pancreatitis, particularly amylase 2b precursor, and 60 kDa heat shock protein and those involved in ATP synthesis and blood osmotic pressure.

Loganin attenuates diabetic nephropathy in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of advanced glycation end products.

PubMed

Liu, Kai; Xu, Huiqin; Lv, Gaohong; Liu, Bin; Lee, Maxwell Kim Kit; Lu, Chunhong; Lv, Xing; Wu, Yunhao

2015-02-15

Diabetic nephropathy is the most common cause of end-stage renal disease in patients with diabetes. Advanced glycation end-products (AGEs) play a prominent role in the development of diabetic nephropathy. We herein evaluated the effects of loganin on diabetic nephropathy in vivo. We established a diabetic nephropathy model in C57BL/6J mice with diabetes induced by streptozotocin and fed with diets containing high level of AGEs. Diabetic symptoms, renal functions, and pathohistology of pancreas and kidney were evaluated. AGE-RAGE pathway and oxidative stress parameters were determined. The model mice exhibited characteristic symptoms of diabetes including weight loss, polydipsia, polyphagia, polyuria, elevated blood glucose levels and low serum insulin levels during the experiments. However, loganin at doses of 0.02 and 0.1g/kg effectively improved these diabetic symptoms. Loganin reduced kidney/body weight ratio, 24h urine protein levels, and serum levels of urea nitrogen and creatinine in diabetic mice to different degrees compared to positive controls. Moreover, loganin improved the histology of pancreas and kidney, and alleviated the structural alterations in endothelial cells, mesangial cells and podocytes in renal cortex. Finally, we found that loganin reduced AGE levels in serum and kidney and downregulated mRNA and protein expression of receptors for AGEs in kidney in diabetic mice. Loganin also reduced the levels of malondialdehyde and increased the levels of superoxide dismutase in serum and kidney. Loganin improved diabetic nephropathy in vivo associated with inhibition of AGE pathways, and could be a promising remedy for diabetic nephropathy. Copyright © 2015 Elsevier Inc. All rights reserved.

Peptide YY induces characteristic meal patterns of aged mice.

PubMed

Mogami, Sachiko; Yamada, Chihiro; Fujitsuka, Naoki; Hattori, Tomohisa

2017-11-01

Changes in eating behavior occur in the elderly due to oral and swallowing dysfunctions. We aimed to clarify the difference between basal meal patterns of young and aged mice in relation to appetite regulating hormones. Thirty two of young (7-week-old) and aged (23-25-month-old) C57BL/6 male mice were acclimated to a single housing and then transferred to a highly sensitive automated feeding monitoring device. Feeding behavior was monitored from the onset of the dark phase after habituation to the device. Plasma peptide YY (PYY) levels were assessed under the several feeding status or after treatment of PYY. PYY and its receptor (NPY Y2 receptor, Y2R) antagonist were intraperitoneally administered 30min before the monitoring. Although the basal 24-h meal amounts did not differ by age, the total meal time and frequency of minimum feeding activity (bout) were significantly increased and the average bout size and time per bout were significantly decreased in aged mice. PYY dynamics were abnormal and the temporal reduction in food intake by exogenous PYY was more prominent in aged mice than in young mice. PYY administration to young mice induced aged-like meal patterns, and Y2R antagonist administration to aged mice induced young-like meal patterns. Aged mice exhibited characteristic meal patterns probably due to PYY metabolism dysfunction and/or enhanced PYY-Y2R signaling, suggesting a novel method for assessing eating difficulties in aged animals and a potential target for the remedy. Copyright © 2017 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

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.

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

Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice.

PubMed

Yuan, Xidi; Klein, Dennis; Kerscher, Susanne; West, Brian L; Weis, Joachim; Katona, Istvan; Martini, Rudolf

2018-05-09

Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age-related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with α-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c-FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ∼70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly. SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging

Identification of a sustainable two-plant diet that effectively prevents age-related metabolic syndrome and extends lifespan in aged mice.

PubMed

Li, Xiang-Yong; Liu, Ying-Hua; Wang, Bin; Chen, Chih-Yu; Zhang, Hong-Man; Kang, Jing X

2018-01-01

The current system of food production is linked to both the increasing prevalence of chronic disease and the deterioration of the environment, and thereby calls for novel ways of producing nutritious foods in a sustainable manner. In the "longevity village" of Bama, China, we have identified two plant foods, hemp seed and bitter vegetable (Sonchus oleraceus), that are commonly consumed by its residents and grow abundantly in unfarmed land without fertilizers or pesticides. Here, we show that a diet composed of these two foods (the "HB diet") provides a sufficient variety of nutrients and confers significant health benefits. Aged mice allowed ad libitum access to the HB diet not only had longer life spans and improved cognitive function but were also protected against age-related metabolic syndrome, fatty liver, gut dysbiosis and chronic inflammation compared to aged mice fed a control Western diet. Furthermore, longevity-related genes (including 5'adenosine monophosphate-activated protein kinase, sirtuin 1, nuclear respiratory factor 1 and forkhead box O3) were significantly up-regulated, while aging-related genes (including mammalian target of rapamycin and nuclear factor kappa B) were down-regulated. These results demonstrate that the HB diet is capable of promoting health and longevity, and present a sustainable source of healthy foods that can help control the prevalence of chronic diseases and reduce agricultural impact on the environment. Copyright © 2017 Elsevier Inc. All rights reserved.

Vitamin D supplementation of initially vitamin D-deficient mice diminishes lung inflammation with limited effects on pulmonary epithelial integrity.

PubMed

Gorman, Shelley; Buckley, Alysia G; Ling, Kak-Ming; Berry, Luke J; Fear, Vanessa S; Stick, Stephen M; Larcombe, Alexander N; Kicic, Anthony; Hart, Prue H

2017-08-01

In disease settings, vitamin D may be important for maintaining optimal lung epithelial integrity and suppressing inflammation, but less is known of its effects prior to disease onset. Female BALB/c dams were fed a vitamin D 3 -supplemented (2280 IU/kg, VitD + ) or nonsupplemented (0 IU/kg, VitD - ) diet from 3 weeks of age, and mated at 8 weeks of age. Male offspring were fed the same diet as their mother. Some offspring initially fed the VitD - diet were switched to a VitD + diet from 8 weeks of age (VitD -/+ ). At 12 weeks of age, signs of low-level inflammation were observed in the bronchoalveolar lavage fluid (BALF) of VitD - mice (more macrophages and neutrophils), which were suppressed by subsequent supplementation with vitamin D 3 There was no difference in the level of expression of the tight junction proteins occludin or claudin-1 in lung epithelial cells of VitD + mice compared to VitD - mice; however, claudin-1 levels were reduced when initially vitamin D-deficient mice were fed the vitamin D 3 -containing diet (VitD -/+ ). Reduced total IgM levels were detected in BALF and serum of VitD -/+ mice compared to VitD + mice. Lung mRNA levels of the vitamin D receptor (VDR) were greatest in VitD -/+ mice. Total IgG levels in BALF were greater in mice fed the vitamin D 3 -containing diet, which may be explained by increased activation of B cells in airway-draining lymph nodes. These findings suggest that supplementation of initially vitamin D-deficient mice with vitamin D 3 suppresses signs of lung inflammation but has limited effects on the epithelial integrity of the lungs. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

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

Restricting feeding to the active phase in middle-aged mice attenuates adverse metabolic effects of a high-fat diet.

PubMed

Duncan, M J; Smith, J T; Narbaiza, J; Mueez, F; Bustle, L B; Qureshi, S; Fieseler, C; Legan, S J

2016-12-01

Time-restricted feeding ameliorates the deleterious effects of a high-fat diet on body weight and metabolism in young adult mice. Because obesity is highly prevalent in the middle-aged population, this study tested the hypothesis that time-restricted feeding alleviates the adverse effects of a high-fat diet in male middle-aged (12months) mice. C57BL6/J mice were fed one of three diets for 21-25weeks: 1) high-fat diet (60% total calories from fat) ad-libitum (HFD-AL), 2) HFD, time-restricted feeding (HFD-TRF), and 3) low-fat diet (10% total calories from fat) ad-libitum (LFD-AL) (n=15 each). HFD-TRF mice only had food access for 8h/day during their active period. HFD-TRF mice gained significantly less weight than HFD-AL mice (~20% vs 55% of initial weight, respectively). Caloric intake differed between these groups only during the first 8weeks and accounted for most but not all of their body weight difference during this time. TRF of a HFD lowered glucose tolerance in terms of incremental area under the curve (iAUC) (p<0.02) to that of LFD-AL mice. TRF of a HFD lowered liver weight (p<0.0001), but not retroperitoneal or epididymal fat pad weight, to that of LFD-AL mice. Neither HFD-AL nor HFD-TRF had any effect on performance in the novel object recognition or object location memory tests. Circulating corticosterone levels either before or after restraint stress were not affected by diet. In conclusion, TRF without caloric restriction is an effective strategy in middle-aged mice for alleviating the negative effects of a HFD on body weight, liver weight, and glucose tolerance. Copyright © 2016 Elsevier Inc. All rights reserved.

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

Regular Exercise Reduces Endothelial Cortical Stiffness in Western Diet-Fed Female Mice.

PubMed

Padilla, Jaume; Ramirez-Perez, Francisco I; Habibi, Javad; Bostick, Brian; Aroor, Annayya R; Hayden, Melvin R; Jia, Guanghong; Garro, Mona; DeMarco, Vincent G; Manrique, Camila; Booth, Frank W; Martinez-Lemus, Luis A; Sowers, James R

2016-11-01

We recently showed that Western diet-induced obesity and insulin resistance promotes endothelial cortical stiffness in young female mice. Herein, we tested the hypothesis that regular aerobic exercise would attenuate the development of endothelial and whole artery stiffness in female Western diet-fed mice. Four-week-old C57BL/6 mice were randomized into sedentary (ie, caged confined, n=6) or regular exercise (ie, access to running wheels, n=7) conditions for 16 weeks. Exercise training improved glucose tolerance in the absence of changes in body weight and body composition. Compared with sedentary mice, exercise-trained mice exhibited reduced endothelial cortical stiffness in aortic explants (sedentary 11.9±1.7 kPa versus exercise 5.5±1.0 kPa; P<0.05), as assessed by atomic force microscopy. This effect of exercise was not accompanied by changes in aortic pulse wave velocity (P>0.05), an in vivo measure of aortic stiffness. In comparison, exercise reduced femoral artery stiffness in isolated pressurized arteries and led to an increase in femoral internal artery diameter and wall cross-sectional area (P<0.05), indicative of outward hypertrophic remodeling. These effects of exercise were associated with an increase in femoral artery elastin content and increased number of fenestrae in the internal elastic lamina (P<0.05). Collectively, these data demonstrate for the first time that the aortic endothelium is highly plastic and, thus, amenable to reductions in stiffness with regular aerobic exercise in the absence of changes in in vivo whole aortic stiffness. Comparatively, the same level of exercise caused destiffening effects in peripheral muscular arteries, such as the femoral artery, that perfuse the working limbs. © 2016 American Heart Association, Inc.

Plantago lanceolata L. leaves prevent obesity in C57BL/6 J mice fed a high-fat diet.

PubMed

Yoshida, Taiji; Rikimaru, Kazuhiro; Sakai, Miho; Nishibe, Sansei; Fujikawa, Takahiko; Tamura, Yoshifumi

2013-01-01

The highly abundant and widely dispersed plant Plantago lanceolata L. (narrow leaf or English plantain) has been used for culinary and medicinal purposes since ancient times. Here, we investigated the anti-obesity effects of P. lanceolata leaf powder (shortly PL) when fed to male C57BL/6 J mice. Addition of PL to a high-fat diet did not affect food intake but significantly reduced food efficiency, suppressed body weight gain and visceral fat accumulation, and reduced serum free-fatty acid and glucose levels. PL-fed mice exhibited marked increases in HSL, Adrd3 and Cpt2 mRNA levels, and significant decreases in Fas transcripts in epididymal white adipose tissue (WAT). These findings suggest that dietary PL exerts anti-obesity effects by stimulating metabolism throughout visceral fat tissue by activating lipolysis, accelerating fatty acid β-oxidation and suppressing fatty acid synthase in WAT. To our knowledge, this is the first demonstration of anti-obesity substances derived from a Plantago species.

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).

Depletion of suppressor T cells by 2'-deoxyguanosine abrogates tolerance in mice fed ovalbumin and permits the induction of intestinal delayed-type hypersensitivity.

PubMed Central

Mowat, A M

1986-01-01

We have re-examined the role of suppressor T cells (Ts) in regulating immune responses to fed proteins by investigating the effect of 2'-deoxyguanosine (dGuo) on systemic and intestinal immunity in mice fed ovalbumin (OVA). Administration of dGuo for 10 days abrogated the suppression of systemic delayed-type hypersensitivity (DTH) and antibody responses normally found after feeding OVA, and also prevented the generation of OVA-specific Ts. In parallel, mice given dGuo and fed OVA developed sensitization to OVA in the gut-associated lymphoid tissues (GALT) after oral challenge with OVA and had increased intraepithelial lymphocyte (IEL) counts and crypt cell production rates (CCPR) in the jejunal mucosa, indicating the presence of a local DTH response. These findings confirm the importance of Ts in preventing hypersensitivity to dietary protein antigens and suggest that enteropathies associated with food hypersensitivity are due to a defect in Ts activity. PMID:2940171

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

Effects of Enzymatically Synthesized Glycogen and Exercise on Abdominal Fat Accumulation in High-Fat Diet-Fed Mice.

PubMed

Tamura, Shohei; Honda, Kazuhisa; Morinaga, Ryoji; Saneyasu, Takaoki; Kamisoyama, Hiroshi

2017-01-01

The combination of diet and exercise is the first choice for the treatment of obesity and metabolic syndrome. We previously reported that enzymatically synthesized glycogen (ESG) suppresses abdominal fat accumulation in obese rats. However, the effect of the combination of ESG and exercise on abdominal fat accumulation has not yet been investigated. Our goal in this study was therefore to evaluate the effects of dietary ESG and its combination with exercise on abdominal fat accumulation in high-fat diet (HFD)-fed mice. Male ICR mice were assigned to four groups: HFD, HFD containing 20% ESG, HFD with exercise, HFD containing 20% ESG with exercise. Treadmill exercise was performed for 3 wk (25 m/min, 30 min/d, 3 d/wk) after 5-d adaption to running at that speed. Both ESG and exercise significantly reduced the weights of abdominal adipose tissues. In addition, the combination of ESG and exercise significantly suppressed abdominal fat accumulation, suggesting that ESG and exercise showed an additive effect. Exercise significantly increased the mRNA levels of lipid metabolism-related genes such as lipoprotein lipase, peroxisome proliferator-activated receptor delta; factor-delta (PPARδ), carnitin palmitoyltransferase b, adipose triglyceride lipase (ATGL), and uncoupling protein-3 in the gastrocnemius muscle. On the other hand, dietary ESG significantly decreased the mRNA levels of PPARδ and ATGL in the gastrocnemius muscle. These results suggest that the combined treatment of ESG and exercise effectively suppresses abdominal fat accumulation in HFD-fed mice by different mechanisms.

Daumone fed late in life improves survival and reduces hepatic inflammation and fibrosis in mice.

PubMed

Park, Jong Hee; Chung, Hae Young; Kim, Minkyu; Lee, Jung Hwa; Jung, Mankil; Ha, Hunjoo

2014-08-01

The liver is one of the most susceptible organs to aging, and hepatic inflammation and fibrosis increase with age. Chronic inflammation has been proposed as the major molecular mechanism underlying aging and age-related diseases, whereas calorie restriction has been shown to be the most effective in extending mammalian lifespan and to have anti-aging effects through its anti-inflammatory action. Thus, it is necessary to develop effective calorie restriction mimetics. Daumone [(2)-(6R)-(3,5-dihydroxy-6-methyltetrahydropyran-2-yloxy)heptanoic acid], a pheromone secreted by Caenorhabditis elegans, forces them to enter the dauer stage when facing inadequate conditions. Because Caenorhabditis elegans live longer during the dauer stage under energy deprivation, it was hypothesized that daumone may improve survival in mammals by mimicking calorie restriction. Daumone (2 mg kg(-1) day(-1) ) was administered orally for 5 months to 24-month-old male C57BL/6J mice. Daumone was found to reduce the risk of death by 48% compared with age-matched control mice, and the increased plasma insulin normally presented in old mice was significantly reduced by daumone. The increased hepatic hypertrophy, senescence-associated β-galactosidase activity, insulin resistance, lipid accumulation, inflammation, oxidative stress, and fibrosis in old mice were significantly attenuated by daumone. From a mechanistic view, daumone reduced the phosphorylation of the IκBα and upregulation of Rela and Nfkbia mRNA in the livers of old mice. The anti-inflammatory effect of daumone was confirmed in lipopolysaccharide-induced liver injury model. Oral administration of daumone improves survival in mice and delivers anti-aging effects to the aged liver by modulating chronic inflammation, indicating that daumone could be developed as an anti-aging compound. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Dietary Tocotrienol/γ-Cyclodextrin Complex Increases Mitochondrial Membrane Potential and ATP Concentrations in the Brains of Aged Mice

PubMed Central

Schloesser, Anke; Esatbeyoglu, Tuba; Piegholdt, Stefanie; Dose, Janina; Ikuta, Naoko; Okamoto, Hinako; Ishida, Yoshiyuki; Terao, Keiji; Matsugo, Seiichi; Rimbach, Gerald

2015-01-01

Brain aging is accompanied by a decrease in mitochondrial function. In vitro studies suggest that tocotrienols, including γ- and δ-tocotrienol (T3), may exhibit neuroprotective properties. However, little is known about the effect of dietary T3 on mitochondrial function in vivo. In this study, we monitored the effect of a dietary T3/γ-cyclodextrin complex (T3CD) on mitochondrial membrane potential and ATP levels in the brain of 21-month-old mice. Mice were fed either a control diet or a diet enriched with T3CD providing 100 mg T3 per kg diet for 6 months. Dietary T3CD significantly increased mitochondrial membrane potential and ATP levels compared to those of controls. The increase in MMP and ATP due to dietary T3CD was accompanied by an increase in the protein levels of the mitochondrial transcription factor A (TFAM). Furthermore, dietary T3CD slightly increased the mRNA levels of superoxide dismutase, γ-glutamyl cysteinyl synthetase, and heme oxygenase 1 in the brain. Overall, the present data suggest that T3CD increases TFAM, mitochondrial membrane potential, and ATP synthesis in the brains of aged mice. PMID:26301044

Systemic activation of NF-κB driven luciferase activity in transgenic mice fed advanced glycation end products modified albumin.

PubMed

Nass, Norbert; Bayreuther, Kristina; Simm, Andreas

2017-04-01

Advanced glycation end products (AGEs) are stable end products of the Maillard reaction and accumulate with progressing ageing and degenerative diseases. Significant amounts of AGE-modified peptides are also consumed with processed food. AGEs bind to specific receptors, especially the receptor of AGEs (RAGE). Activation of RAGE then evokes intracellular signalling, finally resulting in the activation of the NF-κB transcription factor and therefore a proinflammatory state. We here analysed, whether NF-κB is activated in short term upon feeding an AGE-modified protein in-vivo. Transgenic mice expressing firefly luciferase under the control of an NF-κB responsive promoter were intraperitoneally injected or fed with AGE-modified- or control albumin and luciferase expression was analysed by in-vivo imaging and by in-vitro by determination of luciferase enzyme activity in heart, lung, gut, spleen, liver and kidney. In all organs, an activation of the luciferase reporter gene was observed in response to AGE-BSA feeding, however with different intensity and timing. The gut exhibited highest luciferase activity and this activity peaked 6-8 h post AGE-feeding. In heart and kidney, luciferase activity increased for up to 12 h post feeding. All other organs tested, exhibited highest activity at 10 h after AGE-consumption. Altogether, these data demonstrate that feeding AGE-modified protein resulted in a transient and systemic activation of the NF-κB reporter.

Cholera toxin-induced ADP-ribosylation of a 46 kDa protein is decreased in brains of ethanol-fed mice

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

Nhamburo, P.T.; Hoffman, P.L.; Tabakoff, B.

1988-01-01

The acute in vitro effects of ethanol on cerebral cortical adenylate cyclase activity and beta-adrenergic receptor characteristics suggested a site of action of ethanol at Gs, the stimulatory guanine nucleotide binding protein. After chronic ethanol ingestion, the beta-adrenergic receptor appeared to be uncoupled (i.e., the form of the receptor with high affinity for agonist was undetectable), and stimulation of adenylate cyclase activity by isoproterenol or guanine nucleotides was reduced, suggesting an alteration in the properties of Gs. To further characterize this change, cholera and pertussis toxin-mediated /sup 32/P-ADP-ribosylation of mouse cortical membranes was assessed in mice that had chronically ingestedmore » ethanol in a liquid diet. /sup 32/P-labeled proteins were separated by SDS-PAGE and quantitated by autoradiography. There was a selective 30-50% decrease in cholera toxin-induced labeling of 46 kDa protein band in membranes of ethanol-fed mice, with no apparent change in pertussis toxin-induced labeling. The 46 kDa protein has a molecular weight similar to that of the alpha subunit of Gs, suggesting a reduced amount of this protein or a change in its characteristics as a substrate for cholera toxin-induced ADP-ribosylation in cortical membranes of ethanol-fed mice.« less

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.

PubMed

Legry, Vanessa; Van Rooyen, Derrick M; Lambert, Barbara; Sempoux, Christine; Poekes, Laurence; Español-Suñer, Regina; Molendi-Coste, Olivier; Horsmans, Yves; Farrell, Geoffrey C; Leclercq, Isabelle A

2014-10-01

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.

Identification of eQTLs for Hepatic Xbp1s and Socs3 Gene Expression in Mice Fed a High-Fat, High-Caloric Diet

PubMed Central

Pasricha, Sarina; Kenney-Hunt, Jane; Anderson, Kristy; Jafari, Nadereh; Hall, Rabea A.; Lammert, Frank; Cheverud, James; Green, Richard M.

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent form of human hepatic disease and feeding mice a high-fat, high-caloric (HFHC) diet is a standard model of NAFLD. To better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. Two-hundred sixty-five (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 wk. eQTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1s and Socs3 on Chr 1 (164.0–185.4 Mb and 174.4–190.5 Mb, respectively) and Chr 11 (41.1–73.1 Mb and 44.0–68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9–117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (P < 0.05), whereas C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6J phenotype. In addition, we replicated the eQTLs on Chr 1 and Chr 12 (LOD scores ≥3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and Chr 11, and consomic mice confirmed that replacing the C57BL/6J Chr 11 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases. PMID:25617409

Relationship of aging and nutritional status to innate immunity in tube-fed bedridden patients.

PubMed

Takeuchi, Yoshiaki; Tashiro, Tomoe; Yamamura, Takuya; Takahashi, Seiichiro; Katayose, Kozo; Kohga, Shin; Takase, Mitsunori; Imawari, Michio

2017-01-01

Aging and malnutrition are known to influence immune functions. The aim of this study was to investigate the relationship of aging and malnutrition to innate immune functions in tube-fed bedridden patients. A cross-sectional survey was performed in 71 tube-fed bedridden patients aged 50-95 years (mean age±SD, 80.2±8.5 years) with serum albumin concentrations between 2.5 and 3.5 g/dL. We evaluated associations of age and nutritional variables with natural-killer cell activity, neutrophilphagocytic activity, and neutrophil-sterilizing activity. Nutritional variables included body mass index, weightadjusted energy intake, total lymphocyte count, and serum concentrations of albumin, transferrin, prealbumin, total cholesterol, C-reactive protein, and zinc. Natural-killer cell activity, neutrophil-phagocytic activity, and neutrophil-sterilizing activity were normal or increased in 67 (94%), 63 (89%), and 69 (97%) patients, respectively. Multiple linear regression analysis with a backward elimination method showed that natural-killer cell activity correlated negatively with aging and lymphocyte counts (p<0.01 for both) but positively with body mass index and transferrin (p<0.01 for both). Neutrophil-phagocytic and neutrophil-sterilizing activities were not associated with any variables. In tube-fed bedridden patients with hypo-albuminemia, natural-killer cell activity may be associated with aging, body mass index, transferrin, and lymphocyte counts.

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.

Lipid peroxidation in mice fed a choline-deficient diet as evaluated by total hydroxyoctadecadienoic acid.

PubMed

Yoshida, Yasukazu; Itoh, Nanako; Hayakawa, Mieko; Habuchi, Yoko; Inoue, Ruriko; Chen, Zhi-Hua; Cao, Jiaofei; Cynshi, Osamu; Niki, Etsuo

2006-03-01

The relevance of oxidative stress in mice fed a choline-deficient diet (CDD) was investigated in relation to the oxidative stress marker, hydroxyoctadecadienoic acid (HODE) in comparison with F2-isoprostanes. Further, the protective effects of antioxidants against oxidative damage were assessed by using HODE. We recently proposed total HODE as a biomarker for oxidative stress in vivo. Biological samples such as plasma, urine, and tissues were first reduced and then saponified to convert various oxidation products of linoleates to HODE. In the present study, this method was applied to measure oxidative damage in mice induced by CDD for 1 mo. CDD, when compared with choline-controlled diet (CCD), increased liver weight and fatty acid accumulation but the increase in body weight was less significant. Remarkable increases in HODE and 8-iso-prostaglandin F(2alpha) in liver and plasma were observed when mice were fed with the CDD for 1 mo compared with the CCD. The HODE level was about two to three orders higher than the F2-isoprostane level. This increase was decreased to the level of the CCD when alpha-tocopherol or 2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran, a potent synthetic antioxidant, was mixed with the CDD. The stereoisomer ratio of HODE (9-and-13 (Z,E)-HODE/9-and-13 (E,E)-HODE) was decreased by CDD compared with CCD, which was spared by the addition of alpha-tocopherol and 2,3-dihydro-5-hydroxy-4,6-di-tert-butyl-2,2-dipentylbenzofuran. However, the increase in plasma glutamic-pyruvic transaminase and fatty acids in liver induced by the CDD was not recovered by any antioxidant. This study clearly demonstrated that oxidative stress was involved in fatty liver formation induced by the CDD and that HODE was a good biomarker for an oxidative stress in vivo.

Sphingosine rescues aged mice from pulmonary pseudomonas infection.

PubMed

Rice, Teresa C; Pugh, Amanda M; Seitz, Aaron P; Gulbins, Erich; Nomellini, Vanessa; Caldwell, Charles C

2017-11-01

Bacterial lung infection is a leading cause of death for those 65 y or older, often requiring intensive care unit admission and mechanical ventilation, which consumes considerable health care resources. Although administration of antibiotics is the standard of care for bacterial pneumonia, its overuse has led to the emergence of multidrug resistant organisms. Therefore, alternative strategies to help minimize the effects of bacterial pneumonia in the elderly are necessary. As studies have shown that sphingosine (SPH) has inherent bacterial killing properties, our goal was to assess whether it could act as a prophylactic treatment to protect aged mice from pulmonary infection by Pseudomonas aeruginosa. Aged (51 wk) and young (8 wk) C57Bl/6 mice were used in this study. Pulmonary SPH levels were determined by histology. SPH content of microparticles was quantified using a SPH kinase assay. Pneumonia was induced by intranasally treating mice with 10 6  Colony Forming Unit (CFU) P aeruginosa. Microparticles were isolated from young mice, whereas some were further incubated with SPH. We observed that SPH levels are reduced in the bronchial epithelial cells as well as the bronchoalveolar lavage microparticles isolated from aged mice, which correlates with a susceptibility to infection. We demonstrate that SPH or microparticle treatment can protect aged mice from pulmonary P aeruginosa infection. Finally, we observed that enriching microparticles with SPH before treatment eliminated the bacterial load in P aeruginosa-infected aged mice. These data suggest that prophylactic treatment with SPH could reduce lung bacterial infections for the at-risk elderly population. Copyright © 2017 Elsevier Inc. All rights reserved.

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.

Improved muscle function and quality after diet intervention with leucine-enriched whey and antioxidants in antioxidant deficient aged mice

PubMed Central

van Dijk, Miriam; Dijk, Francina J.; Bunschoten, Annelies; van Dartel, Dorien A.M.; van Norren, Klaske; Walrand, Stephane; Jourdan, Marion; Verlaan, Sjors; Luiking, Yvette

2016-01-01

Antioxidant (AOX) deficiencies are commonly observed in older adults and oxidative stress has been suggested to contribute to sarcopenia. Here we investigate if 1) low levels of dietary antioxidants had a negative impact on parameters of muscle mass, function and quality, and 2) to study if nutritional interventions with AOX and/or leucine-enriched whey protein could improve these muscle parameters in aged mice. 18-months-old mice were fed a casein-based antioxidant-deficient (lowox) diet or a casein-based control-diet (CTRL) for 7 months. During the last 3 months, lowox-mice were subjected to either: a) continued lowox, b) supplementation with vitamin A/E, Selenium and Zinc (AOX), c) substitution of casein with leucine-enriched whey protein (PROT) or d) a combination of both AOX and PROT (TOTAL). After 7 months lowox-mice displayed lower muscle strength and more muscle fatigue compared to CTRL. Compared to lowox-mice, PROT-mice showed improved muscle power, grip strength and less muscle fatigue. AOX-mice showed improved oxidative status, less muscle fatigue, improved grip strength and mitochondrial dynamics compared to lowox-mice. The TOTAL-mice showed the combined effects of both interventions compared to lowox-mice. In conclusion, nutritional intervention with AOX and/or leucine-enriched whey protein can play a role in improving muscle health in a AOX-deficient mouse model. PMID:26943770

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

Intake of farmed Atlantic salmon fed soybean oil increases hepatic levels of arachidonic acid-derived oxylipins and ceramides in mice

USDA-ARS?s Scientific Manuscript database

Introduction of vegetable ingredients in fish feed has affected the fatty acid composition in farmed Atlantic salmon (Salmo salar L). Here we investigated how changes in fish feed affected the metabolism of mice fed diets containing fillets from such farmed salmon. We demonstrate that replacement of...

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.

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.

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

Effects of disturbed liver growth and oxidative stress of high-fat diet-fed dams on cholesterol metabolism in offspring mice.

PubMed

Kim, Juyoung; Kim, Juhae; Kwon, Young Hye

2016-08-01

Changes in nutritional status during gestation and lactation have detrimental effects on offspring metabolism. Several animal studies have shown that maternal high-fat diet (HFD) can predispose the offspring to development of obesity and metabolic diseases, however the mechanisms underlying these transgenerational effects are poorly understood. Therefore, we examined the effect of maternal HFD consumption on metabolic phenotype and hepatic expression of involved genes in dams to determine whether any of these parameters were associated with the metabolic outcomes in the offspring. Female C57BL/6 mice were fed a low-fat diet (LFD: 10% calories from fat) or a high-fat diet (HFD: 45% calories from fat) for three weeks before mating, and during pregnancy and lactation. Dams and their male offspring were studied at weaning. Dams fed an HFD had significantly higher body and adipose tissue weights and higher serum triglyceride and cholesterol levels than dams fed an LFD. Hepatic lipid levels and mRNA levels of genes involved in lipid metabolism, including LXRα, SREBP-2, FXR, LDLR, and ABCG8 were significantly changed by maternal HFD intake. Significantly lower total liver DNA and protein contents were observed in dams fed an HFD, implicating the disturbed liver adaptation in the pregnancy-related metabolic demand. HFD feeding also induced significant oxidative stress in serum and liver of dams. Offspring of dams fed an HFD had significantly higher serum cholesterol levels, which were negatively correlated with liver weights of dams and positively correlated with hepatic lipid peroxide levels in dams. Maternal HFD consumption induced metabolic dysfunction, including altered liver growth and oxidative stress in dams, which may contribute to the disturbed cholesterol homeostasis in the early life of male mice offspring.

Prenatal nicotine exposure enhances Cx43 and Panx1 unopposed channel activity in brain cells of adult offspring mice fed a high-fat/cholesterol diet

PubMed Central

Orellana, Juan A.; Busso, Dolores; Ramírez, Gigliola; Campos, Marlys; Rigotti, Attilio; Eugenín, Jaime; von Bernhardi, Rommy

2014-01-01

Nicotine, the most important neuroteratogen of tobacco smoke, can reproduce brain and cognitive disturbances per se when administered prenatally. However, it is still unknown if paracrine signaling among brain cells participates in prenatal nicotine-induced brain impairment of adult offspring. Paracrine signaling is partly mediated by unopposed channels formed by connexins hemichannels (HCs) and pannexins serving as aqueous pores permeable to ions and small signaling molecules, allowing exchange between the intra- and extracellular milieus. Our aim was to address whether prenatal nicotine exposure changes the activity of those channels in adult mice offspring under control conditions or subjected to a second challenge during young ages: high-fat/cholesterol (HFC) diet. To induce prenatal exposure to nicotine, osmotic minipumps were implanted in CF1 pregnant mice at gestational day 5 to deliver nicotine bitartrate or saline (control) solutions. After weaning, offspring of nicotine-treated or untreated pregnant mice were fed ad libitum with chow or HFC diets for 8 weeks. The functional state of connexin 43 (Cx43) and pannexin 1 (Panx1) unopposed channels was evaluated by dye uptake experiments in hippocampal slices from 11-week-old mice. We found that prenatal nicotine increased the opening of Cx43 HCs in astrocytes, and Panx1 channels in microglia and neurons only if offspring mice were fed with HFC diet. Blockade of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2) and prostaglandin E receptor 1 (EP1), ionotropic ATP receptor type 7 (P2X7) and NMDA receptors, showed differential inhibition of prenatal nicotine-induced channel opening in glial cells and neurons. Importantly, inhibition of the above mentioned enzymes and receptors, or blockade of Cx43 and Panx1 unopposed channels greatly reduced adenosine triphosphate (ATP) and glutamate release from hippocampal slices of prenatally nicotine-exposed offspring. We propose that unregulated gliotransmitter

Impact of N-acetylcysteine and sesame oil on lipid metabolism and hypothalamic-pituitary-adrenal axis homeostasis in middle-aged hypercholesterolemic mice

PubMed Central

Korou, Laskarina-Maria; Agrogiannis, George; Koros, Christos; Kitraki, Efthimia; Vlachos, Ioannis S.; Tzanetakou, Irene; Karatzas, Theodore; Pergialiotis, Vasilios; Dimitroulis, Dimitrios; Perrea, Despina N.

2014-01-01

Hyperlipidemia and stress are important factors affecting cardiovascular health in middle-aged individuals. We investigated the effects of N-acetylcysteine (NAC) and sesame oil on the lipidemic status, liver architecture and the hypothalamic-pituitary-adrenal (HPA) axis of middle-aged mice fed a cholesterol-enriched diet. We randomized 36 middle-aged C57bl/6 mice into 6 groups: a control group, a cholesterol/cholic acid diet group, a cholesterol/cholic acid diet group with NAC supplementation, a cholesterol/cholic acid diet enriched with 10% sesame oil and two groups receiving a control diet enriched with NAC or sesame oil. NAC administration prevented the onset of the disturbed lipid profile, exhibiting decreased lipid peroxidation and alkaline phosphatase (ALP) levels, restored nitric oxide bioavailability and reduced hepatic damage, compared to non-supplemented groups. High-cholesterol feeding resulted in increased hypothalamic glucocorticoid receptors (GR) levels, while NAC supplementation prevented this effect. NAC supplementation presented significant antioxidant capacity by means of preventing serum lipid status alterations, hepatic damage, and HPA axis disturbance due to high-cholesterol feeding in middle-aged mice. These findings suggest a beneficial preventive action of plant-derived antioxidants, such as NAC, on lipid metabolism and on the HPA axis. PMID:25348324

Acid sphingomyelinase deficiency in Western diet-fed mice protects against adipocyte hypertrophy and diet-induced liver steatosis.

PubMed

Sydor, Svenja; Sowa, Jan-Peter; Megger, Dominik A; Schlattjan, Martin; Jafoui, Sami; Wingerter, Lena; Carpinteiro, Alexander; Baba, Hideo A; Bechmann, Lars P; Sitek, Barbara; Gerken, Guido; Gulbins, Erich; Canbay, Ali

2017-05-01

Alterations in sphingolipid and ceramide metabolism have been associated with various diseases, including nonalcoholic fatty liver disease (NAFLD). Acid sphingomyelinase (ASM) converts the membrane lipid sphingomyelin to ceramide, thereby affecting membrane composition and domain formation. We investigated the ways in which the Asm knockout (Smpd1 -/- ) genotype affects diet-induced NAFLD. Smpd1 -/- mice and wild type controls were fed either a standard or Western diet (WD) for 6 weeks. Liver and adipose tissue morphology and mRNA expression were assessed. Quantitative proteome analysis of liver tissue was performed. Expression of selected genes was quantified in adipose and liver tissue of obese NAFLD patients. Although Smpd1 -/- mice exhibited basal steatosis with normal chow, no aggravation of NAFLD-type injury was observed with a Western diet. This protective effect was associated with the absence of adipocyte hypertrophy and the increased expression of genes associated with brown adipocyte differentiation. In white adipose tissue from obese patients with NAFLD, no expression of these genes was detectable. To further elucidate which pathways in liver tissue may be affected by Smpd1 -/- , we performed an unbiased proteome analysis. Protein expression in WD-fed Smpd1 -/- mice indicated a reduction in Rictor (mTORC2) activity; this reduction was confirmed by diminished Akt phosphorylation and altered mRNA expression of Rictor target genes. These findings indicate that the protective effect of Asm deficiency on diet-induced steatosis is conferred by alterations in adipocyte morphology and lipid metabolism and by reductions in Rictor activation.

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice.

PubMed

Lund, J; Hafstad, A D; Boardman, N T; Rossvoll, L; Rolim, N P; Ahmed, M S; Florholmen, G; Attramadal, H; Wisløff, U; Larsen, T S; Aasum, E

2015-04-15

Although exercise training has been demonstrated to have beneficial cardiovascular effects in diabetes, the effect of exercise training on hearts from obese/diabetic models is unclear. In the present study, mice were fed a high-fat diet, which led to obesity, reduced aerobic capacity, development of mild diastolic dysfunction, and impaired glucose tolerance. Following 8 wk on high-fat diet, mice were assigned to 5 weekly high-intensity interval training (HIT) sessions (10 × 4 min at 85-90% of maximum oxygen uptake) or remained sedentary for the next 10 constitutive weeks. HIT increased maximum oxygen uptake by 13%, reduced body weight by 16%, and improved systemic glucose homeostasis. Exercise training was found to normalize diastolic function, attenuate diet-induced changes in myocardial substrate utilization, and dampen cardiac reactive oxygen species content and fibrosis. These changes were accompanied by normalization of obesity-related impairment of mechanical efficiency due to a decrease in work-independent myocardial oxygen consumption. Finally, we found HIT to reduce infarct size by 47% in ex vivo hearts subjected to ischemia-reperfusion. This study therefore demonstrated for the first time that exercise training mediates cardioprotection following ischemia in diet-induced obese mice and that this was associated with oxygen-sparing effects. These findings highlight the importance of optimal myocardial energetics during ischemic stress. Copyright © 2015 the American Physiological Society.

Mice Fed a High-Cholesterol Diet Supplemented with Quercetin-3-Glucoside Show Attenuated Hyperlipidemia and Hyperinsulinemia Associated with Differential Regulation of PCSK9 and LDLR in their Liver and Pancreas.

PubMed

Mbikay, Majambu; Mayne, Janice; Sirois, Francine; Fedoryak, Olesya; Raymond, Angela; Noad, Jennifer; Chrétien, Michel

2018-05-01

Hepatic LDL receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) regulate the clearance of plasma LDL-cholesterol (LDL-C): LDLR promotes it, and PCSK9 opposes it. These proteins also express in pancreatic β cells. Using cultured hepatocytes, we previously showed that the plant flavonoid quercetin-3-glucoside (Q3G) inhibits PCSK9 secretion, stimulated LDLR expression, and enhanced LDL-C uptake. Here, we examine whether Q3G supplementation could reverse the hyperlipidemia and hyperinsulinemia of mice fed a high-cholesterol diet, and how it affects hepatic and pancreatic LDLR and PCSK9 expression. For 12 weeks, mice are fed a low- (0%) or high- (1%) cholesterol diet (LCD or HCD), supplemented or not with Q3G at 0.05 or 0.1% (w/w). Tissue LDLR and PCSK9 is analyzed by immunoblotting, plasma PCSK9 and insulin by ELISA, and plasma cholesterol and glucose by colorimetry. In LCD-fed mice, Q3G has no effect. In HCD-fed mice, it attenuates the increase in plasma cholesterol and insulin, accentuates the decrease in plasma PCSK9, and increases hepatic and pancreatic LDLR and PCSK9. In cultured pancreatic β cells, however, it stimulates PCSK9 secretion. In mice, dietary Q3G could counter HCD-induced hyperlipidemia and hyperinsulinemia, in part by oppositely modulating hepatic and pancreatic PCSK9 secretion. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

Microbiota, metabolome, and immune alterations in obese mice fed a high-fat diet containing type 2 resistant starch.

PubMed

Barouei, Javad; Bendiks, Zach; Martinic, Alice; Mishchuk, Darya; Heeney, Dustin; Hsieh, Yu-Hsin; Kieffer, Dorothy; Zaragoza, Jose; Martin, Roy; Slupsky, Carolyn; Marco, Maria L

2017-11-01

We examined the intestinal and systemic responses to incorporating a type 2 resistant starch (RS) into a high fat diet fed to obese mice. Diet-induced obese, C57BL/6J male mice were fed an HF diet without or with 20% (by weight) high-amylose maize resistant starch (HF-RS) for 6 weeks. Serum adiponectin levels were higher with RS consumption, but there were no differences in weight gain and adiposity. With HF-RS, the expression levels of ileal TLR2 and Reg3g and cecal occludin, TLR2, TLR4, NOD1 and NOD2 were induced; whereas colonic concentrations of the inflammatory cytokine IL-17A declined. The intestinal, serum, liver, and urinary metabolomes were also altered. HF-RS resulted in lower amino acid concentrations, including lower serum branched chain amino acids, and increased quantities of urinary di/trimethylamine, 3-indoxylsulfate, and phenylacetylglycine. Corresponding to these changes were enrichments in Bacteroidetes (S24-7 family) and certain Firmicutes taxa (Lactobacillales and Erysipelotrichaceae) with the HF-RS diet. Parabacteroides and S24-7 positively associated with cecal maltose concentrations. These taxa and Erysipelotrichaceae, Allobaculum, and Bifidobacterium were directly correlated with uremic metabolites. Consumption of RS modified the intestinal microbiota, stimulated intestinal immunity and endocrine-responses, and modified systemic metabolomes in obese mice consuming an otherwise obesogenic diet. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Omija fruit ethanol extract improves adiposity and related metabolic disturbances in mice fed a high-fat diet.

PubMed

Park, Hyo Jin; Kim, Hye-Jin; Kim, Sang Ryong; Choi, Myung-Sook; Jung, Un Ju

2017-03-01

This study investigated the biological and molecular mechanisms underlying the antiobesity effect of omija fruit ethanol extract (OFE) in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD (20% fat, w/w) with or without OFE (500 mg/kg body weight) for 16 weeks. Dietary OFE significantly increased brown adipose tissue weight and energy expenditure while concomitantly decreasing white adipose tissue (WAT) weight and adipocyte size by up-regulating the expression of brown fat-selective genes in WAT. OFE also improved hepatic steatosis and dyslipidemia by enhancing hepatic fatty acid oxidation-related enzymes activity and fecal lipid excretion. In addition to steatosis, OFE decreased the expression of pro-inflammatory genes in the liver. Moreover, OFE improved glucose tolerance and lowered plasma glucose, insulin and homeostasis model assessment of insulin resistance, which may be linked to decreases in the activity of hepatic gluconeogenic enzymes and the circulating level of gastric inhibitory polypeptide. These findings suggest that OFE may protect against diet-induced adiposity and related metabolic disturbances by controlling brown-like transformation of WAT, fatty acid oxidation, inflammation in the liver and fecal lipid excretion. Improved insulin resistance may be also associated with its antiobesity effects. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Estrogen effects on cognition and hippocampal transcription in middle-aged mice.

PubMed

Aenlle, Kristina K; Kumar, Ashok; Cui, Li; Jackson, Travis C; Foster, Thomas C

2009-06-01

Young and middle-aged female mice were ovariectomized and given cyclic injections of either estradiol or vehicle treatments. During the fifth week after surgery the Morris water maze was used to assess cognitive function. Age and treatment effects emerged over the course of spatial training such that middle-aged vehicle treated mice exhibited deficits in acquiring a spatial search strategy compared to younger vehicle treated mice and middle-age estradiol treated mice. Following behavioral characterization, mice were maintained on their injection schedule until week seven and hippocampi were collected 24h after the last injection. Hippocampal RNA was extracted and genes responsive to age and estrogen were identified using cDNA microarrays. Estradiol treatment in middle-aged mice altered the expression of genes related to transcriptional regulation, biosynthesis, growth, neuroprotection, and elements of cell signaling pathways. Expression profiles for representative genes were confirmed in a separate set of animals using oligonucleotide arrays and RT-PCR. Our results indicate that estrogen treatment in middle-aged animals may promote hippocampal health during the aging process.

Intestine-specific deletion of microsomal triglyceride transfer protein increases mortality in aged mice.

PubMed

Liang, Zhe; Xie, Yan; Dominguez, Jessica A; Breed, Elise R; Yoseph, Benyam P; Burd, Eileen M; Farris, Alton B; Davidson, Nicholas O; Coopersmith, Craig M

2014-01-01

Mice with conditional, intestine-specific deletion of microsomal triglyceride transfer protein (Mttp-IKO) exhibit a complete block in chylomicron assembly together with lipid malabsorption. Young (8-10 week) Mttp-IKO mice have improved survival when subjected to a murine model of Pseudomonas aeruginosa-induced sepsis. However, 80% of deaths in sepsis occur in patients over age 65. The purpose of this study was to determine whether age impacts outcome in Mttp-IKO mice subjected to sepsis. Aged (20-24 months) Mttp-IKO mice and WT mice underwent intratracheal injection with P. aeruginosa. Mice were either sacrificed 24 hours post-operatively for mechanistic studies or followed seven days for survival. In contrast to young septic Mttp-IKO mice, aged septic Mttp-IKO mice had a significantly higher mortality than aged septic WT mice (80% vs. 39%, p = 0.005). Aged septic Mttp-IKO mice exhibited increased gut epithelial apoptosis, increased jejunal Bax/Bcl-2 and Bax/Bcl-XL ratios yet simultaneously demonstrated increased crypt proliferation and villus length. Aged septic Mttp-IKO mice also manifested increased pulmonary myeloperoxidase levels, suggesting increased neutrophil infiltration, as well as decreased systemic TNFα compared to aged septic WT mice. Blocking intestinal chylomicron secretion alters mortality following sepsis in an age-dependent manner. Increases in gut apoptosis and pulmonary neutrophil infiltration, and decreased systemic TNFα represent potential mechanisms for why intestine-specific Mttp deletion is beneficial in young septic mice but harmful in aged mice as each of these parameters are altered differently in young and aged septic WT and Mttp-IKO mice.

Effects of Capsaicin Coadministered with Eicosapentaenoic Acid on Obesity-Related Dysregulation in High-Fat-Fed Mice.

PubMed

Hirotani, Yoshihiko; Fukamachi, Junta; Ueyama, Rina; Urashima, Yoko; Ikeda, Kenji

2017-01-01

Obesity-induced inflammation contributes to the development of metabolic disorders such as insulin resistance, type 2 diabetes, fatty liver disease, and cardiovascular disease. In this study, we investigated whether the combination of eicosapentaenoic acid (EPA) and capsaicin could protect against high-fat diet (HFD)-induced obesity and related metabolic disorders. The experiments were performed using male C57BL/6J mice that were fed one of the following diets for 10 weeks: standard chow (5.3% fat content) (normal group), a HFD (32.0% fat content) (HFD group), or a HFD supplemented with either 4% (w/w) EPA (EPA group) or a combination of 4% (w/w) EPA and 0.01% (w/w) capsaicin (EPA+Cap group). Our results indicated that the body, fat and liver tissue weights and levels of serum glucose, insulin, total cholesterol, triglyceride, high-density lipoprotein-cholesterol, aspartate aminotransferase, and alanine aminotransferase were significantly higher in HFD group mice than in normal group mice (p<0.05 in all cases). However, the body and fat tissue weights and serum glucose levels and homeostasis model assessment of insulin resistance were significantly lower in EPA+Cap group mice group than in HFD and EPA group mice (p<0.05 in all cases). Thus, our study suggests that the combination of EPA and capsaicin might be beneficial for delaying the progression of obesity-related metabolic dysregulation and subsequent complications.

Anti-Aging Effect of Siraitia grosuenorii by Enhancement of Hematopoietic Stem Cell Function.

PubMed

Bai, Lin; Shi, Guiying; Yang, Yajun; Chen, Wei; Zhang, Lianfeng

2016-01-01

Anti-aging has always been a popular topic, and there are many claims about the existence of factors that can slow, stop, or even reverse the aging process. Siraitia grosuenorii, a local fruit in china, has been used for the treatment of gastritis, sore throats, and whooping cough in traditional Chinese medicine. The individuals who took the juice of Siraitia grosuenorii regularly had increased longevity in the Guangxi Province, which is located in the Southern part of China. In this paper, we fed mice with Siraitia grosuenorii for 10 months to identify the role of Siraitia grosuenorii in anti-aging and to investigate its corresponding mechanism. The results showed that mice fed with Siraitia grosuenorii displayed a slower aging process. The extension of the aging process was due to the enhanced function of HSCs. FACS analysis showed that the number of LSKs, LT-HSCs, ST-HSCs and MPPs from Siraitia grosuenorii mice was decreased. In vitro, a clonigenic assay showed that LT-HSCs from Siraitia grosuenorii mice increased the ability of self-renewal. Moreover, Siraitia grosuenorii mice maintained the quiescence of LSKs, decreased the level of ROS and reduced the amount of senescence associated β-gal positive cells. Furthermore, Siraitia grosuenorii mice decreased the expression of senescence-associated proteins. Siraitia grosuenorii maintained quiescence, decreased senescence and enhanced the function of HSCs, slowing the aging process of mice.

The metabolic footprint of aging in mice.

PubMed

Houtkooper, Riekelt H; Argmann, Carmen; Houten, Sander M; Cantó, Carles; Jeninga, Ellen H; Andreux, Pénélope A; Thomas, Charles; Doenlen, Raphaël; Schoonjans, Kristina; Auwerx, Johan

2011-01-01

Aging is characterized by a general decline in cellular function, which ultimately will affect whole body homeostasis. Although DNA damage and oxidative stress all contribute to aging, metabolic dysfunction is a common hallmark of aging at least in invertebrates. Since a comprehensive overview of metabolic changes in otherwise healthy aging mammals is lacking, we here compared metabolic parameters of young and 2 year old mice. We systemically integrated in vivo phenotyping with gene expression, biochemical analysis, and metabolomics, thereby identifying a distinguishing metabolic footprint of aging. Among the affected pathways in both liver and muscle we found glucose and fatty acid metabolism, and redox homeostasis. These alterations translated in decreased long chain acylcarnitines and increased free fatty acid levels and a marked reduction in various amino acids in the plasma of aged mice. As such, these metabolites serve as biomarkers for aging and healthspan.

The metabolic footprint of aging in mice

PubMed Central

Houtkooper, Riekelt H.; Argmann, Carmen; Houten, Sander M.; Cantó, Carles; Jeninga, Ellen H.; Andreux, Pénélope A.; Thomas, Charles; Doenlen, Raphaël; Schoonjans, Kristina; Auwerx, Johan

2011-01-01

Aging is characterized by a general decline in cellular function, which ultimately will affect whole body homeostasis. Although DNA damage and oxidative stress all contribute to aging, metabolic dysfunction is a common hallmark of aging at least in invertebrates. Since a comprehensive overview of metabolic changes in otherwise healthy aging mammals is lacking, we here compared metabolic parameters of young and 2 year old mice. We systemically integrated in vivo phenotyping with gene expression, biochemical analysis, and metabolomics, thereby identifying a distinguishing metabolic footprint of aging. Among the affected pathways in both liver and muscle we found glucose and fatty acid metabolism, and redox homeostasis. These alterations translated in decreased long chain acylcarnitines and increased free fatty acid levels and a marked reduction in various amino acids in the plasma of aged mice. As such, these metabolites serve as biomarkers for aging and healthspan. PMID:22355651

Neuroinflammation and cognitive function in aged mice following minor surgery

PubMed Central

Rosczyk, H.A.; Sparkman, N. L.; Johnson, R.W.

2009-01-01

Following surgery, elderly patients often suffer from postoperative cognitive dysfunction (POCD) which can persist long after physical recovery. It is known that surgery-induced tissue damage activates the peripheral innate immune system resulting in the release of inflammatory mediators. Compared to adults, aged animals demonstrate increased neuroinflammation and microglial priming that leads to an exaggerated proinflammatory cytokine response following activation of the peripheral immune system. Therefore, we sought to determine if the immune response to surgical trauma results in increased neuroinflammation and cognitive impairment in aged mice. Adult and aged mice underwent minor abdominal surgery and 24 h later hippocampal cytokines were measured and working memory was assessed in a reversal learning version of the Morris water maze. While adult mice showed no signs of neuroinflammation following surgery, aged mice had significantly increased levels of IL-1β mRNA in the hippocampus. Minor surgery did not result in severe cognitive impairment although aged mice that underwent surgery did tend to perseverate in the old target during reversal testing suggesting reduced cognitive flexibility. Overall these results suggest that minor surgery leads to an exaggerated neuroinflammatory response in aged mice but does not result in significantly impaired performance in the Morris water maze. PMID:18602982

Cyanidin 3-glucoside attenuates obesity-associated insulin resistance and hepatic steatosis in high-fat diet-fed and db/db mice via the transcription factor FoxO1.

PubMed

Guo, Honghui; Xia, Min; Zou, Tangbin; Ling, Wenhua; Zhong, Ruimin; Zhang, Weiguo

2012-04-01

Obesity is a major risk factor for the development of type 2 diabetes, and both conditions are now recognized to possess significant inflammatory components underlying their pathophysiologies. Here, we hypothesized that cyanidin 3-glucoside (C3G), a typical anthocyanin reported to possess potent anti-inflammatory properties, would ameliorate obesity-associated inflammation and metabolic disorders, such as insulin resistance and hepatic steatosis in mouse models of diabesity. Male C57BL/6J obese mice fed a high-fat diet for 12 weeks and genetically diabetic db/db mice at an age of 6 weeks received dietary C3G supplementation (0.2%) for 5 weeks. We found that dietary C3G lowered fasting glucose levels and markedly improved the insulin sensitivity in both high-fat diet fed and db/db mice as compared with unsupplemented controls. White adipose tissue messenger RNA levels and serum concentrations of inflammatory cytokines (tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1) were reduced by C3G, as did macrophage infiltration in adipose tissue. Concomitantly, hepatic triglyceride content and steatosis were alleviated by C3G. Moreover, C3G treatment decreased c-Jun N-terminal kinase activation and promoted phosphorylation and nuclear exclusion of forkhead box O1 after refeeding. These findings clearly indicate that C3G has significant potency in antidiabetic effects by modulating the c-Jun N-terminal kinase/forkhead box O1 signaling pathway and the related inflammatory adipocytokines. Crown Copyright © 2012. Published by Elsevier Inc. 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.

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.

Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice

PubMed Central

Wang, Jingjing; Tang, Huang; Zhang, Chenhong; Zhao, Yufeng; Derrien, Muriel; Rocher, Emilie; van-Hylckama Vlieg, Johan ET; Strissel, Katherine; Zhao, Liping; Obin, Martin; Shen, Jian

2015-01-01

Structural disruption of gut microbiota and associated inflammation are considered important etiological factors in high fat diet (HFD)-induced metabolic syndrome (MS). Three candidate probiotic strains, Lactobacillus paracasei CNCM I-4270 (LC), L. rhamnosus I-3690 (LR) and Bifidobacterium animalis subsp. lactis I-2494 (BA), were individually administered to HFD-fed mice (108 cells day−1) for 12 weeks. Each strain attenuated weight gain and macrophage infiltration into epididymal adipose tissue and markedly improved glucose–insulin homeostasis and hepatic steatosis. Weighted UniFrac principal coordinate analysis based on 454 pyrosequencing of fecal bacterial 16S rRNA genes showed that the probiotic strains shifted the overall structure of the HFD-disrupted gut microbiota toward that of lean mice fed a normal (chow) diet. Redundancy analysis revealed that abundances of 83 operational taxonomic units (OTUs) were altered by probiotics. Forty-nine altered OTUs were significantly correlated with one or more host MS parameters and were designated ‘functionally relevant phylotypes'. Thirteen of the 15 functionally relevant OTUs that were negatively correlated with MS phenotypes were promoted, and 26 of the 34 functionally relevant OTUs that were positively correlated with MS were reduced by at least one of the probiotics, but each strain changed a distinct set of functionally relevant OTUs. LC and LR increased cecal acetate but did not affect circulating lipopolysaccharide-binding protein; in contrast, BA did not increase acetate but significantly decreased adipose and hepatic tumor necrosis factor-α gene expression. These results suggest that Lactobacillus and Bifidobacterium differentially attenuate obesity comorbidities in part through strain-specific impacts on MS-associated phylotypes of gut microbiota in mice. PMID:24936764

Microglial K+ Channel Expression in Young Adult and Aged Mice

PubMed Central

Schilling, Tom; Eder, Claudia

2015-01-01

The K+ channel expression pattern of microglia strongly depends on the cells' microenvironment and has been recognized as a sensitive marker of the cells' functional state. While numerous studies have been performed on microglia in vitro, our knowledge about microglial K+ channels and their regulation in vivo is limited. Here, we have investigated K+ currents of microglia in striatum, neocortex and entorhinal cortex of young adult and aged mice. Although almost all microglial cells exhibited inward rectifier K+ currents upon membrane hyperpolarization, their mean current density was significantly enhanced in aged mice compared with that determined in young adult mice. Some microglial cells additionally exhibited outward rectifier K+ currents in response to depolarizing voltage pulses. In aged mice, microglial outward rectifier K+ current density was significantly larger than in young adult mice due to the increased number of aged microglial cells expressing these channels. Aged dystrophic microglia exhibited outward rectifier K+ currents more frequently than aged ramified microglia. The majority of microglial cells expressed functional BK-type, but not IK- or SK-type, Ca2+-activated K+ channels, while no differences were found in their expression levels between microglia of young adult and aged mice. Neither microglial K+ channel pattern nor K+ channel expression levels differed markedly between the three brain regions investigated. It is concluded that age-related changes in microglial phenotype are accompanied by changes in the expression of microglial voltage-activated, but not Ca2+-activated, K+ channels. PMID:25472417

Body Weight Loss and Tissue Wasting in Late Middle-Aged Mice on Slightly Imbalanced Essential/Non-essential Amino Acids Diet.

PubMed

Corsetti, Giovanni; Pasini, Evasio; Romano, Claudia; Calvani, Riccardo; Picca, Anna; Marzetti, Emanuele; Flati, Vincenzo; Dioguardi, Francesco S

2018-01-01

Objective: Inadequate protein intake can impair protein balance thus leading to skeletal muscle atrophy, impaired body growth, and functional decline. Foods provide both non-essential (NEAAs) and essential amino acids (EAAs) that may convey different metabolic stimuli to specific organs and tissues. In this study, we sought to evaluate the impact of six diets, with various EAA/NEAA blends, on body composition and the risk of developing tissue wasting in late middle-aged male mice. Methods: Six groups of late middle-aged male mice were fed for 35 days with iso-nutrients, iso-caloric, and iso-nitrogenous special diets containing different EAA/NEAA ratios ranging from 100/0% to 0/100%. One group fed with standard laboratory rodent diet (StD) served as control. Preliminarily, we verified the palatability of the diets by recording the mice preference, and by making accessible all diets simultaneously, in comparison to StD. Body weight, food and water consumption were measured every 3 days. Blood and urine samples, as well as heart, kidneys, liver, spleen, triceps surae, retroperitoneal WAT, and BAT were harvested and weighed. Results: Mice consuming NEAA-based diets, although showing increased food and calorie intake, suffered the most severe weight loss. Interestingly, the diet containing a EAA/NEAA-imbalance, with moderate NEAAs prevalence, was able to induce catabolic stimuli, generalized body wasting, and systemic metabolic alterations comparable to those observed with diet containing NEAA alone. In addition, complete depletion of retroperitoneal white adipose tissue and a severe loss (>75%) of brown adipose tissue were observed together with muscle wasting. Conversely, EAA-containing diets induced significant decreases in body weight by reducing primarily fat reserves, but at the same time they improved the clinical parameters. On these basis we can deduce that tissue wasting was caused by altered AA quality, independent of reduced nitrogen or caloric intake

Genistein promotes insulin action through adenosine monophosphate-activated protein kinase activation and p70 ribosomal protein S6 kinase 1 inhibition in the skeletal muscle of mice fed a high energy diet.

PubMed

Arunkumar, Elumalai; Anuradha, Carani Venkatraman

2012-08-01

Genistein (GEN), a soy isoflavone, exerts insulin-sensitizing actions in animals; however, the underlying mechanisms have not been determined. Because GEN is a known activator of adenosine monophosphate-activated protein kinase (AMPK), we hypothesize that GEN activates insulin signaling through AMPK activation. To test this hypothesis, a high fat-high fructose diet (HFFD)-fed mice model of insulin resistance was administered GEN, and the insulin signaling pathway proteins in the skeletal muscle were examined. Hyperglycemia and hyperinsulinemia observed in HFFD-fed mice were significantly lowered by GEN. GEN increased insulin-stimulated tyrosine phosphorylation of insulin receptor-β and insulin receptor substrate (IRS) 1 but down-regulated IRS-1 serine phosphorylation in the skeletal muscle of HFFD-fed mice. Furthermore, GEN treatment improved muscle IRS-1-associated phospatidylinositol-3 kinase expression, phosphorylation of Akt at Ser(473), and translocation of glucose transporter subtype 4. Phosphorylation of AMPK at Thr(172) and acetyl coenzyme A carboxylase (ACC) at Ser(79) was augmented, whereas phosphorylation of p70 ribosomal protein S6 kinase 1 at Thr(389) was significantly decreased after GEN treatment in the skeletal muscle of HFFD-fed mice. These results suggest that GEN might improve insulin action in the skeletal muscle by targeting AMPK. Copyright © 2012 Elsevier Inc. All rights reserved.

Chronic administration of methamphetamine promotes atherosclerosis formation in ApoE-/- knockout mice fed normal diet.

PubMed

Gao, Bo; Li, Lun; Zhu, Pengfei; Zhang, Mingjing; Hou, Lingbo; Sun, Yufei; Liu, Xiaoyan; Peng, Xiaohong; Gu, Ye

2015-11-01

Chronic methamphetamine (METH) abuse could induce neurotoxicity due to reactive oxygen species generation and sympathetic activation. Both factors are associated with atherosclerosis, so we tested the hypothesis that chronic METH administration might also promote atherosclerosis formation in Apo E-/- knockout mice fed normal diet. Male ApoE-/- mice (6 weeks-old) were treated with saline (NS) or METH [4 mg/kg/day (M4) or 8 mg/kg/day (M8) through intraperitoneal injection] for 24 weeks. Atherosclerotic lesion area on oil red O stained en face aorta was dose-dependently increased in M4 and M8 groups compared to NS group. Percentage of atherosclerotic lesion area was significantly higher in M8 group compared to NS and M4 groups. Plasma CRP was increased and inflammatory cytokine (ICAM-1, VCAM-1, TNF-α, and INF-γ) expression on aortic root was upregulated in METH groups compared to NS group. Neuropeptide Y (NPY) protein and mRNA expressions in aortic root and myocardial tissue were determined by Western blot and real time PCR, which were significantly upregulated in M4 and M8 groups. Moreover, mRNA expressions of NPY1R, NPY2R and NPY5R in aortic and myocardial tissue were also significantly upregulated in M4 and M8 groups. Raw264.7 cells were treated with NPY, NPY receptor antagonists, METH (10 μM or 100 μM) with or without lipopolysaccharide (LPS), and the expressions of TNF-α, CRP, MCP-1 and reactive oxygen species (ROS) production were significantly increased in METH and LPS + METH groups compared to control and LPS groups. Co-treatment with NPY1R antagonist decreased the expressions of TNF-α, CRP and MCP-1 in NPY and METH treated cells. Chronic METH administration can promote inflammation and atherosclerotic plague formation in ApoE-/- mice fed normal chow. NPY might be involved in the pathogenesis of METH-induced atherogenic effects through NPY Y1 receptor pathway. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Neutral oligosaccharides in feces of breastfed and formula-fed infants at different ages.

PubMed

Dotz, Viktoria; Adam, Rüdiger; Lochnit, Günter; Schroten, Horst; Kunz, Clemens

2016-12-01

Beneficial effects have been proposed for human milk oligosaccharides (HMO), as deduced from in vitro and animal studies. To date, in vivo evidence of the link between certain oligosaccharide structures in milk and their consumption by infant gut microbiota is still missing, although likely. Whereas many studies have described HMO patterns in human milk from larger cohorts, data on the excretion of HMO and possible metabolites produced in the infant gut are still very limited. From smaller-scale studies, an age-dependency according to infant gut maturation and microbiota adaptation has previously been hypothesized. To further investigate this, we profiled neutral fecal oligosaccharides from term-born infants who were exclusively breastfed, formula-fed or mixed-fed at the age of 2 months, and from a follow-up of a subgroup at 7 months of age (INFABIO study). Data on maternal antibiotic exposure was also included. Automated matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analyses revealed the presence of HMO and metabolites in the feces of most, but not all breastfed infants at 2 months, with highly varying patterns that appeared not to differ with maternal antibiotics exposure. Formula-fed infants at 2 months and most of the breastfed infants at 7 months did not excrete HMO-like structures in their feces, the latter corresponding to the hypothesis of age-dependency. Together with our previous results that were partly contradictory to what has been proposed by others, here, we suggest alternative explanations for the described association of oligosaccharide excretion with age and feeding type in infants below 7 months of age. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Resilience in Aging Mice

PubMed Central

Kirkland, James L.; Stout, Michael B.

2016-01-01

Abstract Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an

Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

PubMed Central

van der Heijden, Roel A.; Bijzet, Johan; Meijers, Wouter C.; Yakala, Gopala K.; Kleemann, Robert; Nguyen, Tri Q.; de Boer, Rudolf A.; Schalkwijk, Casper G.; Hazenberg, Bouke P. C.; Tietge, Uwe J. F.; Heeringa, Peter

2015-01-01

Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process. PMID:26563579

Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis.

PubMed

van der Heijden, Roel A; Bijzet, Johan; Meijers, Wouter C; Yakala, Gopala K; Kleemann, Robert; Nguyen, Tri Q; de Boer, Rudolf A; Schalkwijk, Casper G; Hazenberg, Bouke P C; Tietge, Uwe J F; Heeringa, Peter

2015-11-13

Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process.

Muscle-specific deletion of Prkaa1 enhances skeletal muscle lipid accumulation in mice fed a high-fat diet.

PubMed

Wu, Weiche; Xu, Ziye; Zhang, Ling; Liu, Jiaqi; Feng, Jie; Wang, Xinxia; Shan, Tizhong; Wang, Yizhen

2018-05-01

Excessive intramyocellular triacylglycerols (IMTGs, muscle lipids) are associated with the abnormal energy metabolism and insulin resistance of skeletal muscle. AMP-activated protein kinase (AMPK), a crucial cellular energy sensor, consists of α, β and γ subunits. Researchers have not clearly determined whether Prkaa1 (also known as AMPKα1) affects IMTG accumulation in skeletal muscle. Here, we show an important role of Prkaa1 in skeletal muscle lipid metabolism. Deletion of muscle Prkaa1 leads to the delayed development of skeletal muscles but does not affect glucose tolerance or insulin sensitivity in animals fed a normal diet. Notably, when animals are fed a high-fat diet, the skeletal muscle of muscle-specific Prkaa1 knockout mice accumulates more lipids than the skeletal muscle of wild-type (WT) mice, with concomitant upregulation of adipogenic gene expressions and downregulation of the expression of genes associated with mitochondrial oxidation. Muscle-specific Prkaa1 ablation also results in hyperlipidemia, which may contribute to the increased IMTG levels. Furthermore, Prkaa1 deletion activates skeletal muscle mTOR signalling, which has a central role in lipid metabolism and mitochondrial oxidation. Collectively, our study provides new insights into the role of Prkaa1 in skeletal muscle. This knowledge may contribute to the treatment of related metabolic diseases.

Astaxanthin affects oxidative stress and hyposalivation in aging mice

PubMed Central

Kuraji, Manatsu; Matsuno, Tomonori; Satoh, Tazuko

2016-01-01

Oral dryness, a serious problem for the aging Japanese society, is induced by aging-related hyposalivation and causes dysphagia, dysgeusia, inadaptation of dentures, and growth of oral Candida albicans. Oxidative stress clearly plays a role in decreasing saliva secretion and treatment with antioxidants such astaxanthin supplements may be beneficial. Therefore, we evaluated the effects of astaxanthin on the oral saliva secretory function of aging mice. The saliva flow increased in astaxanthin-treated mice 72 weeks after administration while that of the control decreased by half. The plasma d-ROMs values of the control but not astaxanthin-treated group measured before and 72 weeks after treatment increased. The diacron-reactive oxygen metabolites (d-ROMs) value of astaxanthin-treated mice 72 weeks after treatment was significantly lower than that of the control group was. The plasma biological antioxidative potential (BAP) values of the control but not astaxanthin-treated mice before and 72 weeks after treatment decreased. Moreover, the BAP value of the astaxanthin-treated group 72 weeks after treatment was significantly higher than that of the control was. Furthermore, the submandibular glands of astaxanthin-treated mice had fewer inflammatory cells than the control did. Specifically, immunofluorescence revealed a significantly large aquaporin-5 positive cells in astaxanthin-treated mice. Our results suggest that astaxanthin treatment may prevent age-related decreased saliva secretion. PMID:27698533

Effects of Acerola (Malpighia emarginata DC.) Juice Intake on Brain Energy Metabolism of Mice Fed a Cafeteria Diet.

PubMed

Leffa, Daniela Dimer; Rezin, Gislaine Tezza; Daumann, Francine; Longaretti, Luiza M; Dajori, Ana Luiza F; Gomes, Lara Mezari; Silva, Milena Carvalho; Streck, Emílio L; de Andrade, Vanessa Moraes

2017-03-01

Obesity is a multifactorial disease that comes from an imbalance between food intake and energy expenditure. Moreover, studies have shown a relationship between mitochondrial dysfunction and obesity. In the present study, we investigated the effect of acerola juices (unripe, ripe, and industrial) and its main pharmacologically active components (vitamin C and rutin) on the activity of enzymes of energy metabolism in the brain of mice fed a palatable cafeteria diet. Two groups of male Swiss mice were fed on a standard diet (STA) or a cafeteria diet (CAF) for 13 weeks. Afterwards, the CAF-fed animals were divided into six subgroups, each of which received a different supplement for one further month (water, unripe, ripe or industrial acerola juices, vitamin C, or rutin) by gavage. Our results demonstrated that CAF diet inhibited the activity of citrate synthase in the prefrontal cortex, hippocampus, and hypothalamus. Moreover, CAF diet decreased the complex I activity in the hypothalamus, complex II in the prefrontal cortex, complex II-III in the hypothalamus, and complex IV in the posterior cortex and striatum. The activity of succinate dehydrogenase and creatine kinase was not altered by the CAF diet. However, unripe acerola juice reversed the inhibition of the citrate synthase activity in the prefrontal cortex and hypothalamus. Ripe acerola juice reversed the inhibition of citrate synthase in the hypothalamus. The industrial acerola juice reversed the inhibition of complex I activity in the hypothalamus. The other changes were not reversed by any of the tested substances. In conclusion, we suggest that alterations in energy metabolism caused by obesity can be partially reversed by ripe, unripe, and industrial acerola juice.

Age-related T2 changes in hindlimb muscles of mdx mice.

PubMed

Vohra, Ravneet S; Mathur, Sunita; Bryant, Nathan D; Forbes, Sean C; Vandenborne, Krista; Walter, Glenn A

2016-01-01

Magnetic resonance imaging (MRI) was used to monitor changes in the transverse relaxation time constant (T2) in lower hindlimb muscles of mdx mice at different ages. Young (5 weeks), adult (44 weeks), and old mdx (96 weeks), and age-matched control mice were studied. Young mdx mice were imaged longitudinally, whereas adult and old mdx mice were imaged at a single time-point. Mean muscle T2 and percent of pixels with elevated T2 were significantly different between mdx and control mice at all ages. In young mdx mice, mean muscle T2 peaked at 7-8 weeks and declined at 9-11 weeks. In old mdx mice, mean muscle T2 was decreased compared with young and adult mice, which could be attributed to fibrosis. MRI captured longitudinal changes in skeletal muscle integrity of mdx mice. This information will be valuable for pre-clinical testing of potential therapeutic interventions for muscular dystrophy. © 2015 Wiley Periodicals, Inc.

Anti-inflammatory and antiatherogenic effects of the NLRP3 inflammasome inhibitor arglabin in ApoE2.Ki mice fed a high-fat diet.

PubMed

Abderrazak, Amna; Couchie, Dominique; Mahmood, Dler Faieeq Darweesh; Elhage, Rima; Vindis, Cécile; Laffargue, Muriel; Matéo, Véronique; Büchele, Berthold; Ayala, Monica Rubio; El Gaafary, Menna; Syrovets, Tatiana; Slimane, Mohamed-Naceur; Friguet, Bertrand; Fulop, Tamas; Simmet, Thomas; El Hadri, Khadija; Rouis, Mustapha

2015-03-24

This study was designed to evaluate the effect of arglabin on the NLRP3 inflammasome inhibition and atherosclerotic lesion in ApoE2Ki mice fed a high-fat Western-type diet. Arglabin was purified, and its chemical identity was confirmed by mass spectrometry. It inhibited, in a concentration-dependent manner, interleukin (IL)-1β and IL-18, but not IL-6 and IL-12, production in lipopolysaccharide and cholesterol crystal-activated cultured mouse peritoneal macrophages, with a maximum effect at ≈50 nmol/L and EC50 values for both cytokines of ≈ 10 nmol/L. Lipopolysaccharide and cholesterol crystals did not induce IL-1β and IL-18 production in Nlrp3(-/-) macrophages. In addition, arglabin activated autophagy as evidenced by the increase in LC3-II protein. Intraperitoneal injection of arglabin (2.5 ng/g body weight twice daily for 13 weeks) into female ApoE2.Ki mice fed a high-fat diet resulted in a decreased IL-1β plasma level compared with vehicle-treated mice (5.2±1.0 versus 11.7±1.1 pg/mL). Surprisingly, arglabin also reduced plasma levels of total cholesterol and triglycerides to 41% and 42%, respectively. Moreover, arglabin oriented the proinflammatory M1 macrophages into the anti-inflammatory M2 phenotype in spleen and arterial lesions. Finally, arglabin treatment markedly reduced the median lesion areas in the sinus and whole aorta to 54% (P=0.02) and 41% (P=0.02), respectively. Arglabin reduces inflammation and plasma lipids, increases autophagy, and orients tissue macrophages into an anti-inflammatory phenotype in ApoE2.Ki mice fed a high-fat diet. Consequently, a marked reduction in atherosclerotic lesions was observed. Thus, arglabin may represent a promising new drug to treat inflammation and atherosclerosis. © 2015 American Heart Association, Inc.

Alteration of strain background and a high omega-6 fat diet induces earlier onset of pancreatic neoplasia in EL-Kras transgenic mice.

PubMed

Cheon, Eric C; Strouch, Matthew J; Barron, Morgan R; Ding, Yongzeng; Melstrom, Laleh G; Krantz, Seth B; Mullapudi, Bhargava; Adrian, Kevin; Rao, Sambasiva; Adrian, Thomas E; Bentrem, David J; Grippo, Paul J

2011-06-15

Diets containing omega-6 (ω-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of ω-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in ω-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras(G12D) (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high ω-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in ω-6 fatty acid. Copyright © 2010 UICC.

Blueberry supplementation attenuates microglia activation and increases neuroplasticity in mice consuming a high fat diet

USDA-ARS?s Scientific Manuscript database

Objectives: Consuming a high-fat diet (HFD) may result in behavioral deficits similar to those observed in aging animals. Blueberries may prevent and even reverse age-related alterations in neurochemistry and behavior. It was previously demonstrated that middle-aged mice fed HFD had impaired memory;...

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.

The modulatory role of spinally located histamine receptors in the regulation of the blood glucose level in d-glucose-fed mice.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

2014-02-01

The possible roles of spinal histamine receptors in the regulation of the blood glucose level were studied in ICR mice. Mice were intrathecally (i.t.) treated with histamine 1 (H1) receptor agonist (2-pyridylethylamine) or antagonist (cetirizine), histamine 2 (H2) receptor agonist (dimaprit) or antagonist (ranitidine), histamine 3 (H3) receptor agonist (α-methylhistamine) or antagonist (carcinine) and histamine 4 (H4) receptor agonist (VUF 8430) or antagonist (JNJ 7777120), and the blood glucose level was measured at 30, 60 and 120 min after i.t. administration. The i.t. injection with α-methylhistamine, but not carcinine slightly caused an elevation of the blood glucose level. In addition, histamine H1, H2, and H4 receptor agonists and antagonists did not affect the blood glucose level. In D-glucose-fed model, i.t. pretreatment with cetirizine enhanced the blood glucose level, whereas 2-pyridylethylamine did not affect. The i.t. pretreatment with dimaprit, but not ranitidine, enhanced the blood glucose level in D-glucose-fed model. In addition, α-methylhistamine, but not carcinine, slightly but significantly enhanced the blood glucose level D-glucose-fed model. Finally, i.t. pretreatment with JNJ 7777120, but not VUF 8430, slightly but significantly increased the blood glucose level. Although histamine receptors themselves located at the spinal cord do not exert any effect on the regulation of the blood glucose level, our results suggest that the activation of spinal histamine H2 receptors and the blockade of spinal histamine H1 or H3 receptors may play modulatory roles for up-regulation and down-regulation, respectively, of the blood glucose level in D-glucose fed model.

Effects of acute exposure to chlorpyrifos on cholinergic and non-cholinergic targets in normal and high-fat fed male C57BL/6J mice.

PubMed

Kondakala, Sandeep; Lee, Jung Hwa; Ross, Matthew K; Howell, George E

2017-12-15

The prevalence of obesity is increasing at an alarming rate in the United States with 36.5% of adults being classified as obese. Compared to normal individuals, obese individuals have noted pathophysiological alterations which may alter the toxicokinetics of xenobiotics and therefore alter their toxicities. However, the effects of obesity on the toxicity of many widely utilized pesticides has not been established. Therefore, the present study was designed to determine if the obese phenotype altered the toxicity of the most widely used organophosphate (OP) insecticide, chlorpyrifos (CPS). Male C57BL/6J mice were fed normal or high-fat diet for 4weeks and administered a single dose of vehicle or CPS (2.0mg/kg; oral gavage) to assess cholinergic (acetylcholinesterase activities) and non-cholinergic (carboxylesterase and endocannabinoid hydrolysis) endpoints. Exposure to CPS significantly decreased red blood cell acetylcholinesterase (AChE) activity, but not brain AChE activity, in both diet groups. Further, CPS exposure decreased hepatic carboxylesterase activity and hepatic hydrolysis of a major endocannabinoid, anandamide, in a diet-dependent manner with high-fat diet fed animals being more sensitive to CPS-mediated inhibition. These in vivo studies were corroborated by in vitro studies using rat primary hepatocytes, which demonstrated that fatty acid amide hydrolase and CES activities were more sensitive to CPS-mediated inhibition than 2-arachidonoylglycerol hydrolase activity. These data demonstrate hepatic CES and FAAH activities in high-fat diet fed mice were more potently inhibited than those in normal diet fed mice following CPS exposure, which suggests that the obese phenotype may exacerbate some of the non-cholinergic effects of CPS exposure. Copyright © 2017 Elsevier Inc. All rights reserved.

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

Dietary fiber prevents obesity-related liver lipotoxicity by modulating sterol-regulatory element binding protein pathway in C57BL/6J mice fed a high-fat/cholesterol diet.

PubMed

Han, Shufen; Jiao, Jun; Zhang, Wei; Xu, Jiaying; Wan, Zhongxiao; Zhang, Weiguo; Gao, Xiaoran; Qin, Liqiang

2015-10-29

Adequate intake of dietary fibers has proven metabolic and cardiovascular benefits, molecular mechanisms remain still limited. This study was aimed to investigate the effects of cereal dietary fiber on obesity-related liver lipotoxicity in C57BL/6J mice fed a high-fat/cholesterol (HFC) diet and underlying mechanism. Forty-eight adult male C57BL/6J mice were randomly given a reference chow diet, or a high fat/cholesterol (HFC) diet supplemented with or without oat fiber or wheat bran fiber for 24 weeks. Our results showed mice fed oat or wheat bran fiber exhibited lower weight gain, lipid profiles and insulin resistance, compared with HFC diet. The two cereal dietary fibers potently decreased protein expressions of sterol regulatory element binding protein-1 and key factors involved in lipogenesis, including fatty acid synthase and acetyl-CoA carboxylase in target tissues. At molecular level, the two cereal dietary fibers augmented protein expressions of peroxisome proliferator-activated receptor alpha and gamma, liver X receptor alpha, and ATP-binding cassette transporter A1 in target tissues. Our findings indicated that cereal dietary fiber supplementation abrogated obesity-related liver lipotoxicity and dyslipidemia in C57BL/6J mice fed a HFC diet. In addition, the efficacy of oat fiber is greater than wheat bran fiber in normalizing these metabolic disorders and pathological profiles.

Dietary fiber prevents obesity-related liver lipotoxicity by modulating sterol-regulatory element binding protein pathway in C57BL/6J mice fed a high-fat/cholesterol diet

PubMed Central

Han, Shufen; Jiao, Jun; Zhang, Wei; Xu, Jiaying; Wan, Zhongxiao; Zhang, Weiguo; Gao, Xiaoran; Qin, Liqiang

2015-01-01

Adequate intake of dietary fibers has proven metabolic and cardiovascular benefits, molecular mechanisms remain still limited. This study was aimed to investigate the effects of cereal dietary fiber on obesity-related liver lipotoxicity in C57BL/6J mice fed a high-fat/cholesterol (HFC) diet and underlying mechanism. Forty-eight adult male C57BL/6J mice were randomly given a reference chow diet, or a high fat/choleserol (HFC) diet supplemented with or without oat fiber or wheat bran fiber for 24 weeks. Our results showed mice fed oat or wheat bran fiber exhibtied lower weight gain, lipid profiles and insulin resistance, compared with HFC diet. The two cereal dietary fibers potently decreased protein expressions of sterol regulatory element binding protein-1 and key factors involved in lipogenesis, including fatty acid synthase and acetyl-CoA carboxylase in target tissues. At molecular level, the two cereal dietary fibers augmented protein expressions of peroxisome proliferator-activated receptor alpha and gamma, liver X receptor alpha, and ATP-binding cassette transporter A1 in target tissues. Our findings indicated that cereal dietary fiber supplementation abrogated obesity-related liver lipotoxicity and dyslipidemia in C57BL/6J mice fed a HFC diet. In addition, the efficacy of oat fiber is greater than wheat bran fiber in normalizing these metabolic disorders and pathological profiles. PMID:26510459

Post-weaning selenium and folate supplementation affects gene and protein expression and global DNA methylation in mice fed high-fat diets.

PubMed

Bermingham, Emma N; Bassett, Shalome A; Young, Wayne; Roy, Nicole C; McNabb, Warren C; Cooney, Janine M; Brewster, Di T; Laing, William A; Barnett, Matthew P G

2013-03-05

Consumption of high-fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in offspring of female mice fed a high-fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets inadequate in selenium and folate during gestation and lactation can alter global DNA methylation in liver. This may be one factor through which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health.

Post-weaning selenium and folate supplementation affects gene and protein expression and global DNA methylation in mice fed high-fat diets

PubMed Central

2013-01-01

Background Consumption of high-fat diets has negative impacts on health and well-being, some of which may be epigenetically regulated. Selenium and folate are two compounds which influence epigenetic mechanisms. We investigated the hypothesis that post-weaning supplementation with adequate levels of selenium and folate in offspring of female mice fed a high-fat, low selenium and folate diet during gestation and lactation will lead to epigenetic changes of potential importance for long-term health. Methods Female offspring of mothers fed the experimental diet were either maintained on this diet (HF-low-low), or weaned onto a high-fat diet with sufficient levels of selenium and folate (HF-low-suf), for 8 weeks. Gene and protein expression, DNA methylation, and histone modifications were measured in colon and liver of female offspring. Results Adequate levels of selenium and folate post-weaning affected gene expression in colon and liver of offspring, including decreasing Slc2a4 gene expression. Protein expression was only altered in the liver. There was no effect of adequate levels of selenium and folate on global histone modifications in the liver. Global liver DNA methylation was decreased in mice switched to adequate levels of selenium and folate, but there was no effect on methylation of specific CpG sites within the Slc2a4 gene in liver. Conclusions Post-weaning supplementation with adequate levels of selenium and folate in female offspring of mice fed high-fat diets inadequate in selenium and folate during gestation and lactation can alter global DNA methylation in liver. This may be one factor through which the negative effects of a poor diet during early life can be ameliorated. Further research is required to establish what role epigenetic changes play in mediating observed changes in gene and protein expression, and the relevance of these changes to health. PMID:23497688

Fatty liver accompanies an increase in lactobacillus species in the hind gut of C57BL/6 mice fed a high-fat diet.

PubMed

Zeng, Huawei; Liu, Jun; Jackson, Matthew I; Zhao, Feng-Qi; Yan, Lin; Combs, Gerald F

2013-05-01

High-fat (HF) diets can produce obesity and have been linked to the development of nonalcoholic fatty liver disease and changes in the gut microbiome. To test the hypothesis that HF feeding increases certain predominant hind gut bacteria and development of steatohepatitis, C57BL/6 mice were fed an HF (45% energy) or low-fat (LF) (10% energy) diet for 10 wk. At the end of the feeding period, body weights in the HF group were 34% greater than those in the LF group (P < 0.05). These changes were associated with dramatic increases in lipid droplet number and size, inflammatory cell infiltration, and inducible nitric oxide (NO) synthase protein concentration in the livers of mice fed the HF diet. Consistent with the fatty liver phenotype, plasma leptin and tumor necrosis factor-α concentrations were also elevated in mice fed the HF diet, indicative of chronic inflammation. Eight of 12 pairs of polymerase chain reaction (PCR) primers for bacterial species that typically predominate hind gut microbial ecology generated specific PCR products from the fecal DNA samples. The amount of DNA from Lactobacillus gasseri and/or Lactobacillus taiwanensis in the HF group was 6900-fold greater than that in the LF group. Many of these bacteria are bile acid resistant and are capable of bile acid deconjugation. Because bile acids are regulators of hepatic lipid metabolism, the marked increase of gut L. gasseri and/or L. taiwanensis species bacteria with HF feeding may play a role in development of steatohepatitis in this model.

Effects of Supplemental Acerola Juice on the Mineral Concentrations in Liver and Kidney Tissue Samples of Mice Fed with Cafeteria Diet.

PubMed

Leffa, Daniela Dimer; dos Santos, Carla Eliete Iochims; Daumann, Francine; Longaretti, Luiza Martins; Amaral, Livio; Dias, Johnny Ferraz; da Silva, Juliana; Andrade, Vanessa Moraes

2015-09-01

We evaluated the impact of a supplemental acerola juice (unripe, ripe, and industrial) and its main pharmaceutically active components on the concentrations of minerals in the liver and kidney of mice fed with cafeteria diet. Swiss male mice were fed with a cafeteria (CAF) diet for 13 weeks. The CAF consisted of a variety of supermarket products with high energy content. Subsequently, animals received one of the following food supplements for 1 month: water, unripe acerola juice, ripe acerola juice, industrial acerola juice, vitamin C, or rutin. Mineral concentrations of the tissues were determined by particle-induced X-ray emission (PIXE). Our study suggests that the simultaneous intake of acerola juices, vitamin C, or rutin in association with a hypercaloric and hyperlipidic diet provides change in the mineral composition of organisms in the conditions of this study, which plays an important role in the antioxidant defenses of the body. This may help to reduce the metabolism of the fat tissue or even to reduce the oxidative stress.

A ketogenic diet reduces metabolic syndrome-induced allodynia and promotes peripheral nerve growth in mice.

PubMed

Cooper, Michael A; Menta, Blaise W; Perez-Sanchez, Consuelo; Jack, Megan M; Khan, Zair W; Ryals, Janelle M; Winter, Michelle; Wright, Douglas E

2018-08-01

Current experiments investigated whether a ketogenic diet impacts neuropathy associated with obesity and prediabetes. Mice challenged with a ketogenic diet were compared to mice fed a high-fat diet or a high-fat diet plus exercise. Additionally, an intervention switching to a ketogenic diet following 8 weeks of high-fat diet was performed to compare how a control diet, exercise, or a ketogenic diet affects metabolic syndrome-induced neural complications. When challenged with a ketogenic diet, mice had reduced bodyweight and fat mass compared to high-fat-fed mice, and were similar to exercised, high-fat-fed mice. High-fat-fed, exercised and ketogenic-fed mice had mildly elevated blood glucose; conversely, ketogenic diet-fed mice were unique in having reduced serum insulin levels. Ketogenic diet-fed mice never developed mechanical allodynia contrary to mice fed a high-fat diet. Ketogenic diet fed mice also had increased epidermal axon density compared all other groups. When a ketogenic diet was used as an intervention, a ketogenic diet was unable to reverse high-fat fed-induced metabolic changes but was able to significantly reverse a high-fat diet-induced mechanical allodynia. As an intervention, a ketogenic diet also increased epidermal axon density. In vitro studies revealed increased neurite outgrowth in sensory neurons from mice fed a ketogenic diet and in neurons from normal diet-fed mice given ketone bodies in the culture medium. These results suggest a ketogenic diet can prevent certain complications of prediabetes and provides significant benefits to peripheral axons and sensory dysfunction. Published by Elsevier Inc.

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.

Enhanced peroxisomal β-oxidation metabolism in visceral adipose tissues of high-fat diet-fed obesity-resistant C57BL/6 mice

PubMed Central

XIE, WEI-DONG; WANG, HUA; ZHANG, JIN-FANG; LI, JIAN-NA; CAN, YI; QING, LV; KUNG, HSIANG-FU; ZHANG, YA-OU

2011-01-01

This study aimed to investigate the potential mechanisms of natural resistance to high-fat diet-induced obesity. Four-week-old C57BL/6 mice were fed a high-fat diet for 6 weeks and were then designated as high-fat diet-fed obesity-prone (HOP) and obesity-resistant (HOR) animals. Their blood biochemistry was evaluated, and visceral adipose tissue samples were subjected to proteomic, Western blot and quantitative real-time PCR (q-PCR) analyses. The HOR mice showed reduced visceral fat weight and size, as well as lowered serum lipid and leptin levels. Proteomic analysis showed that enoyl coenzyme A hydratase 1, peroxisomal (Ech1) expression was significantly increased in their visceral adipose tissues. Moreover, other proteins, such as α-tropomyosin, myosin light chain, urine-nucleoside phosphorylase and transgelin, were also significantly increased. Furthermore, q-PCR analysis showed that the expression of acyl-CoA oxidase 1 palmitoyl, enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase and 3-oxoacyl-CoA thiolase responsible for peroxisomal β-oxidation was also up-regulated in the visceral adipose tissues of the HOR mice. The expression of peroxisome proliferator-activated receptor α (PPARα) was increased in the HOR mice as shown by Western blot analysis. Obesity-resistant animals show enhanced peroxisomal β-oxidation metabolism and reduced fat accumulation in visceral adipose tissues by up-regulating the expression of Ech1, peroxisomal or other related peroxisomal β-oxidation marker genes, which may be driven or enhanced by the up-regulation of the expression of PPARα. However, further validation in future studies is required. PMID:22977503

Joint dysfunction and functional decline in middle age myostatin null mice.

PubMed

Guo, Wen; Miller, Andrew D; Pencina, Karol; Wong, Siu; Lee, Amanda; Yee, Michael; Toraldo, Gianluca; Jasuja, Ravi; Bhasin, Shalender

2016-02-01

Since its discovery as a potent inhibitor for muscle development, myostatin has been actively pursued as a drug target for age- and disease-related muscle loss. However, potential adverse effects of long-term myostatin deficiency have not been thoroughly investigated. We report herein that male myostatin null mice (mstn(-/-)), in spite of their greater muscle mass compared to wild-type (wt) mice, displayed more significant functional decline from young (3-6months) to middle age (12-15months) than age-matched wt mice, measured as gripping strength and treadmill endurance. Mstn(-/-) mice displayed markedly restricted ankle mobility and degenerative changes of the ankle joints, including disorganization of bone, tendon and peri-articular connective tissue, as well as synovial thickening with inflammatory cell infiltration. Messenger RNA expression of several pro-osteogenic genes was higher in the Achilles tendon-bone insertion in mstn(-/-) mice than wt mice, even at the neonatal age. At middle age, higher plasma concentrations of growth factors characteristic of excessive bone remodeling were found in mstn(-/-) mice than wt controls. These data collectively indicate that myostatin may play an important role in maintaining ankle and wrist joint health, possibly through negative regulation of the pro-osteogenic WNT/BMP pathway. Copyright © 2015 Elsevier Inc. All rights reserved.

Pasture v. standard dairy cream in high-fat diet-fed mice: improved metabolic outcomes and stronger intestinal barrier.

PubMed

Benoit, Bérengère; Plaisancié, Pascale; Géloën, Alain; Estienne, Monique; Debard, Cyrille; Meugnier, Emmanuelle; Loizon, Emmanuelle; Daira, Patricia; Bodennec, Jacques; Cousin, Olivier; Vidal, Hubert; Laugerette, Fabienne; Michalski, Marie-Caroline

2014-08-28

Dairy products derived from the milk of cows fed in pastures are characterised by higher amounts of conjugated linoleic acid and α-linolenic acid (ALA), and several studies have shown their ability to reduce cardiovascular risk. However, their specific metabolic effects compared with standard dairy in a high-fat diet (HFD) context remain largely unknown; this is what we determined in the present study with a focus on the metabolic and intestinal parameters. The experimental animals were fed for 12 weeks a HFD containing 20 % fat in the form of a pasture dairy cream (PDC) or a standard dairy cream (SDC). Samples of plasma, liver, white adipose tissue, duodenum, jejunum and colon were analysed. The PDC mice, despite a higher food intake, exhibited lower fat mass, plasma and hepatic TAG concentrations, and inflammation in the adipose tissue than the SDC mice. Furthermore, they exhibited a higher expression of hepatic PPARα mRNA and adipose tissue uncoupling protein 2 mRNA, suggesting an enhanced oxidative activity of the tissues. These results might be explained, in part, by the higher amounts of ALA in the PDC diet and in the liver and adipose tissue of the PDC mice. Moreover, the PDC diet was found to increase the proportions of two strategic cell populations involved in the protective function of the intestinal epithelium, namely Paneth and goblet cells in the small intestine and colon, compared with the SDC diet. In conclusion, a PDC HFD leads to improved metabolic outcomes and to a stronger gut barrier compared with a SDC HFD. This may be due, at least in part, to the protective mechanisms induced by specific lipids.

Crucial roles of Nox2-derived oxidative stress in deteriorating the function of insulin receptors and endothelium in dietary obesity of middle-aged mice.

PubMed

Du, Junjie; Fan, Lampson M; Mai, Anna; Li, Jian-Mei

2013-11-01

Systemic oxidative stress associated with dietary calorie overload plays an important role in the deterioration of vascular function in middle-aged patients suffering from obesity and insulin resistance. However, effective therapy is still lacking. In this study, we used a mouse model of middle-aged obesity to investigate the therapeutic potential of pharmaceutical inhibition (apocynin, 5 mM supplied in the drinking water) or knockout of Nox2, an enzyme generating reactive oxygen species (ROS), in high-fat diet (HFD)-induced obesity, oxidative stress, insulin resistance and endothelial dysfunction. Littermates of C57BL/6J wild-type (WT) and Nox2 knockout (KO) mice (7 months old) were fed with a HFD (45% kcal fat) or normal chow diet (NCD, 12% kcal fat) for 16 weeks and used at 11 months of age. Compared to NCD WT mice, HFD WT mice developed obesity, insulin resistance, dyslipidaemia and hypertension. Aortic vessels from these mice showed significantly increased Nox2 expression and ROS production, accompanied by significantly increased ERK1/2 activation, reduced insulin receptor expression, decreased Akt and eNOS phosphorylation and impaired endothelium-dependent vessel relaxation to acetylcholine. All these HFD-induced abnormalities (except the hyperinsulinaemia) were absent in apocynin-treated WT or Nox2 KO mice given the same HFD. In conclusion, Nox2-derived ROS played a key role in damaging insulin receptor and endothelial function in dietary obesity after middle-age. Targeting Nox2 could represent a valuable therapeutic strategy in the metabolic syndrome. © 2013 The British Pharmacological Society.

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.

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.

Aging exacerbates obesity-induced oxidative stress and inflammation in perivascular adipose tissue in mice: a paracrine mechanism contributing to vascular redox dysregulation and inflammation.

PubMed

Bailey-Downs, Lora C; Tucsek, Zsuzsanna; Toth, Peter; Sosnowska, Danuta; Gautam, Tripti; Sonntag, William E; Csiszar, Anna; Ungvari, Zoltan

2013-07-01

Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet-fed obese C57BL/6 mice. High-fat diet-induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet-induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals.

Aging Exacerbates Obesity-Induced Oxidative Stress and Inflammation in Perivascular Adipose Tissue in Mice: A Paracrine Mechanism Contributing to Vascular Redox Dysregulation and Inflammation

PubMed Central

Bailey-Downs, Lora C.; Tucsek, Zsuzsanna; Toth, Peter

2013-01-01

Obesity in the elderly individuals is increasing at alarming rates and there is evidence suggesting that elderly individuals are more vulnerable to the deleterious cardiovascular effects of obesity than younger individuals. However, the specific mechanisms through which aging and obesity interact to promote the development of cardiovascular disease remain unclear. The present study was designed to test the hypothesis that aging exacerbates obesity-induced inflammation in perivascular adipose tissue, which contributes to increased vascular oxidative stress and inflammation in a paracrine manner. To test this hypothesis, we assessed changes in the secretome, reactive oxygen species production, and macrophage infiltration in periaortic adipose tissue of young (7 month old) and aged (24 month old) high-fat diet–fed obese C57BL/6 mice. High-fat diet–induced vascular reactive oxygen species generation significantly increased in aged mice, which was associated with exacerbation of endothelial dysfunction and vascular inflammation. In young animals, high-fat diet–induced obesity promoted oxidative stress in the perivascular adipose tissue, which was associated with a marked proinflammatory shift in the profile of secreted cytokines and chemokines. Aging exacerbated obesity-induced oxidative stress and inflammation and significantly increased macrophage infiltration in periaortic adipose tissue. Using cultured arteries isolated from young control mice, we found that inflammatory factors secreted from the perivascular fat tissue of obese aged mice promote significant prooxidative and proinflammatory phenotypic alterations in the vascular wall, mimicking the aging phenotype. Overall, our findings support an important role for localized perivascular adipose tissue inflammation in exacerbation of vascular oxidative stress and inflammation in aging, an effect that likely enhances the risk for development of cardiovascular diseases from obesity in the elderly individuals

Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice

PubMed Central

Buchanan, J.B.; Sparkman, N.L.; Chen, J.; Johnson, R.W.

2008-01-01

Summary Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3–5 mo) and aged (22–23 mo) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 minutes before being tested in a working memory version of the water maze over a 3 day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1β mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible a role for IL-1β. PMID:18407425

Resilience in Aging Mice.

PubMed

Kirkland, James L; Stout, Michael B; Sierra, Felipe

2016-11-01

Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context

Quantitative deviating effects of maple syrup extract supplementation on the hepatic gene expression of mice fed a high-fat diet.

PubMed

Kamei, Asuka; Watanabe, Yuki; Shinozaki, Fumika; Yasuoka, Akihito; Shimada, Kousuke; Kondo, Kaori; Ishijima, Tomoko; Toyoda, Tsudoi; Arai, Soichi; Kondo, Takashi; Abe, Keiko

2017-02-01

Maple syrup contains various polyphenols and we investigated the effects of a polyphenol-rich maple syrup extract (MSXH) on the physiology of mice fed a high-fat diet (HFD). The mice fed a low-fat diet (LFD), an HFD, or an HFD supplemented with 0.02% (002MSXH) or 0.05% MSXH (005MSXH) for 4 weeks. Global gene expression analysis of the liver was performed, and the differentially expressed genes were classified into three expression patterns; pattern A (LFD < HFD > 002MSXH = 005MSXH, LFD > HFD < 002MSXH = 005MSXH), pattern B (LFD < HFD = 002MSXH > 005MSXH, LFD > HFD = 002MSXH < 005MSXH), and pattern C (LFD < HFD > 002MSXH < 005MSXH, LFD > HFD < 002MSXH > 005MSXH). Pattern A was enriched in glycolysis, fatty acid metabolism, and folate metabolism. Pattern B was enriched in tricarboxylic acid cycle while pattern C was enriched in gluconeogenesis, cholesterol metabolism, amino acid metabolism, and endoplasmic reticulum stress-related event. Our study suggested that the effects of MSXH ingestion showed (i) dose-dependent pattern involved in energy metabolisms and (ii) reversely pattern involved in stress responses. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

PubMed

Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a

Age-related Changes in the Hepatic Microcirculation in Mice

PubMed Central

Ito, Yoshiya; Sørensen, Karen K.; Bethea, Nancy W.; Svistounov, Dmitri; McCuskey, Margaret K.; Smedsrød, Bård H.; McCuskey, Robert S.

2007-01-01

Aging of the liver is associated with impaired metabolism of drugs, adverse drug interactions, and susceptibility to toxins. Since reduced hepatic blood flow is suspected to contribute this impairment, we examined age-related alterations in hepatic microcirculation.. Livers of C57Bl/6 mice were examined at 0.8 (pre-pubertal), 3 (young adult), 14 (middle-aged) and 27 (senescent) months of age using in vivo and electron microscopic methods. The results demonstrated a 14% reduction in the numbers of perfused sinusoids between 0.8 and 27 month mice associated with 35% reduction in sinusoidal blood flow. This was accompanied by an inflammatory response evidenced by a 5-fold increase in leukocyte adhesion in 27 month mice, up-regulated expression of ICAM-1, and increases in intrahepatic macrophages. Sinusoidal diameter decreased 6-10%. Liver sinusoidal endothelial cell (LSEC) dysfunction was seen as early as 14 months when there was a 3-fold increase in the numbers of swollen LSEC. The endocytotic capacity of LSEC also was found to be reduced in older animals. The sinusoidal endothelium in 27 month old mice exhibited pseudocapillarization. In conclusion, the results suggest that leukocyte accumulation in the sinusoids and narrowing of sinusoidal lumens due to pseudocapillarization and dysfunction of LSEC reduce sinusoidal blood flow in aged livers. PMID:17582718

Soy Content of Basal Diets Determines the Effects of Supplemental Selenium in Male Mice123

PubMed Central

Quiner, Trevor E.; Nakken, Heather L.; Mason, Brock A.; Lephart, Edwin D.; Hancock, Chad R.; Christensen, Merrill J.

2011-01-01

The effects of supplemental Se in rodent models may depend upon composition of the basal diet to which it is added. Wild-type male littermates of Transgenic Adenocarcinoma of Mouse Prostate mice were fed until 18 wk of age 1 of 2 Se-adequate stock diets high in soy (HS) or low in phytoestrogens (LP) or the same diets supplemented with 3.0 mg Se/kg diet as seleno-methylselenocysteine. Body and abdominal fat pad weights were lower (P < 0.01) in mice fed the HS diet. Supplemental Se reduced fat pad weights in mice receiving the LP diet but increased body and fat pad weights in mice consuming the HS formulation (P-interaction < 0.005). Serum free triiodothyronine concentrations were unaffected by supplemental Se in mice fed the LP diet but were decreased by Se supplementation of mice given the HS feed (P-interaction < 0.02). Free thyroxine concentrations were higher in mice consuming the HS diet regardless of Se intake (P < 0.001). Hepatic mRNA for iodothyronine deiodinase I was lower (P < 0.001) in mice fed the HS diet. Supplementation of Se increased this mRNA (P < 0.001) in both diet groups. Results from this study show a significant interaction between the composition of basal diets and the effects of supplemental Se with respect to body composition. These findings have important implications for future studies in rodent models of the effects of supplemental Se on heart disease, cancer, diabetes, and other conditions related to body weight and composition. PMID:22031663

Dihydrocapsiate improved age-associated impairments in mice by increasing energy expenditure.

PubMed

Ohyama, Kana; Suzuki, Katsuya

2017-11-01

Metabolic dysfunction is associated with aging and results in age-associated chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Hence, there has been a focus on increasing energy expenditure in aged populations to protect them from age-associated diseases. Dihydrocapsiate (DCT) is a compound that belongs to the capsinoid family. Capsinoids are capsaicin analogs that are found in nonpungent peppers and increase whole body energy expenditure. However, their effect on energy expenditure has been reported only in young populations, and to date the effectiveness of DCT in increasing energy expenditure in aged populations has not been investigated. In this study, we investigated whether DCT supplementation in aged mice improves age-associated impairments. We obtained 5-wk-old and 1-yr-old male C57BL/6J mice and randomly assigned the aged mice to two groups, resulting in a total of three groups: 1 ) young mice, 2 ) old mice, and 3 ) old mice supplemented with 0.3% DCT. After 12 wk of supplementation, blood and tissue samples were collected and analyzed. DCT significantly suppressed age-associated fat accumulation, adipocyte hypertrophy, and liver steatosis. In addition, the DCT treatment dramatically suppressed age-associated increases in hepatic inflammation, immune cell infiltration, and oxidative stress. DCT exerted these suppression effects by increasing energy expenditure linked to upregulation of both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that DCT efficiently improves age-associated impairments, including liver steatosis and inflammation, in part by increasing energy expenditure via activation of the fat oxidation pathway in skeletal muscle. Copyright © 2017 the American Physiological Society.

Dietary abscisic acid ameliorates glucose tolerance and obesity-related inflammation in db/db mice fed high-fat diets.

PubMed

Guri, Amir J; Hontecillas, Raquel; Si, Hongwei; Liu, Dongmin; Bassaganya-Riera, Josep

2007-02-01

Despite their efficacy in improving insulin sensitivity, thiazolidinediones (TZDs) are associated with a number of side effects (i.e. weight gain, hepatotoxicity, congestive heart failure) that have limited their use by millions of diabetic patients. We have investigated whether abscisic acid (ABA), a naturally occurring phytochemical with structural similarities to TZDs, could be used as an alternative to TZDs to improve glucose homeostasis. We first examined whether ABA, similar to TZDs, activates PPARgamma in vitro. We next determined the lowest effective dose of dietary ABA (100 mg/kg) and assessed its effect on glucose tolerance, obesity-related inflammation, and mRNA expression of PPARgamma and its responsive genes in white adipose tissue (WAT) of db/db mice fed high-fat diets. We found that ABA induced transactivation of PPARgamma in 3T3-L1 pre-adipocytes in vitro. Dietary ABA-supplementation for 36 days decreased fasting blood glucose concentrations, ameliorated glucose tolerance, and increased mRNA expression of PPARgamma and its responsive genes (i.e., adiponectin, aP2, and CD36) in WAT. We also found that adipocyte hypertrophy, tumor necrosis factor-alpha (TNF-alpha) expression, and macrophage infiltration in WAT were significantly attenuated in ABA-fed mice. These findings suggest that ABA could be used as a nutritional intervention against type II diabetes and obesity-related inflammation.

Salicornia Extract Ameliorates Salt-Induced Aggravation of Nonalcoholic Fatty Liver Disease in Obese Mice Fed a High-Fat Diet.

PubMed

Kim, Jae Hwan; Suk, Sujin; Jang, Woo Jung; Lee, Chang Hyung; Kim, Jong-Eun; Park, Jin-Kyu; Kweon, Mee-Hyang; Kim, Jong Hun; Lee, Ki Won

2017-07-01

High-fat and high-salt intakes are among the major risks of chronic diseases including obesity, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Salicornia is a halophytic plant known to exert antioxidant, antidiabetic, and hypolipidemic effects, and Salicornia-extracted salt (SS) has been used as a salt substitute. In this study, the effects of SS and purified salt (PS) on the aggravation of NAFLD/NASH were compared. C57BL/6J male mice (8-wk-old) were fed a high-fat diet (HFD) for 6 mo and divided into 3 dietary groups, which were additionally fed HFD, HFD + SS, and HFD + PS for 13 wk. PS induced aggravation of NAFLD/NASH in HFD-fed mice. Although the actual salt intake was same between the PS and SS groups as 1% of the diet (extrapolated from the World Health Organization [WHO] guideline), SS induced less liver injury and hepatic steatosis compared to PS. The hepatic mRNA expressions of inflammatory cytokines and fibrosis marker were significantly lower in the SS group than the PS group. Oxidative stress is one of the major causes of inflammation in NAFLD/NASH. Results of the component analysis showed that the major polyphenols that exhibited antioxidant activity in the Salicornia water extract were ferulic acid, caffeic acid, and isorhamnetin. These results suggest that even the level of salt intake recommended by WHO can accelerate the progression of liver disease in obese individuals consuming HFD. It is proposed that SS can be a salt substitute for obese individuals who consume HFD. © 2017 Institute of Food Technologists®.

Glucocorticoid Antagonism Reduces Insulin Resistance and Associated Lipid Abnormalities in High-Fructose-Fed Mice.

PubMed

Priyadarshini, Emayavaramban; Anuradha, Carani Venkatraman

2017-02-01

High intake of dietary fructose causes perturbation in lipid metabolism and provokes lipid-induced insulin resistance. A rise in glucocorticoids (GCs) has recently been suggested to be involved in fructose-induced insulin resistance. The objective of the study was to investigate the effect of GC blockade on lipid abnormalities in insulin-resistant mice. Insulin resistance was induced in mice by administering a high-fructose diet (HFrD) for 60 days. Mifepristone (RU486), a GC antagonist, was administered to HFrD-fed mice for the last 18 days, and the intracellular and extracellular GC levels, the glucocorticoid receptor (GR) activation and the expression of GC-regulated genes involved in lipid metabolism were examined. HFrD elevated the intracellular GC content in both liver and adipose tissue and enhanced the GR nuclear translocation. The plasma GC level remained unchanged. The levels of free fatty acids and triglycerides in plasma were elevated, accompanied by increased plasma insulin and glucose levels and decreased hepatic glycogen content. Treatment with RU486 reduced plasma lipid levels, tissue GC levels and the expression of GC-targeted genes involved in lipid accumulation, and it improved insulin sensitivity. This study demonstrated that HFrD-induced lipid accumulation and insulin resistance are mediated by enhanced GC in liver and adipose tissue and that GC antagonism might reduce fructose-induced lipid abnormalities and insulin resistance. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Andrographis paniculata extract attenuates pathological cardiac hypertrophy and apoptosis in high-fat diet fed mice.

PubMed

Hsieh, You-Liang; Shibu, Marthandam Asokan; Lii, Chong-Kuei; Viswanadha, Vijaya Padma; Lin, Yi-Lin; Lai, Chao-Hung; Chen, Yu-Feng; Lin, Kuan-Ho; Kuo, Wei-Wen; Huang, Chih-Yang

2016-11-04

Andrographis paniculata (Burm. f.) Nees (Acanthaceae) has a considerable medicinal reputation in most parts of Asia as a potent medicine in the treatment of Endocrine disorders, inflammation and hypertension. Water extract of A. paniculata and its active constituent andrographolide are known to possess anti-inflammatory and anti-apoptotic effects. Our aim is to identify whether A. paniculata extract could protect myocardial damage in high-fat diet induced obese mice. The test mice were divided into three groups fed either with normal chow or with high fat diet (obese) or with high fat diet treated with A. paniculata extract (2g/kg/day, through gavage, for a week). We found that the myocardial inflammation pathway related proteins were increased in the obese mouse which potentially contributes to cardiac hypertrophy and myocardial apoptosis. But feeding with A. paniculata extract showed significant inhibition on the effects of high fat diet. Our study strongly suggests that supplementation of A. paniculata extract can be used for prevention and treatment of cardiovascular disease in obese patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Anti-obesity effects of Rapha diet® preparation in mice fed a high-fat diet

PubMed Central

Kim, Jihyun; Kyung, Jangbeen; Kim, Dajeong; Choi, Ehn-Kyoung; Bang, Paul

2012-01-01

The anti-obesity activities of Rapha diet® preparation containing silkworm pupa peptide, Garcinia cambogia, white bean extract, mango extract, raspberry extract, cocoa extract, and green tea extract were investigated in mice with dietary obesity. Male C57BL/6 mice were fed a high-fat diet (HFD) containing 3% Rapha diet® preparation for 8 weeks, and blood and tissue parameters of obesity were analyzed. The HFD markedly enhanced body weight gain by increasing the weights of epididymal, perirenal, and mesenteric adipose tissues. The increased body weight gain induced by HFD was significantly reduced by feeding Rapha diet® preparation, in which decreases in the weight of abdominal adipose tissue and the size of abdominal adipocytes were confirmed by microscopic examination. Long-term feeding of HFD increased blood triglycerides and cholesterol levels, leading to hepatic lipid accumulation. However, Rapha diet® preparation not only reversed the blood lipid levels, but also attenuated hepatic steatosis. The results indicate that Rapha diet® preparation could improve HFD-induced obesity by reducing both lipid accumulation and the size of adipocytes. PMID:23326287

Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice.

PubMed

Tung, Victoria W K; Burton, Thomas J; Quail, Stephanie L; Mathews, Miranda A; Camp, Aaron J

2016-01-01

Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5-6, 8-9 and 27-28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2-3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27-28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27-28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27-28 months. this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed.

Beneficial effects of Allium sativum L. stem extract on lipid metabolism and antioxidant status in obese mice fed a high-fat diet.

PubMed

Kim, Inhye; Kim, Haeng-Ran; Kim, Jae-Hyun; Om, Ae-Son

2013-08-30

This study was designed to examine the potential health benefits of Allium sativum L. (garlic) stem extract (ASSE) on obesity and related disorders in high-fat diet-induced obese mice. Obese mice were orally administered ASSE at doses of 100, 250 and 500 mg kg(-1) body weight day(-1) for 4 weeks. Consumption of ASSE significantly suppressed body weight gain and white adipose tissue (WAT) weight regardless of daily food intake. Obese mice fed ASSE also exhibited a significant decrease in WAT cell size. The decreased level of adiponectin and increased level of leptin in obese mice reverted to near normal mice levels in ASSE-treated mice. ASSE administration significantly improved lipid parameters of the serum and liver and inhibited fat accumulation in the liver by modulating the activities of hepatic lipid-regulating enzymes in obese mice. Administration of ASSE also led to significant increases in antioxidant enzymes and suppressed glutathione depletion and lipid peroxidation in hepatic tissue. These results suggest that ASSE may ameliorate obesity, insulin resistance and oxidative damage in high-fat diet-induced obese mice. © 2013 Society of Chemical Industry.

Corn oil versus lard: Metabolic effects of omega-3 fatty acids in mice fed obesogenic diets with different fatty acid composition.

PubMed

Pavlisova, Jana; Bardova, Kristina; Stankova, Barbora; Tvrzicka, Eva; Kopecky, Jan; Rossmeisl, Martin

2016-05-01

Mixed results have been obtained regarding the level of insulin resistance induced by high-fat diets rich in saturated fatty acids (SFA) when compared to those enriched by polyunsaturated fatty acids (PUFA), and how metabolic effects of marine PUFA of n-3 series, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), depend on dietary lipid background. Here we compared two high-fat diets, in which the major lipid constituent was based either on SFA in the form of pork lard (LHF diet) or PUFA of n-6 series (Omega-6) as corn oil (cHF diet). Both cHF and LHF parental diets were also supplemented with EPA+DHA (∼30 g/kg diet) to produce cHF+F and LHF+F diet, respectively. Male C57BL/6N mice were fed the experimental diets for 8 weeks. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps in mice fed LHF and cHF diets, and then metabolic effects of cHF+F and LHF+F diets were assessed focusing on the liver and epididymal white adipose tissue (eWAT). Both LHF and cHF induced comparable weight gain and the level of insulin resistance, however LHF-fed mice showed increased hepatic steatosis associated with elevated activity of stearoyl-CoA desaturase-1 (SCD1), and lower plasma triacylglycerol levels when compared to cHF. Despite lowering hepatic SCD1 activity, which was concomitant with reduced hepatic steatosis reaching the level observed in cHF+F mice, LHF+F did not decrease adiposity and the weight of eWAT, and rather further impaired insulin sensitivity relative to cHF+F, that tended to improve it. In conclusion, high-fat diets containing as much as ∼35 weight% as lipids induce similar weight gain and impairment of insulin sensitivity irrespective whether they are based on SFA or Omega-6. Although the SFA-rich diet containing EPA+DHA efficiently reduced hepatic steatosis, it did so without a corresponding improvement in insulin sensitivity and in the absence of effect on adiposity. Copyright © 2015 Elsevier B.V. and Société Fran

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.

Fatty Liver Accompanies an Increase in Lactobacillus Species in the Hind Gut of C57BL/6 Mice Fed a High-Fat Diet123

PubMed Central

Zeng, Huawei; Liu, Jun; Jackson, Matthew I.; Zhao, Feng-Qi; Yan, Lin; Combs, Gerald F.

2013-01-01

High-fat (HF) diets can produce obesity and have been linked to the development of nonalcoholic fatty liver disease and changes in the gut microbiome. To test the hypothesis that HF feeding increases certain predominant hind gut bacteria and development of steatohepatitis, C57BL/6 mice were fed an HF (45% energy) or low-fat (LF) (10% energy) diet for 10 wk. At the end of the feeding period, body weights in the HF group were 34% greater than those in the LF group (P < 0.05). These changes were associated with dramatic increases in lipid droplet number and size, inflammatory cell infiltration, and inducible nitric oxide (NO) synthase protein concentration in the livers of mice fed the HF diet. Consistent with the fatty liver phenotype, plasma leptin and tumor necrosis factor-α concentrations were also elevated in mice fed the HF diet, indicative of chronic inflammation. Eight of 12 pairs of polymerase chain reaction (PCR) primers for bacterial species that typically predominate hind gut microbial ecology generated specific PCR products from the fecal DNA samples. The amount of DNA from Lactobacillus gasseri and/or Lactobacillus taiwanensis in the HF group was 6900-fold greater than that in the LF group. Many of these bacteria are bile acid resistant and are capable of bile acid deconjugation. Because bile acids are regulators of hepatic lipid metabolism, the marked increase of gut L. gasseri and/or L. taiwanensis species bacteria with HF feeding may play a role in development of steatohepatitis in this model. PMID:23486979

Epidermal Hydration Is Improved by Enhanced Ceramide Metabolism in Aged C57BL/6J Mice After Dietary Supplementation of Royal Jelly.

PubMed

Jeon, Sanghun; Cho, Yunhi

2015-09-01

Epidermal hydration is maintained by the epidermal lipid barrier, of which ceramide (Cer) is the major constituent. We examined the dietary effect of royal jelly (RJ) on epidermal hydration in aged mice. Altered Cer metabolism was further determined by measuring epidermal levels of individual Cer, glucosylceramide (GC), and sphingomyelin (SM) species, and of Cer-metabolizing enzymes. Aged C57BL/6J mice were fed a control diet (group AGED) or diets with 1% RJ harvested from two different areas (groups AGED+RJ1:AGED + RJ2) for 16 weeks. Aged C57BL/6J mice with no dietary intervention (the control group: group C) represented the onset of aging. In group AGED, epidermal levels of hydration, Cer1/2/5/6/7, GC-A/B/C/D, SM1/2/3, and β-glucocerebrosidase (GCase) protein, an enzyme of GC hydrolysis for Cer generation, were lower than in group C; these levels, as well as those of Cer3/4 and acidic sphingomyelinase (aSMase) protein, an enzyme of SM hydrolysis for Cer generation, were higher in group AGED + RJ1 than in group AGED. Despite increases in GC-B, SM1/2/3, and serine palmitoyltransferase2 protein, an enzyme of de novo Cer synthesis, in group AGED + RJ2 to levels higher than in group AGED, epidermal levels of hydration, Cer1-7, GC-A/C/D, GCase, and aSMase proteins were similar in these two groups. Expression of GCase and aSMase mRNAs, and of Cer synthase3 and ceramidase proteins, enzymes of de novo Cer synthesis and degradation, did not differ among groups. Dietary RJ1 improved epidermal hydration by enhancing Cer metabolism with increased levels of all Cer, GC, and SM species, and of GCase and aSMase proteins.

Dietary aloe vera gel powder and extract inhibit azoxymethane- induced colorectal aberrant crypt foci in mice fed a high- fat diet.

PubMed

Chihara, Takeshi; Shimpo, Kan; Kaneko, Takaaki; Beppu, Hidehiko; Higashiguchi, Takashi; Sonoda, Shigeru; Tanaka, Miyuki; Yamada, Muneo; Abe, Fumiaki

2015-01-01

Aloe vera gel exhibits protective effects against insulin resistance as well as lipid-lowering and anti-diabetic effects. The anti-diabetic compounds in this gel were identified as Aloe-sterols. Aloe vera gel extract (AVGE) containing Aloe-sterols has recently been produced using a new procedure. We previously reported that AVGE reduced large-sized intestinal polyps in Apc-deficient Min mice fed a high fat diet (HFD), suggesting that Aloe vera gel may protect against colorectal cancer. In the present study, we examined the effects of Aloe vera gel powder (AVGP) and AVGE on azoxymethane-induced colorectal preneoplastic aberrant crypt foci (ACF) in mice fed a HFD. Male C57BL/6J mice were given a normal diet (ND), HFD, HFD containing 0.5% carboxymethyl cellulose solution, which was used as a solvent for AVGE (HFDC), HFD containing 3% or 1% AVGP, and HFDC containing 0.0125% (H-) or 0.00375% (L-) AVGE. The number of ACF was significantly lower in mice given 3% AVGP and H-AVGE than in those given HFD or HFDC alone. Moreover, 3% AVGP, H-AVGE and L-AVGE significantly decreased the mean Ki-67 labeling index, assessed as a measure of cell proliferation in the colonic mucosa. In addition, hepatic phase II enzyme glutathione S-transferase mRNA levels were higher in the H-AVGE group than in the HFDC group. These results suggest that both AVGP and AVGE may have chemopreventive effects on colorectal carcinogenesis under the HFD condition. Furthermore, the concentration of Aloe-sterols was similar between 3% AVGP and H-AVGE, suggesting that Aloe-sterols were the main active ingredients in this experiment.

Safety evaluation and lipid-lowering effects of food-grade biopolymer complexes (ε-polylysine-pectin) in mice fed a high-fat diet.

PubMed

Song, Mingyue; Lopez-Pena, Cynthia Lyliam; McClements, David Julian; Decker, Eric Andrew; Xiao, Hang

2017-05-24

ε-Polylysine (ε-PL) is a potent cationic antimicrobial, but its application as a food additive is currently limited because it tends to precipitate with anionic species in food matrices. Previous research has shown that the formation of an electrostatic complex between cationic ε-PL and anionic pectin (P) improved the physical stability of ε-PL while maintaining its antimicrobial activity. However, the impact of complexation on the effects of ε-PL on health is currently unknown. A subchronic toxicity study was therefore carried out to determine the safety of ingested ε-PL-P complexes using high-fat diet-fed male and female mice. After a 13-week dietary treatment with P, ε-PL, or ε-PL-P complexes, no significant toxicological effects were observed on the survival, mean body weight, food consumption, and organ weights of the animals, suggesting that the complexes were safe for oral consumption. Interestingly, the ε-PL-P complexes were found to have several beneficial health effects: suppression of high-fat diet-induced elevation of serum aspartate aminotransferase and alanine aminotransferase activities, reduction in serum total triglyceride and cholesterol levels, and an increase in fecal excretion of triglycerides. These effects were much stronger in female mice than in male mice. Moreover, the lipid-lowering effects were observed only for the ε-PL-P complexes but not for ε-PL or P alone at the same doses. Overall, our results demonstrate the oral safety of ε-PL-P complexes and their gender-specific lipid-lowering effects in high-fat diet-fed mice, which provide an important basis for the utilization of ε-PL-P complexes in food systems as functional ingredients.

Aging-associated oxidative stress inhibits liver progenitor cell activation in mice

PubMed Central

Wang, Bei; Zhou, Hong; Dang, Shipeng; Shi, Yufang; Hao, Li; Luo, Qingquan; Jin, Min; Zhou, Qianjun; Zhang, Yanyun

2017-01-01

Recent studies have discovered aging-associated changes of adult stem cells in various tissues and organs, which potentially contribute to the organismal aging. However, aging-associated changes of liver progenitor cells (LPCs) remain elusive. Employing young (2-month-old) and old (24-month-old) mice, we found diverse novel alterations in LPC activation during aging. LPCs in young mice could be activated and proliferate upon liver injury, whereas the counterparts in old mice failed to respond and proliferate, leading to the impaired liver regeneration. Surprisingly, isolated LPCs from young and old mice did not exhibit significant difference in their clonogenic and proliferative capacity. Later, we uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging. This study demonstrates aging-associated changes in LPC activation and reveals critical roles for the stem cell niche, including neutrophils and hepatic stellate cells, in the negative regulation of LPCs during aging. PMID:28458256

Aging-associated oxidative stress inhibits liver progenitor cell activation in mice.

PubMed

Cheng, Yiji; Wang, Xue; Wang, Bei; Zhou, Hong; Dang, Shipeng; Shi, Yufang; Hao, Li; Luo, Qingquan; Jin, Min; Zhou, Qianjun; Zhang, Yanyun

2017-04-29

Recent studies have discovered aging-associated changes of adult stem cells in various tissues and organs, which potentially contribute to the organismal aging. However, aging-associated changes of liver progenitor cells (LPCs) remain elusive. Employing young (2-month-old) and old (24-month-old) mice, we found diverse novel alterations in LPC activation during aging. LPCs in young mice could be activated and proliferate upon liver injury, whereas the counterparts in old mice failed to respond and proliferate, leading to the impaired liver regeneration. Surprisingly, isolated LPCs from young and old mice did not exhibit significant difference in their clonogenic and proliferative capacity. Later, we uncovered that the decreased activation and proliferation of LPCs were due to excessive reactive oxygen species produced by neutrophils infiltrated into niche, which was resulted from chemokine production from activated hepatic stellate cells during aging. This study demonstrates aging-associated changes in LPC activation and reveals critical roles for the stem cell niche, including neutrophils and hepatic stellate cells, in the negative regulation of LPCs during aging.

The polyphenol oleuropein aglycone protects TgCRND8 mice against Aß plaque pathology.

PubMed

Grossi, Cristina; Rigacci, Stefania; Ambrosini, Stefano; Ed Dami, Teresa; Luccarini, Ilaria; Traini, Chiara; Failli, Paola; Berti, Andrea; Casamenti, Fiorella; Stefani, Massimo

2013-01-01

The claimed beneficial effects of the Mediterranean diet include prevention of several age-related dysfunctions including neurodegenerative diseases and Alzheimer-like pathology. These effects have been related to the protection against cognitive decline associated with aging and disease by a number of polyphenols found in red wine and extra virgin olive oil. The double transgenic TgCRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein), aged 1.5 and 4, and age-matched wild type control mice were used to examine in vivo the effects of 8 weeks dietary supplementation of oleuropein aglycone (50 mg/kg of diet), the main polyphenol found in extra virgin olive oil. We report here that dietary supplementation of oleuropein aglycone strongly improves the cognitive performance of young/middle-aged TgCRND8 mice, a model of amyloid-ß deposition, respect to age-matched littermates with un-supplemented diet. Immunofluorescence analysis of cerebral tissue in oleuropein aglycone-fed transgenic mice showed remarkably reduced ß-amyloid levels and plaque deposits, which appeared less compact and "fluffy"; moreover, microglia migration to the plaques for phagocytosis and a remarkable reduction of the astrocyte reaction were evident. Finally, oleuropein aglycone-fed mice brain displayed an astonishingly intense autophagic reaction, as shown by the increase of autophagic markers expression and of lysosomal activity. Data obtained with cultured cells confirmed the latter evidence, suggesting mTOR regulation by oleuropein aglycone. Our results support, and provide mechanistic insights into, the beneficial effects against Alzheimer-associated neurodegeneration of a polyphenol enriched in the extra virgin olive oil, a major component of the Mediterranean diet.

A histomorphometric study of alveolar bone modelling and remodelling in mice fed a boron-deficient diet.

PubMed

Gorustovich, Alejandro A; Steimetz, Tammy; Nielsen, Forrest H; Guglielmotti, María B

2008-07-01

Emerging evidence indicates that boron (B) plays a role in bone formation and maintenance. Thus, a study was performed to determine whether dietary B-deficiency affects periodontal alveolar bone modelling and remodelling. Weanling Swiss mice (n=30) were divided into three groups: control diet (GI, 3mg B/kg); B-deficient diet (GII, 0.07 mg B/kg); and pair-fed with GII (GIII). The animals were maintained on their respective diets for 9 weeks and then sacrificed. The guidelines of the NIH for the care and use of laboratory animals were observed. The mandibles were resected, fixed, decalcified in 10% EDTA and embedded in paraffin. Buccolingually oriented sections were obtained at the level of the mesial root of the first lower molar and stained with H-E. Histomorphometric studies were performed separately on the buccal and lingual sides of the periodontal alveolar bone. Percentages of osteoblast surfaces (ObSs), eroded surfaces (ESs), and quiescent surfaces (QSs) were determined. No statistically significant differences in food intake and body weight were observed between the groups. When compared with GI and GIII mice, GII mice (B-deficient) had 63% and 48% reductions in ObS and 58% and 73% increases in QS in buccal and lingual plates, respectively. ES were not affected by B nutriture. The results are evidence that dietary boron deprivation in mice alters periodontal alveolar bone modelling and remodelling by inhibiting bone formation.

Use of Nerve Conduction Velocity to Assess Peripheral Nerve Health in Aging Mice

PubMed Central

Walsh, Michael E.; Sloane, Lauren B.; Fischer, Kathleen E.; Austad, Steven N.; Richardson, Arlan

2015-01-01

Nerve conduction velocity (NCV), the speed at which electrical signals propagate along peripheral nerves, is used in the clinic to evaluate nerve function in humans. A decline in peripheral nerve function is associated with a number of age-related pathologies. While several studies have shown that NCV declines with age in humans, there is little information on the effect of age on NCV in peripheral nerves in mice. In this study, we evaluated NCV in male and female C57Bl/6 mice ranging from 4 to 32 months of age. We observed a decline in NCV in both male and female mice after 20 months of age. Sex differences were detected in sensory NCV as well as the rate of decline during aging in motor nerves; female mice had slower sensory NCV and a slower age-related decline in motor nerves compared with male mice. We also tested the effect of dietary restriction on NCV in 30-month-old female mice. Dietary restriction prevented the age-related decline in sciatic NCV but not other nerves. Because NCV is clinically relevant to the assessment of nerve function, we recommend that NCV be used to evaluate healthspan in assessing genetic and pharmacological interventions that increase the life span of mice. PMID:25477428

Restriction on an energy-dense diet improves markers of metabolic health and cellular aging in mice through decreasing hepatic mTOR activity.

PubMed

Schloesser, Anke; Campbell, Graeme; Glüer, Claus-Christian; Rimbach, Gerald; Huebbe, Patricia

2015-02-01

Dietary restriction (DR) on a normal low-fat diet improves metabolic health and may prolong life span. However, it is still uncertain whether restriction of an energy-dense, high-fat diet would also be beneficial and mitigate age-related processes. In the present study, we determined biomarkers of metabolic health, energy metabolism, and cellular aging in obesity-prone mice subjected to 30% DR on a high-fat diet for 6 months. Dietary-restricted mice had significantly lower body weights, less adipose tissue, lower energy expenditure, and altered substrate oxidation compared to their ad libitum-fed counterparts. Hepatic major urinary proteins (Mup) expression, which is linked to glucose and energy metabolism, and biomarkers of metabolic health, including insulin, glucose, cholesterol, and leptin/adiponectin ratio, were likewise reduced in high-fat, dietary-restricted mice. Hallmarks of cellular senescence such as Lamp2a and Hsc70 that mediate chaperone-mediated autophagy were induced and mechanistic target of rapamycin (mTOR) signaling mitigated upon high-fat DR. In contrast to DR applied in low-fat diets, anti-oxidant gene expression, proteasome activity, as well as 5'-adenosine monophosphate-activated protein kinase (AMPK) activation were not changed, suggesting that high-fat DR may attenuate some processes associated with cellular aging without the induction of cellular stress response or energy deprivation.

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice.

PubMed

Rakov, Helena; Engels, Kathrin; Hönes, Georg Sebastian; Brix, Klaudia; Köhrle, Josef; Moeller, Lars Christian; Zwanziger, Denise; Führer, Dagmar

2017-12-22

Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO 4 -/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.

Age, experience and genetic background influence treadmill walking in mice

PubMed Central

Wooley, Christine M.; Xing, Shuqin; Burgess, Robert W.; Cox, Gregory A.; Seburn, Kevin L.

2009-01-01

WOOLEY, C.M., S. XING, R.W. BURGESS, G.A. COX, AND K.L. SEBURN. Age, experience and genetic background influence treadmill walking in mice. PHYSIOL. BEHAV. XX(X), XXX-XXX, 2008 – The use of a treadmill to gather data for gait analysis in mice is a convenient, sensitive method to evaluate motor performance. However, evidence from several species, including mice, shows that treadmill locomotion is a novel task that is not equivalent to over ground locomotion and that may be particularly sensitive to the test environment and protocol. We investigated the effects of age, genetic background and repeated trials on treadmill walking in mice and show that these factors are important considerations in the interpretation of gait data. Specifically we report that as C57BL/6J (B6) mice age, the animals use progressively longer, less frequent strides to maintain the same walking speed. The increase is most rapid between 1 and 6 months of age and is explained, in part, by changes in size and weight. We also extended previous findings showing that repeat trials cause mice to modify their treadmill gait pattern. In general, B6 mice tend to take shorter, more frequent steps and adopt a wider dynamic stance with repeated walking trials. The nature and extent of the response changes with both the number and timing of the trials and was observed with inter-trial intervals as long as 3 months. Finally, we compared the gait pattern of an additional seven inbred strains of mice and found significant variation in the length and frequency of strides used to maintain the same walking speed. The combined results offer the bases for further mechanistic studies and can be used to guide optimal experimental design. PMID:19027767

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.

Intestinal Barrier Function and the Gut Microbiome Are Differentially Affected in Mice Fed a Western-Style Diet or Drinking Water Supplemented with Fructose.

PubMed

Volynets, Valentina; Louis, Sandrine; Pretz, Dominik; Lang, Lisa; Ostaff, Maureen J; Wehkamp, Jan; Bischoff, Stephan C

2017-05-01

Background: The consumption of a Western-style diet (WSD) and high fructose intake are risk factors for metabolic diseases. The underlying mechanisms are largely unclear. Objective: To unravel the mechanisms by which a WSD and fructose promote metabolic disease, we investigated their effects on the gut microbiome and barrier function. Methods: Adult female C57BL/6J mice were fed a sugar- and fat-rich WSD or control diet (CD) for 12 wk and given access to tap water or fructose-supplemented water. The microbiota was analyzed with the use of 16S rRNA gene sequencing. Barrier function was studied with the use of permeability tests, and endotoxin, mucus thickness, and gene expressions were measured. Results: The WSD increased body weight gain but not endotoxin translocation compared with the CD. In contrast, high fructose intake increased endotoxin translocation 2.6- and 3.8-fold in the groups fed the CD + fructose and WSD + fructose, respectively, compared with the CD group. The WSD + fructose treatment also induced a loss of mucus thickness in the colon (-46%) and reduced defensin expression in the ileum and colon. The lactulose:mannitol ratio in the WSD + fructose mice was 1.8-fold higher than in the CD mice. Microbiota analysis revealed that fructose, but not the WSD, increased the Firmicutes:Bacteroidetes ratio by 88% for CD + fructose and 63% for WSD + fructose compared with the CD group. Bifidobacterium abundance was greater in the WSD mice than in the CD mice (63-fold) and in the WSD + fructose mice than in the CD + fructose mice (330-fold). Conclusions: The consumption of a WSD or high fructose intake differentially affects gut permeability and the microbiome. Whether these differences are related to the distinct clinical outcomes, whereby the WSD primarily promotes weight gain and high fructose intake causes barrier dysfunction, needs to be investigated in future studies. © 2017 American Society for Nutrition.

Beneficial Effect of Voluntary Exercise on Experimental Colitis in Mice Fed a High-Fat Diet: The Role of Irisin, Adiponectin and Proinflammatory Biomarkers

PubMed Central

Mazur-Bialy, Agnieszka Irena; Bilski, Jan; Wojcik, Dagmara; Brzozowski, Bartosz; Surmiak, Marcin; Hubalewska-Mazgaj, Magdalena; Chmura, Anna; Magierowski, Marcin; Magierowska, Katarzyna; Mach, Tomasz; Brzozowski, Tomasz

2017-01-01

Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn‘s disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 (p < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice (p < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice (p < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can

Beneficial Effect of Voluntary Exercise on Experimental Colitis in Mice Fed a High-Fat Diet: The Role of Irisin, Adiponectin and Proinflammatory Biomarkers.

PubMed

Mazur-Bialy, Agnieszka Irena; Bilski, Jan; Wojcik, Dagmara; Brzozowski, Bartosz; Surmiak, Marcin; Hubalewska-Mazgaj, Magdalena; Chmura, Anna; Magierowski, Marcin; Magierowska, Katarzyna; Mach, Tomasz; Brzozowski, Tomasz

2017-04-20

Inflammatory bowel diseases (IBDs) are a heterogeneous group of disorders exhibited by two major phenotypic forms: Crohn's disease and ulcerative colitis. Although the aetiology of IBD is unknown, several factors coming from the adipose tissue and skeletal muscles, such as cytokines, adipokines and myokines, were suggested in the pathogenesis of ulcerative colitis; however, it has not been extensively studied whether voluntary exercise can ameliorate that disorder. We explored the effect of moderate exercise (i.e., voluntary wheel running) on the disease activity index (DAI), colonic blood flow (CBF), plasma irisin and adiponectin levels and real-time PCR expression of proinflammatory markers in mesenteric fat in mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS) colitis fed a high-fat diet (HFD) compared to those on a standard chow diet (SD). Macroscopic and microscopic colitis in sedentary SD mice was accompanied by a significant fall in CBF, some increase in colonic tissue weight and a significant increase in the plasma levels of tumour necrosis factor-alpha (TNF-α), IL-6, monocyte chemotactic protein 1 (MCP-1) and IL-13 ( p < 0.05). In sedentary HFD mice, colonic lesions were aggravated, colonic tissue weight increased and the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels significantly increased. Simultaneously, a significant decrease in the plasma irisin and adiponectin levels was observed in comparison with SD mice ( p < 0.05). Exercise significantly decreased macroscopic and microscopic colitis, substantially increased CBF and attenuated the plasma TNF-α, IL-6, MCP-1, IL-1β and leptin levels while raising the plasma irisin and the plasma and WAT concentrations of adiponectin in HFD mice ( p < 0.05). We conclude that: (1) experimental colitis is exacerbated in HFD mice, possibly due to a fall in colonic microcirculation and an increase in the plasma and mesenteric fat content of proinflammatory biomarkers; and (2) voluntary physical activity can

Age-Dependent Ocular Dominance Plasticity in Adult Mice

PubMed Central

Lehmann, Konrad; Löwel, Siegrid

2008-01-01

Background Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known. Methodology/Principal Findings We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift. Conclusions/Significance These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders. PMID:18769674

Motor Performance is Impaired Following Vestibular Stimulation in Ageing Mice

PubMed Central

Tung, Victoria W. K.; Burton, Thomas J.; Quail, Stephanie L.; Mathews, Miranda A.; Camp, Aaron J.

2016-01-01

Balance and maintaining postural equilibrium are important during stationary and dynamic movements to prevent falls, particularly in older adults. While our sense of balance is influenced by vestibular, proprioceptive, and visual information, this study focuses primarily on the vestibular component and its age-related effects on balance. C57Bl/6J mice of ages 1, 5–6, 8–9 and 27–28 months were tested using a combination of standard (such as grip strength and rotarod) and newly-developed behavioral tests (including balance beam and walking trajectory tests with a vestibular stimulus). In the current study, we confirm a decline in fore-limb grip strength and gross motor coordination as age increases. We also show that a vestibular stimulus of low frequency (2–3 Hz) and duration can lead to age-dependent changes in balance beam performance, which was evident by increases in latency to begin walking on the beam as well as the number of times hind-feet slip (FS) from the beam. Furthermore, aged mice (27–28 months) that received continuous access to a running wheel for 4 weeks did not improve when retested. Mice of ages 1, 10, 13 and 27–28 months were also tested for changes in walking trajectory as a result of the vestibular stimulus. While no linear relationship was observed between the changes in trajectory and age, 1-month-old mice were considerably less affected than mice of ages 10, 13 and 27–28 months. Conclusion: this study confirms there are age-related declines in grip strength and gross motor coordination. We also demonstrate age-dependent changes to finer motor abilities as a result of a low frequency and duration vestibular stimulus. These changes showed that while the ability to perform the balance beam task remained intact across all ages tested, behavioral changes in task performance were observed. PMID:26869921

Effect of Diets Containing Sucrose vs. D-tagatose in Hypercholesterolemic Mice

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

Police, S.; Harris, J; Lodder, R

Effects of functional sweeteners on the development of the metabolic syndrome and atherosclerosis are unknown. The objective was to compare the effect of dietary carbohydrate in the form of sucrose (SUCR) to D-tagatose (TAG; an isomer of fructose currently used as a low-calorie sweetener) on body weight, blood cholesterol concentrations, hyperglycemia, and atherosclerosis in low-density lipoprotein receptor deficient (LDLr-/-) mice. LDLr-/- male and female mice were fed either standard murine diet or a diet enriched with TAG or SUCR as carbohydrate sources for 16 weeks. TAG and SUCR diets contained equivalent amounts (g/kg) of protein, fat, and carbohydrate. We measuredmore » food intake, body weight, adipocyte diameter, serum cholesterol and lipoprotein concentrations, and aortic atherosclerosis. Macrophage immunostaining and collagen content were examined in aortic root lesions. CONTROL and TAG-fed mice exhibited similar energy intake, body weights and blood glucose and insulin concentrations, but SUCR-fed mice exhibited increased energy intake and became obese and hyperglycemic. Adipocyte diameter increased in female SUCR-fed mice compared to TAG and CONTROL. Male and female SUCR-fed mice had increased serum cholesterol and triglyceride concentrations compared to TAG and CONTROL. Atherosclerosis was increased in SUCR-fed mice of both genders compared to TAG and CONTROL. Lesions from SUCR-fed mice exhibited pronounced macrophage immunostaining and reductions in collagen content compared to TAG and CONTROL mice. These results demonstrate that in comparison to sucrose, equivalent substitution of TAG as dietary carbohydrate does not result in the same extent of obesity, hyperglycemia, hyperlipidemia, and atherosclerosis.« less

Effect of Diets Containing Sucrose vs. D-tagatose in Hypercholesterolemic Mice

PubMed Central

Police, Sara B.; Harris, J. Clay; Lodder, Robert A.; Cassis, Lisa A.

2010-01-01

Effects of functional sweeteners on the development of the metabolic syndrome and atherosclerosis are unknown. The objective was to compare the effect of dietary carbohydrate in the form of sucrose (SUCR) to D-tagatose (TAG; an isomer of fructose currently used as a low-calorie sweetener) on body weight, blood cholesterol concentrations, hyperglycemia, and atherosclerosis in low-density lipoprotein receptor deficient (LDLr−/−) mice. LDLr−/− male and female mice were fed either standard murine diet or a diet enriched with TAG or SUCR as carbohydrate sources for 16 weeks. TAG and SUCR diets contained equivalent amounts (g/kg) of protein, fat, and carbohydrate. We measured food intake, body weight, adipocyte diameter, serum cholesterol and lipoprotein concentrations, and aortic atherosclerosis. Macrophage immunostaining and collagen content were examined in aortic root lesions. CONTROL and TAG-fed mice exhibited similar energy intake, body weights and blood glucose and insulin concentrations, but SUCR-fed mice exhibited increased energy intake and became obese and hyperglycemic. Adipocyte diameter increased in female SUCR-fed mice compared to TAG and CONTROL. Male and female SUCR-fed mice had increased serum cholesterol and triglyceride concentrations compared to TAG and CONTROL. Atherosclerosis was increased in SUCR-fed mice of both genders compared to TAG and CONTROL. Lesions from SUCR-fed mice exhibited pronounced macrophage immunostaining and reductions in collagen content compared to TAG and CONTROL mice. These results demonstrate that in comparison to sucrose, equivalent substitution of TAG as dietary carbohydrate does not result in the same extent of obesity, hyperglycemia, hyperlipidemia, and atherosclerosis. PMID:19008872

Effect of diets containing sucrose vs. D-tagatose in hypercholesterolemic mice.

PubMed

Police, Sara B; Harris, J Clay; Lodder, Robert A; Cassis, Lisa A

2009-02-01

Effects of functional sweeteners on the development of the metabolic syndrome and atherosclerosis are unknown. The objective was to compare the effect of dietary carbohydrate in the form of sucrose (SUCR) to D-tagatose (TAG; an isomer of fructose currently used as a low-calorie sweetener) on body weight, blood cholesterol concentrations, hyperglycemia, and atherosclerosis in low-density lipoprotein receptor deficient (LDLr(-/-)) mice. LDLr(-/-) male and female mice were fed either standard murine diet or a diet enriched with TAG or SUCR as carbohydrate sources for 16 weeks. TAG and SUCR diets contained equivalent amounts (g/kg) of protein, fat, and carbohydrate. We measured food intake, body weight, adipocyte diameter, serum cholesterol and lipoprotein concentrations, and aortic atherosclerosis. Macrophage immunostaining and collagen content were examined in aortic root lesions. CONTROL and TAG-fed mice exhibited similar energy intake, body weights and blood glucose and insulin concentrations, but SUCR-fed mice exhibited increased energy intake and became obese and hyperglycemic. Adipocyte diameter increased in female SUCR-fed mice compared to TAG and CONTROL. Male and female SUCR-fed mice had increased serum cholesterol and triglyceride concentrations compared to TAG and CONTROL. Atherosclerosis was increased in SUCR-fed mice of both genders compared to TAG and CONTROL. Lesions from SUCR-fed mice exhibited pronounced macrophage immunostaining and reductions in collagen content compared to TAG and CONTROL mice. These results demonstrate that in comparison to sucrose, equivalent substitution of TAG as dietary carbohydrate does not result in the same extent of obesity, hyperglycemia, hyperlipidemia, and atherosclerosis.

Decursin, an active compound isolated from Angelica gigas, inhibits fat accumulation, reduces adipocytokine secretion and improves glucose tolerance in mice fed a high-fat diet.

PubMed

Hwang, Jin-Taek; Kim, Sung Hee; Hur, Haeng Jeon; Kim, Hyun Jin; Park, Jae Ho; Sung, Mi Jeong; Yang, Hye Jeong; Ryu, Shi Yong; Kim, Young Sup; Cha, Mi Ran; Kim, Myung Sunny; Kwon, Dae Young

2012-05-01

Decursin (De), an active component of Angelica gigas, is known to exert anticancer and neuroprotective effects. However, its antiobesity and antidiabetic potential has not yet been investigated. This study evaluated the antiobesity effect of decursin, particularly focusing on its ability to inhibit adipocyte differentiation in 3T3-L1 cells. Decursin treatment resulted in the inhibition of adipocyte differentiation and the expression of fatty acid synthase. The study further investigated these antiobesity effects using mice fed a normal diet (ND), a high-fat diet (HFD) and a HFD plus decursin 200 mg/kg diet (HFD + De) for 7 weeks. Mice administered HFD plus decursin showed a drastic decrease in weight gain, triglyceride content, total cholesterol content and fat size compared with those that received the HFD alone; this was observed despite similar quantities of total food intake. Furthermore, decursin improved glucose tolerance in mice fed a HFD. Finally, administration of decursin along with the HFD significantly reduced the secretion of HFD-induced adipocytokines such as leptin, resistin, IL-6 and MCP-1. These results suggest that decursin might be useful for the treatment of obesity and diabetes. Copyright © 2011 John Wiley & Sons, Ltd.

Impact of diesel exhaust exposure on the liver of mice fed on omega-3 polyunsaturated fatty acids-deficient diet.

PubMed

Umezawa, Masakazu; Nakamura, Masayuki; El-Ghoneimy, Ashraf A; Onoda, Atsuto; Shaheen, Hazem M; Hori, Hiroshi; Shinkai, Yusuke; El-Sayed, Yasser S; El-Far, Ali H; Takeda, Ken

2018-01-01

Exposure to diesel exhaust (DE) exacerbates non-alcoholic fatty liver disease, and may systemically affect lipid metabolism. Omega-3 polyunsaturated fatty acids (n-3 PUFA) have anti-inflammatory activity and suppresses hepatic triacylglycerol accumulation, but many daily diets are deficient in this nutrient. Therefore, the effect of DE exposure in mice fed n-3 PUFA-deficient diet was investigated. Mice were fed control chow or n-3 PUFA-deficient diet for 4 weeks, then exposed to clean air or DE by inhalation for further 4 weeks. Liver histology, plasma parameters, and expression of fatty acid synthesis-related genes were evaluated. N-3 PUFA-deficient diet increased hepatic lipid droplets accumulation and expression of genes promoting fatty acid synthesis: Acaca, Acacb, and Scd1. DE further increased the plasma leptin and the expression of fatty acid synthesis-related genes: Acacb, Fasn, and Scd1. N-3 PUFA-deficient diet and DE exposure potentially enhanced hepatic fatty acid synthesis and subsequently accumulation of lipid droplets. The combination of low-dose DE exposure and intake of n-3 PUFA-deficient diet may be an additional risk factor for the incidence of non-alcoholic fatty liver disease. The present study suggests an important mechanism for preventing toxicity of DE on the liver through the incorporation of n-3 PUFAs in the diet. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of social isolation, re-socialization and age on cognitive and aggressive behaviors of Kunming mice and BALB/c mice.

PubMed

An, Dong; Chen, Wei; Yu, De-Qin; Wang, Shi-Wei; Yu, Wei-Zhi; Xu, Hong; Wang, Dong-Mei; Zhao, Dan; Sun, Yi-Ping; Wu, Jun-Cheng; Tang, Yi-Yuan; Yin, Sheng-Ming

2017-05-01

Both Kunming (KM) mice and BALB/c mice have been widely used as rodent models to investigate stress-associated mental diseases. However, little is known about the different behaviors of KM mice and BALB/c mice after social isolation, particularly cognitive and aggressive behaviors. In this study, the behaviors of KM and BALB/c mice isolated for 2, 4 and 8 weeks and age-matched controls were evaluated using object recognition, object location and resident-intruder tests. The recovery of behavioral deficits by re-socialization was also examined for the isolated mice in adolescence. Our study showed that isolation for 2, 4 and 8 weeks led to cognitive deficits and increased aggressiveness for both KM and BALB/c mice. An important finding is that re-socialization could completely recover spatial/non-spatial cognitive deficits resulted from social isolation for both KM and BALB/c mice. In addition, age only impacted aggressiveness of KM mice. Moreover, isolation duration showed different impacts on cognitive and aggressive behaviors for both KM and BALB/c mice. Furthermore, BALB/c mice showed weak spatial/non-spatial memory and low aggressiveness when they were at the same age and isolation duration, compared to KM mice. In conclusion, KM mice and BALB/c mice behaved characteristically under physiology and isolation conditions. © 2016 Japanese Society of Animal Science.

[Effects of aquaporin-4 gene knockout on behavior changes and cerebral morphology during aging in mice].

PubMed

Su, Shengan; Lu, Yunbi; Zhang, Weiping

2013-05-01

To investigate the effects of aquaporin-4 (AQP4) gene knockout on the behavior changes and cerebral morphology during aging in mice,and to compare that of young and aged mice between AQP4 knockout mice (AQP4(-/-)) and wild type mice (AQP4(+/+)). Fifty-eight CD-1 mice were divided into four groups: young (2-3 months old) AQP4(-/-), aged (17-19 months old) AQP4(-/-), young AQP4(+/+) and aged AQP4(+/+). The activity levels and exploring behavior of mice were tested in open field. The neurons were stained with toluidine blue and NeuN, the astrocytes and microglia were stained with GFAP and Iba-1, respectively. The morphological changes of neuron, astrocyte and microglia were then analyzed. Compared with young mice, the total walking distance in open field of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 41.2% and 44.1%, respectively (P<0.05); while there was no difference in the ratio of distance and retention time in the central area of open field. The density of neuron in cortex of aged AQP4(+/+) mice and aged AQP4(-/-) mice decreased 19.6% and 15.8%, respectively (P<0.05), while there was no difference in the thickness of neuron cell body in hippocampus CA1 region. The density of astrocyte in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 57.7% and 64.3%, respectively (P<0.001), while there was no difference in the area of astrocyte. The area of microglia in hippocampus CA3 region of aged AQP4(+/+) mice and aged AQP4(-/-) mice increased 46.9% and 52.0%, respectively (P<0.01), while there was no difference in the density of microglia. Compared with AQP4(+/+) mice, the young and aged AQP4(-/-) mice showed smaller area of astrocyte in hippocampus CA3 region, reduced 18.0% in young mice and 23.6% in aged mice. There was no difference between AQP4(+/+) mice and AQP4(-/-) mice for other observed indexes. AQP4 may be involved in change of astrocyte and astrocyte-related behaviors during aging. AQP4 gene knockout may have limited

Circadian rhythm resynchronization improved isoflurane-induced cognitive dysfunction in aged mice.

PubMed

Song, Jia; Chu, Shuaishuai; Cui, Yin; Qian, Yue; Li, Xiuxiu; Xu, Fangxia; Shao, Xueming; Ma, Zhengliang; Xia, Tianjiao; Gu, Xiaoping

2018-04-13

Postoperative cognitive dysfunction (POCD) is a common clinical phenomenon characterized by cognitive deficits in patients after anesthesia and surgery. Advanced age is a significant independent risk factor for POCD. We previously reported that in young mice, sleep-wake rhythm is involved in the isoflurane-induced memory impairment. In present study, we sought to determine whether advanced age increased the risk of POCD through aggravated and prolonged post-anesthetic circadian disruption in the elderly. We constructed POCD model by submitting the mice to 5-h 1.3% isoflurane anesthesia from Zeitgeber Time (ZT) 14 to ZT19. Under novel object recognition assay (NOR) and Morris water maze (MWM) test, We found 5-h isoflurane anesthesia impaired the cognition of young mice for early 3 days after anesthesia but damaged the aged for at least 1 week. With Mini-Mitter continuously monitoring, a 3.22 ± 0.75 h gross motor activity acrophase delay was manifested in young mice on D1, while in the aged mice, the gross motor activity phase shift lasted for 3 days, consistent with the body temperature rhythm trends of change. Melatonin has been considered as an effective remedy for circadian rhythm shift. In aged mice, melatonin was pretreated intragastrically at the dose of 10 mg/kg daily for 7 consecutive days before anesthesia. We found that melatonin prevented isoflurane-induced cognitive impairments by restoring the locomotor activity and temperature circadian rhythm via clock gene resynchronization. Overall, these results indicated that Long-term isoflurane anesthesia induced more aggravated and prolonged memory deficits and circadian rhythms disruption in aged mice. Melatonin could prevent isoflurane-induced cognitive impairments by circadian rhythm resynchronization. Copyright © 2018. Published by Elsevier Inc.

Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice.

PubMed

Selvaratnam, Johanna S; Robaire, Bernard

2016-09-01

Advanced paternal age is linked to complications in pregnancy and genetic diseases in offspring. Aging results in excess reactive oxygen species (ROS) and DNA damage in spermatozoa; this damage can be transmitted to progeny with detrimental consequences. Although there is a loss of antioxidants with aging, the impact on aging male germ cells of the complete absence of either catalase (CAT) or superoxide dismutase 1 (SOD1) has not been investigated. We used CAT-null (Cat(-/-)) and SOD1-null (Sod(-/-)) mice to determine whether loss of these antioxidants increases germ cell susceptibility to redox dysfunction with aging. Aging reduced fertility and the numbers of Sertoli and germ cells in all mice. Aged Sod(-/-) mice displayed an increased loss of fertility compared to aged wild-type mice. Treatment with the pro-oxidant SIN-10 increased ROS in spermatocytes of aged wild-type and Sod(-/-) mice, while aged Cat(-/-) mice were able to neutralize this ROS. The antioxidant peroxiredoxin 1 (PRDX1) increased with age in wild-type and Cat(-/-) mice but was consistently low in young and aged Sod(-/-) mice. DNA damage and repair markers (γ-H2AX and 53BP1) were reduced with aging and lower in young Sod(-/-) and Cat(-/-) mice. Colocalization of γ-H2AX and 53BP1 suggested active repair in young wild-type mice but reduced in young Cat(-/-) and in Sod(-/-) mice and with age. Oxidative DNA damage (8-oxodG) increased in young Sod(-/-) mice and with age in all mice. These studies show that aged Sod(-/-) mice display severe redox dysfunction, while wild-type and Cat(-/-) mice have compensatory mechanisms to partially alleviate oxidative stress and reduce age-related DNA damage in spermatozoa. Thus, SOD1 but not CAT is critical to the maintenance of germ cell quality with aging. © 2016 by the Society for the Study of Reproduction, Inc.

Hearts from Mice Fed a Non-Obesogenic High-Fat Diet Exhibit Changes in Their Oxidative State, Calcium and Mitochondria in Parallel with Increased Susceptibility to Reperfusion Injury

PubMed Central

Littlejohns, Ben; Pasdois, Philippe; Duggan, Simon; Bond, Andrew R.; Heesom, Kate; Jackson, Christopher L.; Angelini, Gianni D.; Halestrap, Andrew P.; Suleiman, M.-Saadeh

2014-01-01

Rationale High-fat diet with obesity-associated co-morbidities triggers cardiac remodeling and renders the heart more vulnerable to ischemia/reperfusion injury. However, the effect of high-fat diet without obesity and associated co-morbidities is presently unknown. Objectives To characterize a non-obese mouse model of high-fat diet, assess the vulnerability of hearts to reperfusion injury and to investigate cardiac cellular remodeling in relation to the mechanism(s) underlying reperfusion injury. Methods and Results Feeding C57BL/6J male mice high-fat diet for 20 weeks did not induce obesity, diabetes, cardiac hypertrophy, cardiac dysfunction, atherosclerosis or cardiac apoptosis. However, isolated perfused hearts from mice fed high-fat diet were more vulnerable to reperfusion injury than those from mice fed normal diet. In isolated cardiomyocytes, high-fat diet was associated with higher diastolic intracellular Ca2+ concentration and greater damage to isolated cardiomyocytes following simulated ischemia/reperfusion. High-fat diet was also associated with changes in mitochondrial morphology and expression of some related proteins but not mitochondrial respiration or reactive oxygen species turnover rates. Proteomics, western blot and high-performance liquid chromatography techniques revealed that high-fat diet led to less cardiac oxidative stress, higher catalase expression and significant changes in expression of putative components of the mitochondrial permeability transition pore (mPTP). Inhibition of the mPTP conferred relatively more cardio-protection in the high-fat fed mice compared to normal diet. Conclusions This study shows for the first time that high-fat diet, independent of obesity-induced co-morbidities, triggers changes in cardiac oxidative state, calcium handling and mitochondria which are likely to be responsible for increased vulnerability to cardiac insults. PMID:24950187

The Effect of Flax Seed (Linum Usitatissimum) Hydroalcoholic Extract on Brain, Weight and Plasma Sexual Hormone Levels in Aged and Young Mice.

PubMed

Bahmanpour, Soghra; Kamali, Mahsa

2016-05-01

Flax is a food and fiber crop that is grown in some regions of the world. Its value will account for its great popularity as a food, medical and cosmetic applications. Flax fibers are taken from the stem of the plant and are two to three times as strong as cotton. In this study, we compared brain weight and plasma sex hormone levels in young and aged mice after the administration of Linum usitatissimum (flax seed) hydro alcoholic extract. In this study, 32 aged and 32 young mice were divided into 4 groups. Controls remained untreated and experimental groups were fed with flax seed hydroalcoholic extract by oral gavages during 3 weeks. After 3 weeks, the brain was removed and blood samples were collected to measure sex hormone levels by ELISA. Data analysis was done by statistical ANOVA test using SPSS version 18 (P<0.05). The results of this study shows that the brain weight of mice did not change significantly, but the sex hormone levels in the experimental groups in comparison with the control groups increased significantly (P<0.05). The hydroalcoholic extract of flax seed had no effect on the brain weight, but this extract improved the sexual hormone levels.

Hematopoiesis and aging. V. A decline in hematocrit occurs in all aging female B6D2F1 mice

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

Boggs, D.R.; Patrene, K.

Longitudinal studies of hematocrits were done in aging B6D2F1 female mice at 54, 64, 91, 105 and 115 weeks of age. A modest decline in hematocrit was observed in 41/42 mice; we have previously shown that the decreased hematocrit of aged as compared to young mice is due to an expansion of plasma volume. Mice which died spontaneously after 91 weeks had lower hematocrits at 91 weeks and 105 weeks than did those which survived to 115 weeks. At each time interval, a sub-group of mice was killed and uptake of /sup 59/Fe into blood, foreleg, spleen and liver wasmore » studied and total nucleated cells per humerus was determined. The results were generally compatible with the thesis that aging mice maintain normal rates of erythropoiesis under basal conditions. Thus, it would appear that a decrease in hematocrit can be considered an expected part of the aging process in this mouse.« less

Colonic inflammation and enhanced-beta-catenin signaling accompany an increase of the Lachnospiraceae/Streptococcaceae in the hind gut of high-fat diet-fed mice

USDA-ARS?s Scientific Manuscript database

Consumption of an obesigenic / high-fat (HF) diet is associated with an increase of inflammation-related colon cancer risk and may alter the gut microbiota. To test the hypothesis that a HF feeding accelerates inflammatory processes and changes gut microbiome composition, C57BL/6 mice were fed a HF ...

The effect of aging on efferent nerve fibers regeneration in mice.

PubMed

Verdú, E; Butí, M; Navarro, X

1995-10-23

This study evaluates the influence of aging on nerve regeneration and reinnervation of target organs in mice aged 2, 6, 9, 12, 18 and 24 months. In animals of each age group the sciatic nerve was subjected to crush, section or section and suture. Reinnervation of plantar muscles and sweat glands (SG) was evaluated over three months after operation by functional methods. Reappearance of SG secretion and motor responses occurred slightly earlier in young than older mice. The degree of motor and sudomotor reinnervation, with respect to preoperative control values, was also significantly higher in young than old animals. The differences were more pronounced after 12 months of age. The degree of recovery progressively decreased with the severity of the lesion, differences being more marked in older mice. Neurorraphy improved recovery, comparatively more in older than in young mice. These results indicate that, after injuries of peripheral nerves, axonal regeneration and reinnervation are maintained throughout life, but tend to be more delayed and slightly less effective with aging.

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.

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

Effect of dietary docosahexaenoic acid connecting phospholipids on the lipid peroxidation of the brain in mice.

PubMed

Hiratsuka, Seiichi; Ishihara, Kenji; Kitagawa, Tomoko; Wada, Shun; Yokogoshi, Hidehiko

2008-12-01

The effect of dietary docosahexaenoic acid (DHA, C22:6n-3) with two lipid types on lipid peroxidation of the brain was investigated in streptozotocin (STZ)-induced diabetic mice. Each group of female Balb/c mice was fed a diet containing DHA-connecting phospholipids (DHA-PL) or DHA-connecting triacylglycerols (DHA-TG) for 5 wk. Safflower oil was fed as the control. The lipid peroxide level of the brain was significantly lower in the mice fed the DHA-PL diet when compared to those fed the DHA-TG and safflower oil diets, while the alpha-tocopherol level was significantly higher in the mice fed the DHA-PL diet than in those fed the DHA-TG and safflower oil diets. The DHA level of phosphatidylethanolamine in the brain was significantly higher in the mice fed the DHA-PL diet than in those fed the safflower oil diet. The dimethylacetal levels were significantly higher in the mice fed the DHA-PL diet than in those fed the safflower oil and DHA-TG diets. These results suggest that the dietary DHA-connecting phospholipids have an antioxidant activity on the brain lipids in mice, and the effect may be related to the brain plasmalogen.

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.

Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet

PubMed Central

Cai, Weijing; He, John Cijiang; Zhu, Li; Chen, Xue; Wallenstein, Sylvan; Striker, Gary E.; Vlassara, Helen

2007-01-01

Aging is accompanied by increased oxidative stress (OS) and accumulation of advanced glycation end products (AGEs). AGE formation in food is temperature-regulated, and ingestion of nutrients prepared with excess heat promotes AGE formation, OS, and cardiovascular disease in mice. We hypothesized that sustained exposure to the high levels of pro-oxidant AGEs in normal diets (RegAGE) contributes to aging via an increased AGE load, which causes AGER1 dysregulation and depletion of anti-oxidant capacity, and that an isocaloric, but AGE-restricted (by 50%) diet (LowAGE), would decrease these abnormalities. C57BL6 male mice with a life-long exposure to a LowAGE diet had higher than baseline levels of tissue AGER1 and glutathione/oxidized glutathione and reduced plasma 8-isoprostanes and tissue RAGE and p66shc levels compared with mice pair-fed the regular (RegAGE) diet. This was associated with a reduction in systemic AGE accumulation and amelioration of insulin resistance, albuminuria, and glomerulosclerosis. Moreover, lifespan was extended in LowAGE mice, compared with RegAGE mice. Thus, OS-dependent metabolic and end organ dysfunction of aging may result from life-long exposure to high levels of glycoxidants that exceed AGER1 and anti-oxidant reserve capacity. A reduced AGE diet preserved these innate defenses, resulting in decreased tissue damage and a longer lifespan in mice. PMID:17525257

Comparative evaluation of anti-obesity effect of Aloe vera and Gymnema sylvestre supplementation in high-fat diet fed C57BL/6J mice.

PubMed

Pothuraju, Ramesh; Sharma, Raj Kumar; Rather, Sarver Ahmed; Singh, Satvinder

2016-01-01

The aim of the present study was to investigate, anti-obesity effect of Aloe vera (AV), and Gymnema sylvestre (GS) whole extract powders administration to high-fat diet (HFD) fed C57BL/6J mice for 12 weeks. At the end of experiment, different parameters such as body weight, feed intake, organ weights, fasting blood glucose, oral glucose tolerance test, plasma lipid levels, and expression analysis of adipocytokines were evaluated. At the end of experimental period, oral administration of both herbs showed a significant ( P < 0.05 and P < 0.001) decrease in the plasma glucose and lipid levels in HFD fed mice. In addition, increased in the epididymal fat (E. fat) weight in the HFD group was significantly ( P < 0.05) reduced on GS administration alone. Finally, quantitative mRNA expression analysis of adiponectin gene was significantly up-regulated in AV supplementation. Further, no effect was observed with the both herbs on pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor-a) in the E. fat tissue of HFD fed group. The anti-obesity and other metabolic studies depend on the type of diet, different parts of herbal extractions, and animal models used. Further studies are required in this area to strengthen the anti-obesity effects of herbs with active component, and it can be used a pro-drug instead of whole extract.

Momordica charantia ameliorates insulin resistance and dyslipidemia with altered hepatic glucose production and fatty acid synthesis and AMPK phosphorylation in high-fat-fed mice.

PubMed

Shih, Chun-Ching; Shlau, Min-Tzong; Lin, Cheng-Hsiu; Wu, Jin-Bin

2014-03-01

Momordica charantia Linn. (Cucurbitaceae) fruit is commonly known as bitter melon. C57BL/6J mice were firstly divided randomly into two groups: the control (CON) group was fed with a low-fat diet, whereas the experimental group was fed a 45% high-fat (HF) diet for 8 weeks. Afterwards, the CON group was treated with vehicle, whereas the HF group was subdivided into five groups and still on HF diet and was given orally M. charantia extract (MCE) or rosiglitazone (Rosi) or not for 4 weeks. M. charantia decreased the weights of visceral fat and caused glucose lowering. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. MCE significantly increases the hepatic protein contents of AMPK phosphorylation by 126.2-297.3% and reduces expression of phosphenolpyruvate carboxykinase (PEPCK) and glucose production. Most importantly, MCE decreased expression of hepatic 11beta hydroxysteroid dehydroxygenase (11beta-HSD1) gene, which contributed in attenuating diabetic state. Furthermore, MCE lowered serum triglycerides (TGs) by inhibition of hepatic fatty acid synthesis by dampening sterol response element binding protein 1c and fatty acid synthase mRNA leading to reduction in TGs synthesis. This study demonstrates M. charantia ameliorates diabetic and hyperlipidemic state in HF-fed mice occurred by regulation of hepatic PEPCK, 11beta-HSD1 and AMPK phosphorylation. Copyright © 2013 John Wiley & Sons, Ltd.

Antilithiasic and Hypolipidaemic Effects of Raphanus sativus L. var. niger on Mice Fed with a Lithogenic Diet

PubMed Central

Castro-Torres, Ibrahim Guillermo; Naranjo-Rodríguez, Elia Brosla; Domínguez-Ortíz, Miguel Ángel; Gallegos-Estudillo, Janeth; Saavedra-Vélez, Margarita Virginia

2012-01-01

In Mexico, Raphanus sativus L. var. niger (black radish) has uses for the treatment of gallstones and for decreasing lipids serum levels. We evaluate the effect of juice squeezed from black radish root in cholesterol gallstones and serum lipids of mice. The toxicity of juice was analyzed according to the OECD guidelines. We used female C57BL/6 mice fed with a lithogenic diet. We performed histopathological studies of gallbladder and liver, and measured concentrations of cholesterol, HDL cholesterol and triglycerides. The juice can be considered bioactive and non-toxic; the lithogenic diet significantly induced cholesterol gallstones; increased cholesterol and triglycerides levels, and decreased HDL levels; gallbladder wall thickness increased markedly, showing epithelial hyperplasia and increased liver weight. After treatment with juice for 6 days, cholesterol gallstones were eradicated significantly in the gallbladder of mice; cholesterol and triglycerides levels decreased too, and there was also an increase in levels of HDL (P < 0.05). Gallbladder tissue continued to show epithelial hyperplasia and granulocyte infiltration; liver tissue showed vacuolar degeneration. The juice of black radish root has properties for treatment of cholesterol gallstones and for decreasing serum lipids levels; therefore, we confirm in a preclinical study the utility that people give it in traditional medicine. PMID:23093836

Colonic inflammation and enhanced-beta-catenin signaling accompany an increase of the Lachnospiraceae/Streptococcaceae in the hind gut of high-fat diet-fed mice

USDA-ARS?s Scientific Manuscript database

Consumption of an obesigenic / high-fat (HF) diet is associated with a high colon cancer risk, and may alter the gut microbiota. To test the hypothesis that a HF feeding accelerates inflammatory process and changes gut microbiome composition, C57BL/6 mice were fed a HF (45% energy) or low-fat (LF) (...

Psychological stress exposure to aged mice causes abnormal feeding patterns with changes in the bout number.

PubMed

Yamada, Chihiro; Mogami, Sachiko; Hattori, Tomohisa

2017-11-09

Stress responses are affected by aging. However, studies on stress-related changes in feeding patterns with aging subject are minimal. We investigated feeding patterns induced by two psychological stress models, revealing characteristics of stress-induced feeding patterns as "meal" and "bout" (defined as the minimum feeding behavior parameters) in aged mice. Feeding behaviors of C57BL/6J mice were monitored for 24 h by an automatic monitoring device. Novelty stress reduced the meal amount over the 24 h in both young and aged mice, but as a result of a time course study it was persistent in aged mice. In addition, the decreased bout number was more pronounced in aged mice than in young mice. The 24-h meal and bout parameters did not change in either the young or aged mice following water avoidance stress (WAS). However, the meal amount and bout number increased in aged mice for 0-6 h after WAS exposure but remained unchanged in young mice. Our findings suggest that changes in bout number may lead to abnormal stress-related feeding patterns and may be one tool for evaluating eating abnormality in aged mice.

Suppression of Oxidative Stress by Resveratrol After Isometric Contractions in Gastrocnemius Muscles of Aged Mice

PubMed Central

Ryan, Michael J.; Jackson, Janna R.; Hao, Yanlei; Williamson, Courtney L.; Dabkowski, Erinne R.; Hollander, John M.

2010-01-01

This study tested the hypothesis that resveratrol supplementation would lower oxidative stress in exercised muscles of aged mice. Young (3 months) and aged (27 months) C57BL/6 mice received a control or a 0.05% trans-resveratrol-supplemented diet for 10 days. After 7 days of dietary intervention, 20 maximal electrically evoked isometric contractions were obtained from the plantar flexors of one limb in anesthetized mice. Exercise was conducted for three consecutive days. Resveratrol supplementation blunted the exercise-induced increase in xanthine oxidase activity in muscles from young (25%) and aged (53%) mice. Resveratrol lowered H2O2 levels in control (13%) and exercised (38%) muscles from aged animals, reduced Nox4 protein in both control and exercised muscles of young (30%) and aged mice (40%), and increased the ratio of reduced glutathione to oxidized glutathione in exercised muscles from young (38%) and aged (135%) mice. Resveratrol prevented the increase in lipid oxidation, increased catalase activity, and increased MnSOD activity in exercised muscles from aged mice. These data show that dietary resveratrol suppresses muscle indicators of oxidative stress in response to isometric contractions in aged mice. PMID:20507922

Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype.

PubMed

Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy; Tucsek, Zsuzsanna; Hertelendy, Peter; Kiss, Tamas; Gautam, Tripti; Zhang, Xin A; Sonntag, William E; de Cabo, Rafael; Farkas, Eszter; Elliott, Michael H; Kinter, Michael T; Deak, Ferenc; Ungvari, Zoltan; Csiszar, Anna

2018-06-14

Obesity has deleterious effects on cognitive function in the elderly adults. In mice, aging exacerbates obesity-induced oxidative stress, microvascular dysfunction, blood-brain barrier (BBB) disruption, and neuroinflammation, which compromise cognitive health. However, the specific mechanisms through which aging and obesity interact to remain elusive. Previously, we have shown that Nrf2 signaling plays a critical role in microvascular resilience to obesity and that aging is associated with progressive Nrf2 dysfunction, promoting microvascular impairment. To test the hypothesis that Nrf2 deficiency exacerbates cerebromicrovascular dysfunction induced by obesity Nrf2+/+ and Nrf2-/-, mice were fed an adipogenic high-fat diet (HFD). Nrf2 deficiency significantly exacerbated HFD-induced oxidative stress and cellular senescence, impairment of neurovascular coupling responses, BBB disruption, and microglia activation, mimicking the aging phenotype. Obesity in Nrf2-/- mice elicited complex alterations in the amyloidogenic gene expression profile, including upregulation of amyloid precursor protein. Nrf2 deficiency and obesity additively reduced long-term potentiation in the CA1 area of the hippocampus. Collectively, Nrf2 dysfunction exacerbates the deleterious effects of obesity, compromising cerebromicrovascular and brain health by impairing neurovascular coupling mechanisms, BBB integrity and synaptic function and promoting neuroinflammation. These results support a possible role for age-related Nrf2 dysfunction in the pathogenesis of vascular cognitive impairment and Alzheimer's disease.

Coordinated improvement in glucose tolerance, liver steatosis and obesity-associated inflammation by cannabinoid 1 receptor antagonism in fat Aussie mice.

PubMed

Bell-Anderson, K S; Aouad, L; Williams, H; Sanz, F R; Phuyal, J; Larter, C Z; Farrell, G C; Caterson, I D

2011-12-01

Fat Aussie mice (foz/foz) are morbidly obese, glucose intolerant and have liver steatosis that develops into steatohepatitis on a high-fat diet. The cannabinoid 1 receptor (CB1) antagonist SR141716 has been shown to improve obesity-associated metabolic complications in humans and rodent models. The aim of this study was to assess the effect of SR141716 in foz/foz mice. Male wildtype (WT) and foz/foz mice were fed a chow or high-fat diet (45% saturated fat). Vehicle or SR141716 (10 mg kg(-1) per day) was administered in jelly once daily for 4 weeks from 4 months of age. Foz/foz mice were obese but had less epididymal adipose tissue mass than fat-fed WT mice despite being significantly heavier. Liver weight was increased by twofold in foz/foz compared with WT mice and showed significant steatogenesis associated with impaired liver function. Foz/foz and fat-fed WT mice were glucose intolerant as determined by oral glucose tolerance test. In chow-fed foz/foz mice, SR141716 reduced body weight, liver weight, reversed hepatosteatosis and glucose intolerance. Subcutaneous white adipose tissue gene expression of the macrophage-specific marker Cd68 reflected the improvements in the metabolic status by SR141716 in these mice. The results are consistent with the hypothesis that foz/foz mice have defective lipid metabolism, are unable to adequately store fat in adipose tissue but instead sequester fat ectopically in other metabolic tissues (liver) leading to insulin resistance and hepatic steatosis associated with inflammation. Our findings suggest that SR141716 can improve liver lipid metabolism in foz/foz mice in line with improved insulin sensitivity and adipose tissue inflammation.

Sod2 haploinsufficiency does not accelerate aging of telomere dysfunctional mice

PubMed Central

Guachalla, Luis Miguel; Ju, Zhenyu; Koziel, Rafal; von Figura, Guido; Song, Zhangfa; Fusser, Markus; Epe, Bernd; Jansen-Dűrr, Pidder; Rudolph, K. Lenhard

2009-01-01

Telomere shortening represents a causal factor of cellular senescence. At the same time, several lines of evidence indicate a pivotal role of oxidative DNA damage for the aging process in vivo. A causal connection between the two observations was suggested by experiments showing accelerated telomere shorting under conditions of oxidative stress in cultured cells, but has never been studied in vivo. We therefore have analysed whether an increase in mitochondrial derived oxidative stress in response to heterozygous deletion of superoxide dismutase (Sod2+/-) would exacerbate aging phenotypes in telomere dysfunctional (mTerc-/-) mice. Heterozygous deletion of Sod2 resulted in reduced SOD2 protein levels and increased oxidative stress in aging telomere dysfunctional mice, but this did not lead to an increase in basal levels of oxidative nuclear DNA damage, an accumulation of nuclear DNA breaks, or an increased rate of telomere shortening in the mice. Moreover, heterozygous deletion of Sod2 did not accelerate the depletion of stem cells and the impairment in organ maintenance in aging mTerc-/- mice. In agreement with these observations, Sod2 haploinsufficiency did not lead to a further reduction in lifespan of mTerc-/- mice. Together, these results indicate that a decrease in SOD2-dependent antioxidant defence does not exacerbate aging in the context of telomere dysfunction. PMID:20195488

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.

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.

Aging-related changes in respiratory system mechanics and morphometry in mice.

PubMed

Elliott, Jonathan E; Mantilla, Carlos B; Pabelick, Christina M; Roden, Anja C; Sieck, Gary C

2016-07-01

Previous work investigating respiratory system mechanics in mice has reported an aging-related increase in compliance and mean linear intercept (Lm). However, these changes were assessed using only a young (2-mo-old) and old (20- and 26-mo-old) group yet were interpreted to reflect a linear evolution across the life span. Therefore, to investigate respiratory system mechanics and lung morphometry across a more complete spectrum of ages, we utilized 2 (100% survival, n = 6)-, 6 (100% survival, n = 12)-, 18 (90% survival, n = 12)-, 24 (75% survival, n = 12)-, and 30 (25% survival, n = 12)-mo-old C57BL/6 mice. We found a nonlinear aging-related decrease in respiratory system resistance and increase in dynamic compliance and hysteresis between 2- and 24-mo-old mice. However, in 30-mo-old mice, respiratory system resistance increased, and dynamic compliance and hysteresis decreased relative to 24-mo-old mice. Respiratory system impedance spectra were measured between 1-20.5 Hz at positive end-expiratory pressures (PEEP) of 1, 3, 5, and 7 cmH2O. Respiratory system resistance and reactance at each level of PEEP were increased and decreased, respectively, only in 2-mo-old animals. No differences in the respiratory system impedance spectra were observed in 6-, 18-, 24-, and 30-mo-old mice. Additionally, lungs were fixed following tracheal instillation of 4% paraformaldehyde at 25 cmH2O and processed for Lm and airway collagen deposition. There was an aging-related increase in Lm consistent with emphysematous-like changes and no evidence of increased airway collagen deposition. Accordingly, we demonstrate nonlinear aging-related changes in lung mechanics and morphometry in C57BL/6 mice. Copyright © 2016 the American Physiological Society.

Sex differences in neurochemical markers that correlate with behavior in aging mice.

PubMed

Frick, K M; Burlingame, L A; Delaney, S S; Berger-Sweeney, J

2002-01-01

Sex differences in neurochemical markers that correlate with behavior in aging mice NEUROBIOL AGING. We examined whether the enzymatic activities of choline acetyltransferase (ChAT) and glutamic acid decarboxylase (GAD) were altered similarly with age in male and female mice, and whether these changes were correlated with age-related alterations in memory and anxiety. ChAT and GAD activities were measured in neocortex, hippocampus, and striatum of behaviorally characterized male and female C57BL/6 mice (5, 17, and 25 months). Generally, ChAT activity was increased, and GAD activity decreased, with age. However, disparate changes were revealed between the sexes; activities of both enzymes were decreased in 17-month males, whereas alterations in females were not observed until 25-months. Furthermore, enzyme-behavior correlations differed between the sexes; in males, ChAT activity was related to one behavioral task, whereas in females, activities of both enzymes were correlated with multiple tasks. Significant enzyme-behavior correlations were most evident at 17 months of age, likely the result of behavioral and enzymatic sex differences at this age. These data represent the first comprehensive report illustrating differential alterations of ChAT and GAD activities in aging male and female 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.

Cuprizone-induced demyelination in mice: age-related vulnerability and exploratory behavior deficit.

PubMed

Wang, Hongkai; Li, Chengren; Wang, Hanzhi; Mei, Feng; Liu, Zhi; Shen, Hai-Ying; Xiao, Lan

2013-04-01

Schizophrenia is a mental disease that mainly affects young individuals (15 to 35 years old) but its etiology remains largely undefined. Recently, accumulating evidence indicated that demyelination and/or dysfunction of oligodendrocytes is an important feature of its pathogenesis. We hypothesized that the vulnerability of young individuals to demyelination may contribute to the onset of schizophrenia. In the present study, three different age cohorts of mice, i.e. juvenile (3 weeks), young-adult (6 weeks) and middle-aged (8 months), were subjected to a 6-week diet containing 0.2% cuprizone (CPZ) to create an animal model of acute demyelination. Then, age-related vulnerability to CPZ-induced demyelination, behavioral outcomes, and myelination-related molecular biological changes were assessed. We demonstrated: (1) CPZ treatment led to more severe demyelination in juvenile and young-adult mice than in middle-aged mice in the corpus callosum, a region closely associated with the pathophysiology of schizophrenia; (2) the higher levels of demyelination in juvenile and young-adult mice were correlated with a greater reduction of myelin basic protein, more loss of CC-1-positive mature oligodendrocytes, and higher levels of astrocyte activation; and (3) CPZ treatment resulted in a more prominent exploratory behavior deficit in juvenile and young-adult mice than in middle-aged mice. Together, our data demonstrate an age-related vulnerability to demyelination with a concurrent behavioral deficit, providing supporting evidence for better understanding the susceptibility of the young to the onset of schizophrenia.

Impact of pioglitazone and bradykinin type 1 receptor antagonist on type 2 diabetes in high-fat diet-fed C57BL/6J mice.

PubMed

El Akoum, S; Haddad, Y; Couture, R

2017-09-01

Type 2 diabetes (T2D) is a major complication of obesity and a leading cause of morbidity and mortality. Antagonizing bradykinin type 1 receptor (B1R) improved body and tissue fat mass and reversed vascular and adipose tissue inflammation in a rat model of insulin resistance. This study aimed at evaluating further the role of B1R in a mouse model of T2D by comparing the antidiabetic and anti-inflammatory effects of the B1R antagonist SSR240612 (SSR) in adipose tissue with those of pioglitazone (TZD), an activator of peroxisome proliferator-activated receptor gamma. C57BL/6J mice were fed with high-fat diet (HFD) or standard diet (control) for 20 weeks. Yet, during the last 4 weeks, HFD-fed mice were administered SSR and TZD (10 mg kg -1  d -1 each) as monotherapy or combined therapy subcutaneously. The impact of treatments was measured on metabolic hormones levels (ELISA), adipose tissue inflammatory status and the expression of candidate genes involved in T2D (quantitative real-time polymerase chain reaction and western blot). SSR240612 and TZD treatments improved hyperglycaemia, hyperinsulinaemia, insulin resistance, adipose tissue inflammation (expression of B1R, chemokine ligand 2, F4/80 and tumour necrosis factor) and modulated adipogenesis (peroxisome proliferator-activated receptor gamma, adipocytes' protein 2 and CD40 expressions) in HFD-fed mice. Yet, SSR was more effective than TZD to reduce visceral fat mass and resistin. TZD/SSR combined treatment had an additive effect to improve insulin sensitivity and glucose intolerance. Bradykinin type 1 receptor antagonism could represent a promising therapeutic tool in combination with TZD for the treatment of T2D, obesity and insulin resistance.

Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice

PubMed Central

García, Mayra; Misplon, Julia A.; Price, Graeme E.; Lo, Chia-Yun; Epstein, Suzanne L.

2016-01-01

Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11–17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice.

PubMed

García, Mayra; Misplon, Julia A; Price, Graeme E; Lo, Chia-Yun; Epstein, Suzanne L

2016-01-01

Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11-17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life.

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

Altered left ventricular performance in aging physically active mice with an ankle sprain injury.

PubMed

Turner, Michael J; Guderian, Sophie; Wikstrom, Erik A; Huot, Joshua R; Peck, Bailey D; Arthur, Susan T; Marino, Joseph S; Hubbard-Turner, Tricia

2016-02-01

We assessed the impact of differing physical activity levels throughout the lifespan, using a musculoskeletal injury model, on the age-related changes in left ventricular (LV) parameters in active mice. Forty male mice (CBA/J) were randomly placed into one of three running wheel groups (transected CFL group, transected ATFL/CFL group, SHAM group) or a SHAM Sedentary group (SHAMSED). Before surgery and every 6 weeks after surgery, LV parameters were measured under 2.5 % isoflurane inhalation. Group effects for daily distance run was significantly greater for the SHAM and lesser for the ATLF/CFL mice (p = 0.013) with distance run decreasing with age for all mice (p < 0.0001). Beginning at 6 months of age, interaction (group × age) was noted with LV posterior wall thickness-to-radius ratios (h/r) where h/r increased with age in the ATFL/CFL and SHAMSED mice while the SHAM and CFL mice exhibited decreased h/r with age (p = 0.0002). Passive filling velocity (E wave) was significantly greater in the SHAM mice and lowest for the ATFL/CFL and SHAMSED mice (p < 0.0001) beginning at 9 months of age. Active filling velocity (A wave) was not different between groups (p = 0.10). Passive-to-active filling velocity ratio (E/A ratio) was different between groups (p < 0.0001), with higher ratios for the SHAM mice and lower ratios for the ATFL/CFL and SHAMSED mice in response to physical activity beginning at 9 months of age. Passive-to-active filling velocity ratio decreased with age (p < 0.0001). Regular physical activity throughout the lifespan improved LV structure, passive filling velocity, and E/A ratio by 6 to 9 months of age and attenuated any negative alterations throughout the second half of life. The diastolic filling differences were found to be significantly related to the amount of activity performed by 9 months and at the end of the lifespan.

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

Lycopersicon esculentum Extract Enhances Cognitive Function and Hippocampal Neurogenesis in Aged Mice

PubMed Central

Bae, Jung-Soo; Han, Mira; Shin, Hee Soon; Shon, Dong-Hwa; Lee, Soon-Tae; Shin, Chang-Yup; Lee, Yuri; Lee, Dong Hun; Chung, Jin Ho

2016-01-01

A decrease in adult neurogenesis is associated with the aging process, and this decrease is closely related to memory impairment. Tomato (Lycopersicon esculentum) is a fruit with diverse bioactive nutrients that is consumed worldwide. In this study, we investigated the cognition-enhancing effect of tomato ethanolic extracts (TEE) in aged mice. Six weeks of oral TEE administration in 12-month-old aged mice significantly increased their exploration time of novel objects when compared to vehicle-treated mice. The TEE supplement increased doublecortin (DCX)-positive cells and postsynaptic density-95 (PSD95) expression in mice hippocampus. Moreover, we found an increased expression of brain-derived neurotrophic factor (BDNF) and subsequently-activated extracellular-signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling pathway in the TEE-supplemented mice hippocampus. In conclusion, the oral administration of TEE exhibits a cognition-enhancing effect, and the putative underlying mechanism is the induction of BDNF signaling-mediated proliferation and synapse formation in the hippocampus. These findings indicate that TEE could be a candidate for treatment of age-related memory impairment and neurodegenerative disorders. PMID:27792185

Lycopersicon esculentum Extract Enhances Cognitive Function and Hippocampal Neurogenesis in Aged Mice.

PubMed

Bae, Jung-Soo; Han, Mira; Shin, Hee Soon; Shon, Dong-Hwa; Lee, Soon-Tae; Shin, Chang-Yup; Lee, Yuri; Lee, Dong Hun; Chung, Jin Ho

2016-10-26

A decrease in adult neurogenesis is associated with the aging process, and this decrease is closely related to memory impairment. Tomato ( Lycopersicon esculentum ) is a fruit with diverse bioactive nutrients that is consumed worldwide. In this study, we investigated the cognition-enhancing effect of tomato ethanolic extracts (TEE) in aged mice. Six weeks of oral TEE administration in 12-month-old aged mice significantly increased their exploration time of novel objects when compared to vehicle-treated mice. The TEE supplement increased doublecortin (DCX)-positive cells and postsynaptic density-95 (PSD95) expression in mice hippocampus. Moreover, we found an increased expression of brain-derived neurotrophic factor (BDNF) and subsequently-activated extracellular-signal-regulated kinase (ERK)/cAMP response element binding (CREB) signaling pathway in the TEE-supplemented mice hippocampus. In conclusion, the oral administration of TEE exhibits a cognition-enhancing effect, and the putative underlying mechanism is the induction of BDNF signaling-mediated proliferation and synapse formation in the hippocampus. These findings indicate that TEE could be a candidate for treatment of age-related memory impairment and neurodegenerative disorders.

Proteomic analysis of specific brain proteins in aged SAMP8 mice treated with alpha-lipoic acid: implications for aging and age-related neurodegenerative disorders.

PubMed

Poon, H Fai; Farr, Susan A; Thongboonkerd, Visith; Lynn, Bert C; Banks, William A; Morley, John E; Klein, Jon B; Butterfield, D Allan

2005-01-01

Free radical-mediated damage to neuronal membrane components has been implicated in the etiology of Alzheimer's disease (AD) and aging. The senescence accelerated prone mouse strain 8 (SAMP8) exhibits age-related deterioration in memory and learning along with increased oxidative markers. Therefore, SAMP8 is a suitable model to study brain aging and, since aging is the major risk factor for AD and SAMP8 exhibits many of the biochemical findings of AD, perhaps as a model for and the early phase of AD. Our previous studies reported higher oxidative stress markers in brains of 12-month-old SAMP8 mice when compared to that of 4-month-old SAMP8 mice. Further, we have previously shown that injecting the mice with alpha-lipoic acid (LA) reversed brain lipid peroxidation, protein oxidation, as well as the learning and memory impairments in SAMP8 mice. Recently, we reported the use of proteomics to identify proteins that are expressed differently and/or modified oxidatively in aged SAMP8 brains. In order to understand how LA reverses the learning and memory deficits of aged SAMP8 mice, in the current study, we used proteomics to compare the expression levels and specific carbonyl levels of proteins in brains from 12-month-old SAMP8 mice treated or not treated with LA. We found that the expressions of the three brain proteins (neurofilament triplet L protein, alpha-enolase, and ubiquitous mitochondrial creatine kinase) were increased significantly and that the specific carbonyl levels of the three brain proteins (lactate dehydrogenase B, dihydropyrimidinase-like protein 2, and alpha-enolase) were significantly decreased in the aged SAMP8 mice treated with LA. These findings suggest that the improved learning and memory observed in LA-injected SAMP8 mice may be related to the restoration of the normal condition of specific proteins in aged SAMP8 mouse brain. Moreover, our current study implicates neurofilament triplet L protein, alpha-enolase, ubiquitous mitochondrial

Effects of Aging and Oxidative Stress on Spermatozoa of Superoxide-Dismutase 1- and Catalase-Null Mice1

PubMed Central

Selvaratnam, Johanna S.; Robaire, Bernard

2016-01-01

Advanced paternal age is linked to complications in pregnancy and genetic diseases in offspring. Aging results in excess reactive oxygen species (ROS) and DNA damage in spermatozoa; this damage can be transmitted to progeny with detrimental consequences. Although there is a loss of antioxidants with aging, the impact on aging male germ cells of the complete absence of either catalase (CAT) or superoxide dismutase 1 (SOD1) has not been investigated. We used CAT-null (Cat−/−) and SOD1-null (Sod−/−) mice to determine whether loss of these antioxidants increases germ cell susceptibility to redox dysfunction with aging. Aging reduced fertility and the numbers of Sertoli and germ cells in all mice. Aged Sod−/− mice displayed an increased loss of fertility compared to aged wild-type mice. Treatment with the pro-oxidant SIN-10 increased ROS in spermatocytes of aged wild-type and Sod−/− mice, while aged Cat−/− mice were able to neutralize this ROS. The antioxidant peroxiredoxin 1 (PRDX1) increased with age in wild-type and Cat−/− mice but was consistently low in young and aged Sod−/− mice. DNA damage and repair markers (γ-H2AX and 53BP1) were reduced with aging and lower in young Sod−/− and Cat−/− mice. Colocalization of γ-H2AX and 53BP1 suggested active repair in young wild-type mice but reduced in young Cat−/− and in Sod−/− mice and with age. Oxidative DNA damage (8-oxodG) increased in young Sod−/− mice and with age in all mice. These studies show that aged Sod−/− mice display severe redox dysfunction, while wild-type and Cat−/− mice have compensatory mechanisms to partially alleviate oxidative stress and reduce age-related DNA damage in spermatozoa. Thus, SOD1 but not CAT is critical to the maintenance of germ cell quality with aging. PMID:27465136

In Vivo Hypocholesterolemic Effect of MARDI Fermented Red Yeast Rice Water Extract in High Cholesterol Diet Fed Mice

PubMed Central

Beh, Boon Kee; Kong, Joan; Ho, Wan Yong; Mohd Yusof, Hamidah; Hussin, Aminuddin bin; Jaganath, Indu Bala; Alitheen, Noorjahan Banu; Jamaluddin, Anisah

2014-01-01

Fermented red yeast rice has been traditionally consumed as medication in Asian cuisine. This study aimed to determine the in vivo hypocholesterolemic and antioxidant effects of fermented red yeast rice water extract produced using Malaysian Agricultural Research and Development Institute (MARDI) Monascus purpureus strains in mice fed with high cholesterol diet. Absence of monacolin-k, lower level of γ-aminobutyric acid (GABA), higher content of total amino acids, and antioxidant activities were detected in MARDI fermented red yeast rice water extract (MFRYR). In vivo MFRYR treatment on hypercholesterolemic mice recorded similar lipid lowering effect as commercial red yeast rice extract (CRYR) as it helps to reduce the elevated serum liver enzyme and increased the antioxidant levels in liver. This effect was also associated with the upregulation of apolipoproteins-E and inhibition of Von Willebrand factor expression. In summary, MFRYR enriched in antioxidant and amino acid without monacolin-k showed similar hypocholesterolemic effect as CRYR that was rich in monacolin-k and GABA. PMID:25031606

Dietary Blueberry Attenuates Whole-Body Insulin Resistance in High Fat-Fed Mice by Reducing Adipocyte Death and Its Inflammatory Sequelae1–3

PubMed Central

DeFuria, Jason; Bennett, Grace; Strissel, Katherine J.; Perfield, James W.; Milbury, Paul E.; Greenberg, Andrew S.; Obin, Martin S.

2009-01-01

Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMΦ). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-α, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMΦ (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMΦ gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-κB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology. PMID:19515743

Sex-related differences in the wheel-running activity of mice decline with increasing age.

PubMed

Bartling, Babett; Al-Robaiy, Samiya; Lehnich, Holger; Binder, Leonore; Hiebl, Bernhard; Simm, Andreas

2017-01-01

Laboratory mice of both sexes having free access to running wheels are commonly used to study mechanisms underlying the beneficial effects of physical exercise on health and aging in human. However, comparative wheel-running activity profiles of male and female mice for a long period of time in which increasing age plays an additional role are unknown. Therefore, we permanently recorded the wheel-running activity (i.e., total distance, median velocity, time of breaks) of female and male mice until 9months of age. Our records indicated higher wheel-running distances for females than males which were highest in 2-month-old mice. This was mainly reached by higher running velocities of the females and not by longer running times. However, the sex-related differences declined in parallel to the age-associated reduction in wheel-running activities. Female mice also showed more variances between the weekly running distances than males, which were recorded most often for females being 4-6months old but not older. Additional records of 24-month-old mice of both sexes indicated highly reduced wheel-running activities at old age. Surprisingly, this reduction at old age resulted mainly from lower running velocities and not from shorter running times. Old mice also differed in their course of night activity which peaked later compared to younger mice. In summary, we demonstrated the influence of sex on the age-dependent activity profile of mice which is somewhat contrasting to humans, and this has to be considered when transferring exercise-mediated mechanism from mouse to human. Copyright © 2016. Published by Elsevier Inc.

Raspberry promotes brown and beige adipocyte development in mice fed high-fat diet through activation of AMP-activated protein kinase (AMPK) α1.

PubMed

Zou, Tiande; Wang, Bo; Yang, Qiyuan; de Avila, Jeanene M; Zhu, Mei-Jun; You, Jinming; Chen, Daiwen; Du, Min

2018-05-01

Development of brown and beige/brite adipocytes increases thermogenesis and helps to reduce obesity and metabolic syndrome. Our previous study suggests that dietary raspberry can ameliorate metabolic syndromes in diet-induced obese mice. Here, we further evaluated the effects of raspberry on energy expenditure and adaptive thermogenesis and determined whether these effects were mediated by AMP-activated protein kinase (AMPK). Mice deficient in the catalytic subunit of AMPKα1 and wild-type (WT) mice were fed a high-fat diet (HFD) or HFD supplemented with 5% raspberry (RAS) for 10 weeks. The thermogenic program and related regulatory factors in adipose tissue were assessed. RAS improved the insulin sensitivity and reduced fat mass in WT mice but not in AMPKα1 -/- mice. In the absence of AMPKα1, RAS failed to increase oxygen consumption and heat production. Consistent with this, the thermogenic gene expression in brown adipose tissue and brown-like adipocyte formation in subcutaneous adipose tissue were not induced by RAS in AMPKα1 -/- mice. In conclusion, AMPKα1 is indispensable for the effects of RAS on brown and beige/brite adipocyte development, and prevention of obesity and metabolic dysfunction. Copyright © 2018. Published by Elsevier Inc.

Oxygen saturation and heart rate during feeding in breast-fed infants at 1 week and 2 months of age.

PubMed

Suiter, Debra M; Ruark-McMurtrey, Jacki

2007-12-01

To gather normative data about cardiopulmonary changes during feeding in breast-fed infants at 1 week and 2 months of age. Prospective cohort study. General community. Twenty-two term-born, breast-fed infants. Not applicable. Oxygen saturation (SpO2), the percentage of oxygenized hemoglobin, and heart rate were monitored and recorded every 30 seconds for 5 minutes before oral feeding, during the first 10 minutes of feeding, and the first 10 minutes immediately after feeding. The observations were made at 1 week and 2 months of age. Mean SpO2 levels were significantly higher in 2-month-old infants (mean, 97.57) than in 1-week-old infants (mean, 96.35) (P=.001). SpO2 was not affected by any of the 3 trials (before, during, and after feeding). Heart rate was significantly affected by trial. Mean heart rate during feeding (mean, 152.45) was significantly higher than heart rate prefeeding (mean, 146.51) (P<.001), and heart rate postfeeding (mean, 147.12) (P=.002). Heart rate was not affected by age. Little is known about the association between feeding and cardiopulmonary status in term-born, breast-fed infants. This longitudinal study contributes to our knowledge about feeding-related cardiopulmonary changes in term-born, breast-fed infants.

Triticale Bran Alkylresorcinols Enhance Resistance to Oxidative Stress in Mice Fed a High-Fat Diet

PubMed Central

Agil, Rania; Patterson, Zachary R.; Mackay, Harry; Abizaid, Alfonso; Hosseinian, Farah

2016-01-01

Triticale (× Triticosecale Whitm.) is a cereal grain with high levels of alkyresorcinols (AR) concentrated in the bran. These phenolic lipids have been shown to reduce or inhibit triglyceride accumulation and protect against oxidation; however, their biological effects have yet to be evaluated in vivo. The purpose of this study was to determine the effects of ARs extracted from triticale bran (TB) added to a high–fat diet on the development of obesity and oxidative stress. CF-1 mice were fed a standard low-fat (LF) diet, a 60% high-fat diet (HF) and HF diets containing either 0.5% AR extract (HF-AR), 10% TB (HF-TB), or 0.5% vitamin E (HF-VE). Energy intake, weight gain, glucose tolerance, fasting blood glucose (FBG) levels, and body composition were determined. Oxygen radical absorbance capacity (ORAC), superoxide dismutase (SOD) activity, and glutathione (GSH) assays were performed on mice liver and heart tissues. The findings suggest that ARs may serve as a preventative measure against risks of oxidative damage associated with high-fat diets and obesity through their application as functional foods and neutraceuticals. Future studies aim to identify the in vivo mechanisms of action of ARs and the individual homologs involved in their favorable biological effects. PMID:28231100

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

RADIATION INDUCED AGING IN MICE

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

Curtis, H.J.; Gebhard, K.L.

1958-10-31

. Experiments were undertaken in an effort to determine the degree of similarity between natural and radiation induced aging, and to determine the causes for the latter. Several severe non-specific stresses were applied to mice either as single massive doses or as smaller doses administered over a large fraction of the life span of the animals. Stresses used included typhoid vaccine, tetanus toxin and tetanus toxoid and turpentine. None of these produced any premature aging comparable to that produced by radiation. The somatic mutation theory of aging and expecially radiationinduced aging has been tested by applying the chemical mutatgen, nitrogenmore » mustard, either as a massive single dose or as smaller single doses repeated over long periods of time. No shortening of the life span has been observed and it is concluded that the somatic mutation theory is untenable. Experiments designed to determine the organ system responsible for radiation induced aging have demonstrated that the hematopoietic system is not primarily involved in this phenomenon. (auth)« less

Influence of chewing behaviour on memory and spatial learning in albino BALB/c mice.

PubMed

Aguirre Siancas, E E

2017-05-01

Since the relationship between chewing and cognitive functions has not been fully elucidated, this study aimed to determine the impact of chewing behaviour on spatial learning and memory in albino male BALB/c mice. Twenty mice aged 8 weeks were divided into 2 equal groups. The regular chewing group was fed with uncrushed grains (the same diet given to all 20 mice since they were weaned) and the limited chewing group was fed with crushed grains. At 16 weeks of age, the mice were evaluated over 5 days, including a 4-day acquisition phase prior to a probe test of spatial learning and memory in the Morris water maze on the fifth day. A comparison of the regular chewing group and the limited chewing group found no significant differences in either the acquisition phase or the probe test. However, there were significant differences in the acquisition phase for just the regular chewing group when comparing results from the first day to those from the other 3 days. The results suggest that regular chewing affects spatial learning and memory since mice in the regular chewing group decreased their times to find the hidden platform during the acquisition phase. Copyright © 2015 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment.

PubMed

Wang, Tina; Tsui, Brian; Kreisberg, Jason F; Robertson, Neil A; Gross, Andrew M; Yu, Michael Ku; Carter, Hannah; Brown-Borg, Holly M; Adams, Peter D; Ideker, Trey

2017-03-28

Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0 months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1 df/df dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.

Idh2 deficiency accelerates renal dysfunction in aged mice.

PubMed

Lee, Su Jeong; Cha, Hanvit; Lee, Seoyoon; Kim, Hyunjin; Ku, Hyeong Jun; Kim, Sung Hwan; Park, Jung Hyun; Lee, Jin Hyup; Park, Kwon Moo; Park, Jeen-Woo

2017-11-04

The free radical or oxidative stress theory of aging postulates that senescence is due to an accumulation of cellular oxidative damage, caused largely by reactive oxygen species (ROS) that are produced as by-products of normal metabolic processes in mitochondria. The oxidative stress may arise as a result of either increased ROS production or decreased ability to detoxify ROS. The availability of the mitochondrial NADPH pool is critical for the maintenance of the mitochondrial antioxidant system. The major enzyme responsible for generating mitochondrial NADPH is mitochondrial NADP + -dependent isocitrate dehydrogenase (IDH2). Depletion of IDH2 in mice (idh2 -/- ) shortens life span and accelerates the degeneration of multiple age-sensitive traits, such as hair grayness, skin pathology, and eye pathology. Among the various internal organs tested in this study, IDH2 depletion-induced acceleration of senescence was uniquely observed in the kidney. Renal function and structure were greatly deteriorated in 24-month-old idh2 -/- mice compared with wild-type. In addition, disruption of redox status, which promotes oxidative damage and apoptosis, was more pronounced in idh2 -/- mice. These data support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice, and thus support the oxidative stress theory of aging. Copyright © 2017 Elsevier Inc. All rights reserved.

Hexim1 heterozygosity stabilizes atherosclerotic plaque and decreased steatosis in ApoE null mice fed atherogenic diet.

PubMed

Dhar-Mascareno, Manya; Rozenberg, Inna; Iqbal, Jahangir; Hussain, M Mahmood; Beckles, Daniel; Mascareno, Eduardo

2017-02-01

Hexim-1 is an inhibitor of RNA polymerase II transcription elongation. Decreased Hexim-1 expression in animal models of chronic diseases such as left ventricular hypertrophy, obesity and cancer triggered significant changes in adaptation and remodeling. The main aim of this study was to evaluate the role of Hexim1 in lipid metabolism focused in the progression of atherosclerosis and steatosis. We used the C57BL6 apolipoprotein E (ApoE null) crossed bred to C57BL6Hexim1 heterozygous mice to obtain ApoE null - Hexim1 heterozygous mice (ApoE-HT). Both ApoE null backgrounds were fed high fat diet for twelve weeks. Then, we evaluated lipid metabolism, atherosclerotic plaque formation and liver steatosis. In order to understand changes in the transcriptome of both backgrounds during the progression of steatosis, we performed Affymetrix mouse 430 2.0 microarray. After 12 weeks of HFD, ApoE null and ApoE-HT showed similar increase of cholesterol and triglycerides in plasma. Plaque composition was altered in ApoE-HT. Additionally, liver triglycerides and steatosis were decreased in ApoE-HT mice. Affymetrix analysis revealed that decreased steatosis might be due to impaired inducible SOCS3 expression in ApoE-HT mice. In conclusion, decreased Hexim-1 expression does not alter cholesterol metabolism in ApoE null background after HFD. However, it promotes stable atherosclerotic plaque and decreased steatosis by promoting the anti-inflammatory TGFβ pathway and blocking the expression of the inducible and pro-inflammatory expression of SOCS3 respectively. Published by Elsevier Ltd.

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.

Effects of cereal fiber on leptin resistance and sensitivity in C57BL/6J mice fed a high-fat/cholesterol diet.

PubMed