Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice.

PubMed

Larter, Claire Z; Yeh, Matthew M; Van Rooyen, Derrick M; Teoh, Narci C; Brooling, John; Hou, Jing Yun; Williams, Jacqueline; Clyne, Matthew; Nolan, Christopher J; Farrell, Geoffrey C

2009-10-01

We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model. Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks. After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma. In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome.

Genistein treatment increases bone mass in obese, hyperglycemic mice

PubMed Central

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Background Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. Methods In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Results Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Conclusion Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight. PMID:27042131

Genistein treatment increases bone mass in obese, hyperglycemic mice.

PubMed

Michelin, Richard M; Al-Nakkash, Layla; Broderick, Tom L; Plochocki, Jeffrey H

2016-01-01

Obesity and type 2 diabetes mellitus are associated with elevated risk of limb bone fracture. Incidences of these conditions are on the rise worldwide. Genistein, a phytoestrogen, has been shown by several studies to demonstrate bone-protective properties and may improve bone health in obese type 2 diabetics. In this study, we test the effects of genistein treatment on limb bone and growth plate cartilage histomorphometry in obese, hyperglycemic ob/ob mice. Six-week-old ob/ob mice were divided into control and genistein-treated groups. Genistein-treated mice were fed a diet containing 600 mg genistein/kg for a period of 4 weeks. Cross-sectional geometric and histomorphometric analyses were conducted on tibias. Genistein-treated mice remained obese and hyperglycemic. However, histomorphometric comparisons show that genistein-treated mice have greater tibial midshaft diameters and ratios of cortical bone to total tissue area than the controls. Genistein-treated mice also exhibit decreased growth plate thickness of the proximal tibia. Our results indicate that genistein treatment affects bone of the tibial midshaft in the ob/ob mouse, independent of improvements in the hyperglycemic state and body weight.

INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSITION AND ELIMINATION OF TCDD IN MICE

EPA Science Inventory

INFLUENCE OF TYPE II DIABETES AND OBESITY ON THE DISPOSTION AND ELIMINATION OF TCDD IN MICE. MJ DeVito', JJ Diliberto', DG Ross', C Emond2, VM Richardson', and LS Birnbaum', 'ETD, NHEERL, ORD, US EPA, RTP, NC, 27711, USA, 2National Research Council.
One possible explanation fo...

Induction of resistance to diabetes in non-obese diabetic mice by targeting CD44 with a specific monoclonal antibody

PubMed Central

Weiss, Lola; Slavin, Shimon; Reich, Shoshana; Cohen, Patrizia; Shuster, Svetlana; Stern, Robert; Kaganovsky, Ella; Okon, Elimelech; Rubinstein, Ariel M.; Naor, David

2000-01-01

Inflammatory destruction of insulin-producing β cells in the pancreatic islets is the hallmark of insulin-dependent diabetes mellitus, a spontaneous autoimmune disease of non-obese diabetic mice resembling human juvenile (type I) diabetes. Histochemical analysis of diabetic pancreata revealed that mononuclear cells infiltrating the islets and causing autoimmune insulitis, as well as local islet cells, express the CD44 receptor; hyaluronic acid, the principal ligand of CD44, is detected in the islet periphery and islet endothelium. Injection of anti-CD44 mAb 1 hr before cell transfer of diabetogenic splenocytes and subsequently on alternate days for 4 weeks induced considerable resistance to diabetes in recipient mice, reflected by reduced insulitis. Contact sensitivity to oxazolone was not influenced by this treatment. A similar antidiabetic effect was observed even when the anti-CD44 mAb administration was initiated at the time of disease onset: i.e., 4–7 weeks after cell transfer. Administration of the enzyme hyaluronidase also induced appreciable resistance to insulin-dependent diabetes mellitus, suggesting that the CD44–hyaluronic acid interaction is involved in the development of the disease. These findings demonstrate that CD44-positive inflammatory cells may be a potential therapeutic target in insulin-dependent diabetes. PMID:10618410

Red raspberry (Rubus idaeus L.) intake decreases oxidative stress in obese diabetic (db/db) mice.

PubMed

Noratto, Giuliana D; Chew, Boon P; Atienza, Liezl M

2017-07-15

Red raspberry fruit intake was investigated on obese diabetic (db/db) mice for 8weeks. Animals fed isocaloric diets (5.3% freeze-dried raspberry, or control) were assessed for obesity-diabetes-disease risk biomarkers. Results showed that raspberry intake improved antioxidant status and lessened plasma interleukin (IL)-6 (0.3-fold of control, p<0.1); most likely through enhancing glutathione peroxidase (GPx) activity in liver (4.3-fold of control), and in blood (2.1-fold of control). Other disease-risk biomarkers were similar between groups (p>0.05). Plasma levels of total cholesterol (T-CHL), low density lipoprotein-cholesterol (LDL-CHL), and resistin were higher in the raspberry group. Overall, the enhanced detoxifying cell defenses exerted by raspberry intake might be due to its polyphenolics and fibre. This study demonstrates in vivo that raspberry intake, at a dose that can be achieved by human consumption, might protect against diabetes-induced oxidative stress. Copyright © 2017 Elsevier Ltd. All rights reserved.

Preferential suppression of limbic Fos expression by intermittent hypoxia in obese diabetic mice.

PubMed

Mukai, Takahiro; Nagao, Yuki; Nishioka, Satoshi; Hayashi, Tetsuya; Shimizu, Saki; Ono, Asuka; Sakagami, Yoshihisa; Watanabe, Sho; Ueda, Yoko; Hara, Madoka; Tokudome, Kentaro; Kato, Ryuji; Matsumura, Yasuo; Ohno, Yukihiro

2013-12-01

Sleep apnea (SA) causes not only sleep disturbances, but also neurocognitive impairments and/or psychoemotional disorders. Here, we studied the effects of intermittent hypoxia (IH) on forebrain Fos expression using obese diabetic db/db mice to explore the pathophysiological alterations in neural activities and the brain regions related to SA syndrome. Male db/db mice were exposed to IH stimuli (repetitive 6-min cycles of 1min with 5% oxygen followed by 5min with 21% oxygen) for 8h (80 cycles) per day or normoxic condition (control group) for 14 days. Fos protein expression was immunohistochemically examined a day after the last IH exposure. Mapping analysis revealed a significant reduction of Fos expression by IH in limbic and paralimbic structures, including the cingulate and piriform cortices, the core part of the nucleus accumbens and most parts of the amygdala (i.e., the basolateral and basomedial amygdaloid nuclei, cortical amygdaloid area and medial amygdaloid nucleus). In the brain stem regions, Fos expression was region-specifically reduced in the ventral tegmental area while other regions including the striatum, thalamus and hypothalamus, were relatively resistant against IH. In addition, db/db mice exposed to IH showed a trend of sedative and/or depressive behavioral signs in the open field and forced swim tests. The present results illustrate that SA in the obese diabetic model causes neural suppression preferentially in the limbic and paralimbic regions, which may be related to the neuropsychological disturbances associated with SA. Copyright © 2013. Published by Elsevier Ireland Ltd.

Novel Humanized mice to test Therapeutics for Human Type 1 Diabetes

DTIC Science & Technology

2014-01-06

performed in non- obese diabetic (NOD) mice, the closest animal model for human T1D, have identified different immune cells involved in pancreatic β-cell...periphery. Each MHC class II chain contributes to the formation of a groove where the peptide is embedded (78). 17 The polygenetic factor underlying...diabetes mellitus in non- obese diabetic mice by transgenes encoding modified I-A beta-chain or normal I-E alpha-chain. Nature 345:727-9 63. Marek

Therapeutic potential of flurbiprofen against obesity in mice.

PubMed

Hosoi, Toru; Baba, Sachiko; Ozawa, Koichiro

2014-06-20

Obesity is associated with several diseases including diabetes, nonalcoholic steatohepatitis (NASH), hypertension, cardiovascular disease, and cancer. Therefore, anti-obesity drugs have the potential to prevent these diseases. In the present study, we demonstrated that flurbiprofen, a nonsteroidal anti-inflammatory drug (NSAID), exhibited therapeutic potency against obesity. Mice were fed a high-fat diet (HFD) for 6 months, followed by a normal-chow diet (NCD). The flurbiprofen treatment simultaneously administered. Although body weight was significantly decreased in flurbiprofen-treated mice, growth was not affected. Flurbiprofen also reduced the HFD-induced accumulation of visceral fat. Leptin resistance, which is characterized by insensitivity to the anti-obesity hormone leptin, is known to be involved in the development of obesity. We found that one of the possible mechanisms underlying the anti-obesity effects of flurbiprofen may have been mediated through the attenuation of leptin resistance, because the high circulating levels of leptin in HFD-fed mice were decreased in flurbiprofen-treated mice. Therefore, flurbiprofen may exhibit therapeutic potential against obesity by reducing leptin resistance. Copyright © 2014 Elsevier Inc. All rights reserved.

High-fat, carbohydrate-free diet markedly aggravates obesity but prevents beta-cell loss and diabetes in the obese, diabetes-susceptible db/db strain.

PubMed

Mirhashemi, Farshad; Kluth, Oliver; Scherneck, Stephan; Vogel, Heike; Kluge, Reinhart; Schurmann, Annette; Joost, Hans-Georg; Neschen, Susanne

2008-01-01

We have previously reported that a high-fat, carbohydrate-free diet prevents diabetes and beta-cell destruction in the New Zealand Obese (NZO) mouse strain. Here we investigated the effect of diets with and without carbohydrates on obesity and development of beta-cell failure in a second mouse model of type 2 diabetes, the db/db mouse. When kept on a carbohydrate-containing standard (SD; with (w/w) 5.1, 58.3, and 17.6% fat, carbohydrates and protein, respectively) or high-fat diet (HFD; 14.6, 46.7 and 17.1%), db/db mice developed severe diabetes (blood glucose >20 mmol/l, weight loss, polydipsia and polyurea) associated with a selective loss of pancreatic beta-cells, reduced GLUT2 expression in the remaining beta-cells, and reduced plasma insulin levels. In contrast, db/db mice kept on a high-fat, carbohydrate-free diet (CFD; with 30.2 and 26.4% (w/w) fat or protein) did not develop diabetes and exhibited near-normal, hyperplastic islets in spite of a morbid obesity (fat content >60%) associated with hyperinsulinaemia. These data indicate that in genetically different mouse models of obesity-associated diabetes, obesity and dietary fat are not sufficient, and dietary carbohydrates are required, for beta-cell destruction.

Obesity-induced diabetes in mouse strains treated with gold thioglucose: a novel animal model for studying β-cell dysfunction.

PubMed

Karasawa, Hiroshi; Takaishi, Kiyosumi; Kumagae, Yoshihiro

2011-03-01

An obesity-induced diabetes model using genetically normal mouse strains would be invaluable but remains to be established. One reason is that several normal mouse strains are resistant to high-fat diet-induced obesity. In the present study, we show the effectiveness of gold thioglucose (GTG) in inducing hyperphagia and severe obesity in mice, and demonstrate the development of obesity-induced diabetes in genetically normal mouse strains. GTG treated DBA/2, C57BLKs, and BDF1 mice gained weight rapidly and exhibited significant increases in nonfasting plasma glucose levels 8-12 weeks after GTG treatment. These mice showed significantly impaired insulin secretion, particularly in the early phase after glucose load, and reduced insulin content in pancreatic islets. Interestingly, GTG treated C57BL/6 mice did not become diabetic and retained normal early insulin secretion and islet insulin content despite being as severely obese and insulin resistant as the other mice. These results suggest that the pathogenesis of obesity-induced diabetes in GTG-treated mice is attributable to the inability of their pancreatic β-cells to secrete enough insulin to compensate for insulin resistance. Mice developing obesity-induced diabetes after GTG treatment might be a valuable tool for investigating obesity-induced diabetes. Furthermore, comparing the genetic backgrounds of mice with different susceptibilities to diabetes may lead to the identification of novel genetic factors influencing the ability of pancreatic β-cells to secrete insulin.

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice.

PubMed

Weiss, L; Zeira, M; Reich, S; Har-Noy, M; Mechoulam, R; Slavin, S; Gallily, R

2006-03-01

Cannabidinoids are components of the Cannabis sativa (marijuana) plant that have been shown capable of suppressing inflammation and various aspects of cell-mediated immunity. Cannabidiol (CBD), a non-psychoactive cannabidinoid has been previously shown by us to suppress cell-mediated autoimmune joint destruction in an animal model of rheumatoid arthritis. We now report that CBD treatment significantly reduces the incidence of diabetes in NOD mice from an incidence of 86% in non-treated control mice to an incidence of 30% in CBD-treated mice. CBD treatment also resulted in the significant reduction of plasma levels of the pro-inflammatory cytokines, IFN-gamma and TNF-alpha. Th1-associated cytokine production of in vitro activated T-cells and peritoneal macrophages was also significantly reduced in CBD-treated mice, whereas production of the Th2-associated cytokines, IL-4 and IL-10, was increased when compared to untreated control mice. Histological examination of the pancreatic islets of CBD-treated mice revealed significantly reduced insulitis. Our results indicate that CBD can inhibit and delay destructive insulitis and inflammatory Th1-associated cytokine production in NOD mice resulting in a decreased incidence of diabetes possibly through an immunomodulatory mechanism shifting the immune response from Th1 to Th2 dominance.

Maternal obesity and diabetes induces latent metabolic defects and widespread epigenetic changes in isogenic mice

PubMed Central

Li, Cheryl C.Y.; Young, Paul E.; Maloney, Christopher A.; Eaton, Sally A.; Cowley, Mark J.; Buckland, Michael E; Preiss, Thomas; Henstridge, Darren C.; Cooney, Gregory J.; Febbraio, Mark A.; Martin, David I.K.; Cropley, Jennifer E.; Suter, Catherine M.

2013-01-01

Intrauterine nutrition can program metabolism, creating stable changes in physiology that may have significant health consequences. The mechanism underlying these changes is widely assumed to involve epigenetic changes to the expression of metabolic genes, but evidence supporting this idea is limited. Here we have performed the first study of the epigenomic consequences of exposure to maternal obesity and diabetes. We used a mouse model of natural-onset obesity that allows comparison of genetically identical mice whose mothers were either obese and diabetic or lean with a normal metabolism. We find that the offspring of obese mothers have a latent metabolic phenotype that is unmasked by exposure to a Western-style diet, resulting in glucose intolerance, insulin resistance and hepatic steatosis. The offspring show changes in hepatic gene expression and widespread but subtle alterations in cytosine methylation. Contrary to expectation, these molecular changes do not point to metabolic pathways but instead reside in broadly developmental ontologies. We propose that, rather than being adaptive, these changes may simply produce an inappropriate response to suboptimal environments; maladaptive phenotypes may be avoidable if postnatal nutrition is carefully controlled. PMID:23764993

[Effects of diabetes and obesity on the higher brain functions in rodents].

PubMed

Asato, Megumi; Ikeda, Hiroko; Kamei, Junzo

2012-11-01

Metabolic disorders, such as diabetes and obesity, have been indicated to disturb the function of the central nervous system (CNS) as well as several peripheral organs. Clinically, it is well recognized that the prevalence of anxiety and depression is higher in diabetic and obesity patients than in the general population. We have recently indicated that streptozotocin-induced diabetic and diet-induced obesity mice have enhanced fear memory and higher anxiety-like behavior in several tests such as the conditioned fear, tail-suspension, hole-board and elevated open-platform tests. The changes in fear memory and anxiety-like behavior of diabetic and obese mice are due to the dysfunction of central glutamatergic and monoaminergic systems, which is mediated by the changes of intracellular signaling. These results suggest that metabolic disorders strongly affect the function of the CNS and disturb the higher brain functions. These dysfunctions of the CNS in diabetes and obesity are involved in the increased prevalence of anxiety disorders and depression. Normalization of these dysfunctions in the CNS will be a new attractive target to treat the metabolic disorders and their complications.

Long-term reversal of diabetes in non-obese diabetic mice by liver-directed gene therapy.

PubMed

Ren, Binhai; O'Brien, Bronwyn A; Byrne, Michelle R; Ch'ng, Edwin; Gatt, Prudence N; Swan, M Anne; Nassif, Najah T; Wei, Ming Q; Gijsbers, Rik; Debyser, Zeger; Simpson, Ann M

2013-01-01

Type 1 diabetes (T1D) results from an autoimmune attack against the insulin-producing β-cells of the pancreas. The present study aimed to reverse T1D by gene therapy. We used a novel surgical technique, which involves isolating the liver from the circulation before the delivery of a lentiviral vector carrying furin-cleavable human insulin (INS-FUR) or empty vector to the livers of diabetic non-obese diabetic mice (NOD). This was compared with the direct injection of the vector into the portal circulation. Mice were monitored for body weight and blood glucose. Intravenous glucose tolerance tests were performed. Expression of insulin and pancreatic transcription factors was determined by the reverse transcriptase-polymerase chain reaction and immunohistochemistry and immunoelectron microscopy was used to localise insulin. Using the novel surgical technique, we achieved long-term transduction (42% efficiency) of hepatocytes, restored normoglycaemia for 150 days (experimental endpoint) and re-established normal glucose tolerance. We showed the expression of β-cell transcription factors, murine insulin, glucagon and somatostatin, and hepatic storage of insulin in granules. The expression of hepatic markers, C/EBP-β, G6PC, AAT and GLUI was down-regulated in INS-FUR-treated livers. Liver function tests remained normal, with no evidence of intrahepatic inflammation or autoimmune destruction of the insulin-secreting liver tissue. By comparison, direct injection of INS-FUR reduced blood glucose levels, and no pancreatic transdifferentiation or normal glucose tolerance was observed. This gene therapy protocol has, for the first time, permanently reversed T1D with normal glucose tolerance in NOD mice and, as such, represents a novel therapeutic strategy for the treatment of T1D. Copyright © 2013 John Wiley & Sons, Ltd.

Daily Coffee Intake Inhibits Pancreatic Beta Cell Damage and Nonalcoholic Steatohepatitis in a Mouse Model of Spontaneous Metabolic Syndrome, Tsumura-Suzuki Obese Diabetic Mice.

PubMed

Watanabe, Syunsuke; Takahashi, Tetsuyuki; Ogawa, Hirohisa; Uehara, Hisanori; Tsunematsu, Takaaki; Baba, Hayato; Morimoto, Yuki; Tsuneyama, Koichi

2017-05-01

Metabolic syndrome is one of the most important health issues worldwide. Obesity causes insulin resistance, hyperlipidemia, diabetes, and various diseases throughout the body. The liver phenotype, which is called nonalcoholic steatohepatitis (NASH), frequently progresses to hepatocellular carcinoma. We recently established a new animal model, Tsumura-Suzuki obese diabetic (TSOD) mice, which spontaneously exhibit obesity, diabetes, hyperlipidemia, and NASH with liver nodules. We examined the effects of coffee intake on various conditions of the metabolic syndrome using TSOD mice. The daily volume of coffee administered was limited so that it reflected the appropriate quantities consumed in humans. To clarify the effects of the specific components, animals were divided into two coffee-intake groups that included with and without caffeine. Coffee intake did not significantly affect obesity and hyperlipidemia in TSOD mice. In contrast, coffee intake caused various degrees of improvement in the pancreatic beta cell damage and steatohepatitis with liver carcinogenesis. Most of the effects were believed to be caused by a synergistic effect of caffeine with other components such as polyphenols. However, the antifibrotic effects of coffee appeared to be due to the polyphenols rather than the caffeine. A daily habit of drinking coffee could possibly play a role in the prevention of metabolic syndrome.

Effect of diet induced obesity or type 1 or type 2 diabetes on corneal nerves and peripheral neuropathy in C57Bl/6J mice

PubMed Central

Yorek, Matthew S.; Obrosov, Alexander; Shevalye, Hanna; Holmes, Amey; Harper, Matthew M.; Kardon, Randy H.; Yorek, Mark A.

2015-01-01

We determined the impact diet induced obesity (DIO) and types 1 and 2 diabetes has on peripheral neuropathy with emphasis on corneal nerve structural changes in C57Bl/6J mice. Endpoints examined included nerve conduction velocity, response to thermal and mechanical stimuli and innervation of the skin and cornea. DIO mice and to a greater extent type 2 diabetic mice were insulin resistant. DIO and both types 1 and 2 diabetic mice developed motor and sensory nerve conduction deficits. In the cornea of DIO and type 2 diabetic mice there was a decrease in sub-epithelial corneal nerves, innervation of the corneal epithelium and corneal sensitivity. Type 1 diabetic mice did not present with any significant changes in corneal nerve structure until after 20 weeks of hyperglycemia. DIO and type 2 diabetic mice developed corneal structural damage more rapidly than type 1 diabetic mice even though hemoglobin A1C values were significantly higher in type 1 diabetic mice. This suggests that DIO with or without hyperglycemia contributes to development and progression of peripheral neuropathy and nerve structural damage in the cornea. PMID:25858759

Ashitaba (Angelica Keiskei) Exudate Prevents Increases in Plasminogen Activator Inhibitor-1 Induced by Obesity in Tsumura Suzuki Obese Diabetic Mice.

PubMed

Ohta, Mitsuhiro; Fujinami, Aya; Oishi, Katsutaka; Kobayashi, Norihiro; Ohnishi, Katsunori; Ohkura, Naoki

2018-04-30

Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI-1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-α) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals.

Saccharomyces boulardii administration changes gut microbiota and reduces hepatic steatosis, low-grade inflammation, and fat mass in obese and type 2 diabetic db/db mice.

PubMed

Everard, Amandine; Matamoros, Sébastien; Geurts, Lucie; Delzenne, Nathalie M; Cani, Patrice D

2014-06-10

Growing evidence shows that gut microbes are key factors involved in the regulation of energy homeostasis, metabolic inflammation, lipid metabolism, and glucose metabolism. Therefore, gut microbiota modulations caused by selectively fermented oligosaccharides or probiotic bacteria constitute an interesting target in the physiopathology of obesity. However, to date, no probiotic yeast has been investigated in this context. Therefore, our study aimed to evaluate the impact of the most-studied probiotic yeast (i.e., Saccharomyces boulardii Biocodex) on obesity and associated metabolic features, such as fat mass development, hepatic steatosis, and low-grade inflammation, in obese mice. S. boulardii was administered daily by oral gavage to leptin-resistant obese and type 2 diabetic mice (db/db) for 4 weeks. We found that S. boulardii-treated mice exhibited reduced body weight, fat mass, hepatic steatosis, and inflammatory tone. Interestingly, these effects of S. boulardii on host metabolism were associated with local effects in the intestine. S. boulardii increased cecum weight and cecum tissue weight but also induced dramatic changes in the gut microbial composition at the phylum, family, and genus levels. These gut microbiota changes in response to S. boulardii may also be correlated with the host metabolism response. In conclusion, this study demonstrates for the first time that S. boulardii may act as a beneficial probiotic treatment in the context of obesity and type 2 diabetes. To date, no probiotic yeast have been investigated in the context of obesity and type 2 diabetes. Here we found that type 2 diabetic and obese mice (db/db) treated with Saccharomyces boulardii exhibited reduced body weight, fat mass, hepatic steatosis, and inflammatory tone. These effects on host metabolism were associated with local effects in the intestine. Importantly, by using pyrosequencing, we found that S. boulardii treatment induces changes of the gut microbiota composition at the

Increased plasma citrulline in mice marks diet-induced obesity and may predict the development of the metabolic syndrome.

PubMed

Sailer, Manuela; Dahlhoff, Christoph; Giesbertz, Pieter; Eidens, Mena K; de Wit, Nicole; Rubio-Aliaga, Isabel; Boekschoten, Mark V; Müller, Michael; Daniel, Hannelore

2013-01-01

In humans, plasma amino acid concentrations of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) increase in states of obesity, insulin resistance and diabetes. We here assessed whether these putative biomarkers can also be identified in two different obesity and diabetic mouse models. C57BL/6 mice with diet-induced obesity (DIO) mimic the metabolic impairments of obesity in humans characterized by hyperglycemia, hyperinsulinemia and hepatic triglyceride accumulation. Mice treated with streptozotocin (STZ) to induce insulin deficiency were used as a type 1 diabetes model. Plasma amino acid profiling of two high fat (HF) feeding trials revealed that citrulline and ornithine concentrations are elevated in obese mice, while systemic arginine bioavailability (ratio of plasma arginine to ornithine + citrulline) is reduced. In skeletal muscle, HF feeding induced a reduction of arginine levels while citrulline levels were elevated. However, arginine or citrulline remained unchanged in their key metabolic organs, intestine and kidney. Moreover, the intestinal conversion of labeled arginine to ornithine and citrulline in vitro remained unaffected by HF feeding excluding the intestine as prime site of these alterations. In liver, citrulline is mainly derived from ornithine in the urea cycle and DIO mice displayed reduced hepatic ornithine levels. Since both amino acids share an antiport mechanism for mitochondrial import and export, elevated plasma citrulline may indicate impaired hepatic amino acid handling in DIO mice. In the insulin deficient mice, plasma citrulline and ornithine levels also increased and additionally these animals displayed elevated BCAA and AAA levels like insulin resistant and diabetic patients. Therefore, type 1 diabetic mice but not DIO mice show the "diabetic fingerprint" of plasma amino acid changes observed in humans. Additionally, citrulline may serve as an early indicator of the obesity-dependent metabolic impairments.

Brd2 gene disruption causes ‘metabolically healthy’ obesity: Epigenetic and chromatin-based mechanisms that uncouple obesity from Type 2 diabetes

PubMed Central

Wang, Fangnian; Deeney, Jude T.; Denis, Gerald V.

2014-01-01

Disturbed body energy balance can lead to obesity and obesity-driven diseases such as Type 2 diabetes, which have reached an epidemic level. Evidence indicates that obesity induced inflammation is a major cause of insulin resistance and Type 2 diabetes. Environmental factors, such as nutrients, affect body energy balance through epigenetic or chromatin-based mechanisms. As a bromodomain and external domain family transcription regulator, Brd2 regulates expression of many genes through interpretation of chromatin codes, and participates in the regulation of body energy balance and immune function. In the severely obese state, Brd2 knockdown in mice prevented obesity-induced inflammatory responses, protected animals from Type 2 diabetes, and thus uncoupled obesity from diabetes. Brd2 provides an important model for investigation of the function of transcription regulators and the development of obesity and diabetes; it also provides a possible target to treat obesity and diabetes through modulation of the function of a chromatin code reader. PMID:23374712

Cannabidiol Arrests Onset of Autoimmune Diabetes in NOD Mice

PubMed Central

Weiss, Lola; Zeira, Michael; Reich, Shoshana; Slavin, Shimon; Raz, Itamar; Mechoulam, Raphael; Gallily, Ruth

2008-01-01

We have previously reported that cannabidiol (CBD) lowers the incidence of diabetes in young non-obese diabetes-prone (NOD) female mice. In the present study we show that administration of CBD to 11–14 week old female NOD mice, which are either in a latent diabetes stage or with initial symptoms of diabetes, ameliorates the manifestations of the disease. Diabetes was diagnosed in only 32% of the mice in the CBD-treated group, compared to 86% and 100% in the emulsifier-treated and untreated groups, respectively. In addition, the level of the proinflammatory cytokine IL-12 produced by splenocytes was significantly reduced, whereas the level of the anti-inflammatory IL-10 was significantly elevated following CBD-treatment. Histological examination of the pancreata of CBD-treated mice revealed more intact islets than in the controls. Our data strengthen our previous assumption that CBD, known to be safe in man, can possibly be used as a therapeutic agent for treatment of type 1 diabetes. PMID:17714746

Boron supplementation improves bone health of non-obese diabetic mice.

PubMed

Dessordi, Renata; Spirlandeli, Adriano Levi; Zamarioli, Ariane; Volpon, José Batista; Navarro, Anderson Marliere

2017-01-01

Diabetes Mellitus is a condition that predisposes a higher risk for the development of osteoporosis. The objective of this study was to investigate the influence of boron supplementation on bone microstructure and strength in control and non-obese diabetic mice for 30days. The animals were supplemented with 40μg/0,5ml of boron solution and controls received 0,5ml of distilled water daily. We evaluated the biochemical parameters: total calcium, phosphorus, magnesium and boron; bone analysis: bone computed microtomography, and biomechanical assay with a three point test on the femur. This study consisted of 28 animals divided into four groups: Group water control - Ctrl (n=10), Group boron control - Ctrl±B (n=8), Group diabetic water - Diab (n=5) and Group diabetic boron - Diab±B (n=5). The results showed that cortical bone volume and the trabecular bone volume fraction were higher for Diab±B and Ctrl±B compared to the Diab and Ctrl groups (p≤0,05). The trabecular specific bone surface was greater for the Diab±B group, and the trabecular thickness and structure model index had the worst values for the Diab group. The boron serum concentrations were higher for the Diab±B group compared to non-supplemented groups. The magnesium concentration was lower for Diab and Diab±B compared with controls. The biomechanical test on the femur revealed maintenance of parameters of the bone strength in animals Diab±B compared to the Diab group and controls. The results suggest that boron supplementation improves parameters related to bone strength and microstructure of cortical and trabecular bone in diabetic animals and the controls that were supplemented. Copyright © 2016 Elsevier GmbH. All rights reserved.

Bile acid signaling in lipid metabolism: Metabolomic and lipidomic analysis of lipid and bile acid markers linked to anti-obesity and anti-diabetes in mice

PubMed Central

Qi, Yunpeng; Jiang, Changtao; Cheng, Jie; Krausz, Kristopher W.; Li, Tiangang; Ferrell, Jessica M.; Gonzalez, Frank J.; Chiang, John Y.L.

2014-01-01

Bile acid synthesis is the major pathway for catabolism of cholesterol. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway in the liver and plays an important role in regulating lipid, glucose and energy metabolism. Transgenic mice overexpressing CYP7A1 (CYP7A1-tg mice) were resistant to high-fat diet (HFD)-induced obesity, fatty liver, and diabetes. However the mechanism of resistance to HFD-induced obesity of CYP7A1-tg mice has not been determined. In this study, metabolomic and lipidomic profiles of CYP7A1-tg mice were analyzed to explore the metabolic alterations in CYP7A1-tg mice that govern the protection against obesity and insulin resistance by using ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry combined with multivariate analyses. Lipidomics analysis identified seven lipid markers including lysophosphatidylcholines, phosphatidylcholines, sphingomyelins and ceramides that were significantly decreased in serum of HFD-fed CYP7A1-tg mice. Metabolomics analysis identified 13 metabolites in bile acid synthesis including taurochenodeoxycholic acid, taurodeoxycholic acid, tauroursodeoxycholic acid, taurocholic acid, and tauro-β-muricholic acid (T-β-MCA) that differed between CYP7A1-tg and wild-type mice. Notably, T-β-MCA, an antagonist of the farnesoid X receptor (FXR) was significantly increased in intestine of CYP7A1-tg mice. This study suggests that reducing 12α-hydroxylated bile acids and increasing intestinal T-β-MCA may reduce high fat diet-induced increase of phospholipids, sphingomyelins and ceramides, and ameliorate diabetes and obesity. PMID:24796972

FGF21 improves glucose homeostasis in an obese diabetes-prone mouse model independent of body fat changes.

PubMed

Laeger, Thomas; Baumeier, Christian; Wilhelmi, Ilka; Würfel, Josefine; Kamitz, Anne; Schürmann, Annette

2017-11-01

Fibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes. Male NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints. FGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression. FGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice.

Intermittent fasting preserves beta-cell mass in obesity-induced diabetes via the autophagy-lysosome pathway.

PubMed

Liu, Haiyan; Javaheri, Ali; Godar, Rebecca J; Murphy, John; Ma, Xiucui; Rohatgi, Nidhi; Mahadevan, Jana; Hyrc, Krzysztof; Saftig, Paul; Marshall, Connie; McDaniel, Michael L; Remedi, Maria S; Razani, Babak; Urano, Fumihiko; Diwan, Abhinav

2017-01-01

Obesity-induced diabetes is characterized by hyperglycemia, insulin resistance, and progressive beta cell failure. In islets of mice with obesity-induced diabetes, we observe increased beta cell death and impaired autophagic flux. We hypothesized that intermittent fasting, a clinically sustainable therapeutic strategy, stimulates autophagic flux to ameliorate obesity-induced diabetes. Our data show that despite continued high-fat intake, intermittent fasting restores autophagic flux in islets and improves glucose tolerance by enhancing glucose-stimulated insulin secretion, beta cell survival, and nuclear expression of NEUROG3, a marker of pancreatic regeneration. In contrast, intermittent fasting does not rescue beta-cell death or induce NEUROG3 expression in obese mice with lysosomal dysfunction secondary to deficiency of the lysosomal membrane protein, LAMP2 or haplo-insufficiency of BECN1/Beclin 1, a protein critical for autophagosome formation. Moreover, intermittent fasting is sufficient to provoke beta cell death in nonobese lamp2 null mice, attesting to a critical role for lysosome function in beta cell homeostasis under fasting conditions. Beta cells in intermittently-fasted LAMP2- or BECN1-deficient mice exhibit markers of autophagic failure with accumulation of damaged mitochondria and upregulation of oxidative stress. Thus, intermittent fasting preserves organelle quality via the autophagy-lysosome pathway to enhance beta cell survival and stimulates markers of regeneration in obesity-induced diabetes.

Marked augmentation of PLGA nanoparticle-induced metabolically beneficial impact of γ-oryzanol on fuel dyshomeostasis in genetically obese-diabetic ob/ob mice.

PubMed

Kozuka, Chisayo; Shimizu-Okabe, Chigusa; Takayama, Chitoshi; Nakano, Kaku; Morinaga, Hidetaka; Kinjo, Ayano; Fukuda, Kotaro; Kamei, Asuka; Yasuoka, Akihito; Kondo, Takashi; Abe, Keiko; Egashira, Kensuke; Masuzaki, Hiroaki

2017-11-01

Our previous works demonstrated that brown rice-specific bioactive substance, γ-oryzanol acts as a chaperone, attenuates exaggerated endoplasmic reticulum (ER) stress in brain hypothalamus and pancreatic islets, thereby ameliorating metabolic derangement in high fat diet (HFD)-induced obese diabetic mice. However, extremely low absorption efficiency from intestine of γ-oryzanol is a tough obstacle for the clinical application. Therefore, in this study, to overcome extremely low bioavailability of γ-oryzanol with super-high lipophilicity, we encapsulated γ-oryzanol in polymer poly (DL-lactide-co-glycolide) (PLGA) nanoparticles (Nano-Orz), and evaluated its metabolically beneficial impact in genetically obese-diabetic ob/ob mice, the best-known severest diabetic model in mice. To our surprise, Nano-Orz markedly ameliorated fuel metabolism with an unexpected magnitude (∼1000-fold lower dose) compared with regular γ-oryzanol. Furthermore, such a conspicuous impact was achievable by its administration once every 2 weeks. Besides the excellent impact on dysfunction of hypothalamus and pancreatic islets, Nano-Orz markedly decreased ER stress and inflammation in liver and adipose tissue. Collectively, nanotechnology-based developments of functional foods oriented toward γ-oryzanol shed light on the novel approach for the treatment of a variety of metabolic diseases in humans.

A study of hearing function and histopathologic changes in the cochlea of the type 2 diabetes model Tsumura Suzuki obese diabetes mouse.

PubMed

Tsuda, Junko; Sugahara, Kazuma; Hori, Takeshi; Kanagawa, Eiju; Takaki, Eiichi; Fujimoto, Mitsuaki; Nakai, Akira; Yamashita, Hiroshi

2016-11-01

This study used Tsumura Suzuki Obese Diabetes (TSOD) mice as a spontaneous type 2 diabetes model and Tsumura Suzuki Non-obesity (TSNO) mice as controls to investigate factors involved in the onset of hearing impairment. Body weight, blood glucose levels, and auditory brainstem responses (ABRs) were measured. The cochleae were excised and evaluated histopathologically. The TSOD mice showed significant hyperglycemia at 2-7 months and severe obesity at 5-10 months; significantly elevated ABR thresholds at 8-10 months; and the capillary lumens in the cochlea stria vascularis were narrower in the TSOD mice than in the TSNO mice. At 17 months, India ink vascular staining of the TSOD mice's cochleae revealed decreased capillary density in the stria vascularis. The vascular area of capillaries in the stria vascularis and the vascular area were significantly smaller in TSOD mice. Histopathological analysis showed vessel wall thickening in the modiolus and narrowed capillaries in the stria vascularis, suggesting reduced blood flow to the inner ear. The diabetes mice model used in our study showed early age-associated hearing loss, and histopathology showed findings of vessel wall thickening in the modiolus, narrowing of capillaries in the stria vascularis, and chronically reduced blood flow in the cochlea.

Protection from obesity and diabetes by blockade of TGF-β/Smad3 signaling

PubMed Central

Yadav, Hariom; Quijano, Celia; Kamaraju, Anil K.; Gavrilova, Oksana; Malek, Rana; Chen, Weiping; Zerfas, Patricia; Zhigang, Duan; Wright, Elizabeth C.; Stuelten, Christina; Sun, Peter; Lonning, Scott; Skarulis, Monica; Sumner, Anne E.; Finkel, Toren; Rane, Sushil G.

2011-01-01

SUMMARY Imbalances in glucose and energy homeostasis are at the core of the worldwide epidemic of obesity and diabetes. Here, we illustrate an important role of the TGF-β/Smad3 signaling pathway in regulating glucose and energy homeostasis. Smad3 deficient mice are protected from diet-induced obesity and diabetes. Interestingly, the metabolic protection is accompanied by Smad3−/− white adipose tissue acquiring the bioenergetic and gene expression profile of brown fat/skeletal muscle. Smad3−/− adipocytes demonstrate a marked increase in mitochondrial biogenesis, with a corresponding increase in basal respiration, and Smad3 acts as a repressor of PGC-1α expression. We observe significant correlation between TGF-β1 levels and adiposity in rodents and humans. Further, systemic blockade of TGF-β1 signaling protects mice from obesity, diabetes and hepatic steatosis. Together, these results demonstrate that TGF-β signaling regulates glucose tolerance and energy homeostasis and suggest that modulation of TGF-β1 activity might be an effective treatment strategy for obesity and diabetes. PMID:21723505

Effects of Melatonin, Aluminum Oxide, and Polymethylsiloxane Complex on the Expression of LYVE-1 in the Liver of Mice with Obesity and Type 2 Diabetes Mellitus.

PubMed

Michurina, S V; Ishchenko, I Yu; Arkhipov, S A; Klimontov, V V; Rachkovskaya, L N; Konenkov, V I; Zavyalov, E L

2016-12-01

The effects of melatonin, aluminum oxide, and polymethylsiloxane complex on the expression of LYVE-1 (lymphatic vessel endothelial hyaluronan receptor) in the liver were studied in db/db mice with experimental obesity and type 2 diabetes mellitus. The complex or placebo was administered daily by gavage from week 8 to week 16 of life. The animals receiving the complex exhibited enhanced, in comparison with the placebo group, immunohistochemical LYVE-1+ staining of endothelial cells in sinusoids. Enhanced expression of LYVE-1 was associated with less pronounced dilatation of interlobular arteries, veins, and lymphatic vessels. Thee findings suggest a protective effect of the complex towards structural changes in the liver of mice with obesity and type 2 diabetes.

Chronic ethanol consumption lessens the gain of body weight, liver triglycerides, and diabetes in obese ob/ob mice.

PubMed

Fromenty, Bernard; Vadrot, Nathalie; Massart, Julie; Turlin, Bruno; Barri-Ova, Nadège; Lettéron, Philippe; Fautrel, Alain; Robin, Marie-Anne

2009-10-01

Clinical studies suggest that moderate alcohol consumption can have beneficial effects, in particular regarding cardiovascular events, insulin resistance, and type 2 diabetes. In this study, lean and obese diabetic ob/ob mice were submitted or not to chronic ethanol intake via the drinking water for 6 months, which was associated with moderate levels of plasma ethanol. Plasma levels of alanine aminotransferase and aspartate aminotransferase were not increased by alcohol intake. Ethanol consumption progressively reduced the gain of body weight in ob/ob mice, but not in lean mice, and this was observed despite higher calorie intake. Increased plasma free fatty acids and glycerol in ethanol-treated ob/ob mice suggested peripheral lipolysis. Glycemia and insulinemia were significantly reduced, whereas adiponectinemia was increased in ethanol-treated ob/ob mice. Liver weight and triglycerides were significantly decreased in ethanol-treated ob/ob mice, and this was associated with less microvesicular steatosis. Hepatic levels of AMP-activated protein kinase and the phosphorylated form of acetyl-CoA carboxylase were higher in ethanol-treated ob/ob mice, suggesting better fatty acid oxidation. However, hepatic mRNA expression of several lipogenic genes was not reduced by ethanol consumption. Finally, mild oxidative stress was noticed in the liver of ethanol-treated mice, regardless of their genotype. Hence, our data are in keeping with clinical studies suggesting that moderate ethanol intake can have beneficial effects on type 2 diabetes and insulin sensitivity, at least in part through increased levels of plasma adiponectin. However, further studies are needed to determine whether long-term drinking of light-to-moderate amounts of ethanol is safe for the liver.

Exaggerated Increases in Microglia Proliferation, Brain Inflammatory Response and Sickness Behaviour upon Lipopolysaccharide Stimulation in Non-Obese Diabetic Mice.

PubMed

McGuiness, Barry; Gibney, Sinead M; Beumer, Wouter; Versnel, Marjan A; Sillaber, Inge; Harkin, Andrew; Drexhage, Hemmo A

2016-01-01

The non-obese diabetic (NOD) mouse, an established model for autoimmune diabetes, shows an exaggerated reaction of pancreas macrophages to inflammatory stimuli. NOD mice also display anxiety when immune-stimulated. Chronic mild brain inflammation and a pro-inflammatory microglial activation is critical in psychiatric behaviour. To explore brain/microglial activation and behaviour in NOD mice at steady state and after systemic lipopolysaccharide (LPS) injection. Affymetrix analysis on purified microglia of pre-diabetic NOD mice (8-10 weeks) and control mice (C57BL/6 and CD1 mice, the parental non-autoimmune strain) at steady state and after systemic LPS (100 μg/kg) administration. Quantitative PCR was performed on the hypothalamus for immune activation markers (IL-1β, IFNγ and TNFα) and growth factors (BDNF and PDGF). Behavioural profiling of NOD, CD1, BALB/c and C57BL/6 mice at steady state was conducted and sickness behaviour/anxiety in NOD and CD1 mice was monitored before and after LPS injection. Genome analysis revealed cell cycle/cell death and survival aberrancies of NOD microglia, substantiated as higher proliferation on BrdU staining. Inflammation signs were absent. NOD mice had a hyper-reactive response to novel environments with some signs of anxiety. LPS injection induced a higher expression of microglial activation markers, a higher brain pro-inflammatory set point (IFNγ, IDO) and a reduced expression of BDNF and PDGF after immune stimulation in NOD mice. NOD mice displayed exaggerated and prolonged sickness behaviour after LPS administration. After stimulation with LPS, NOD mice display an increased microglial proliferation and an exaggerated inflammatory brain response with reduced BDNF and PDGF expression and increased sickness behaviour as compared to controls. © 2016 S. Karger AG, Basel.

Elevated Steroid Hormone Production in the db/db Mouse Model of Obesity and Type 2 Diabetes.

PubMed

Hofmann, Anja; Peitzsch, Mirko; Brunssen, Coy; Mittag, Jennifer; Jannasch, Annett; Frenzel, Annika; Brown, Nicholas; Weldon, Steven M; Eisenhofer, Graeme; Bornstein, Stefan R; Morawietz, Henning

2017-01-01

Obesity and type 2 diabetes have become a major public health problem worldwide. Steroid hormone dysfunction appears to be linked to development of obesity and type 2 diabetes and correction of steroid abnormalities may offer new approaches to therapy. We therefore analyzed plasma steroids in 15-16 week old obese and diabetic db/db mice using liquid chromatography-tandem mass spectrometry. Lean db/+ served as controls. Db/db mice developed obesity, hyperglycemia, hyperleptinemia, and hyperlipidemia. Hepatic triglyceride storage was increased and adiponectin and pancreatic insulin were lowered. Aldosterone, corticosterone, 11-deoxycorticosterone, and progesterone were respectively increased by 3.6-, 2.9-, 3.4, and 1.7-fold in db/db mice compared to controls. Ratios of aldosterone-to-progesterone and corticosterone-to-progesterone were respectively 2.0- and 1.5-fold higher in db/db mice. Genes associated with steroidogenesis were quantified in the adrenal glands and gonadal adipose tissues. In adrenals, Cyp11b2 , Cyp11b1 , Cyp21a1 , Hsd3b1 , Cyp11a1 , and StAR were all significantly increased in db/db mice compared with db/+ controls. In adipose tissue, no Cyp11b2 or Cyp11b1 transcripts were detected and no differences in Cyp21a1 , Hsd3b1 , Cyp11a1 , or StAR expression were found between db/+ and db/db mice. In conclusion, the present study showed an elevated steroid hormone production and adrenal steroidogenesis in the db/db model of obesity and type 2 diabetes. © Georg Thieme Verlag KG Stuttgart · New York.

Endogenous ω-3 Polyunsaturated Fatty Acid Production Confers Resistance to Obesity, Dyslipidemia, and Diabetes in Mice

PubMed Central

Li, Jie; Li, Fanghong R.; Wei, Dong; Jia, Wei; Kang, Jing X.; Stefanovic-Racic, Maja

2014-01-01

Despite the well-documented health benefits of ω-3 polyunsaturated fatty acids (PUFAs), their use in clinical management of hyperglycemia and obesity has shown little success. To better define the mechanisms of ω-3 PUFAs in regulating energy balance and insulin sensitivity, we deployed a transgenic mouse model capable of endogenously producing ω-3 PUFAs while reducing ω-6 PUFAs owing to the expression of a Caenorhabditis elegans fat-1 gene encoding an ω-3 fatty acid desaturase. When challenged with high-fat diets, fat-1 mice strongly resisted obesity, diabetes, hypercholesterolemia, and hepatic steatosis. Endogenous elevation of ω-3 PUFAs and reduction of ω-6 PUFAs did not alter the amount of food intake but led to increased energy expenditure in the fat-1 mice. The requirements for the levels of ω-3 PUFAs as well as the ω-6/ω-3 ratios in controlling blood glucose and obesity are much more stringent than those in lipid metabolism. These metabolic phenotypes were accompanied by attenuation of the inflammatory state because tissue levels of prostaglandin E2, leukotriene B4, monocyte chemoattractant protein-1, and TNF-α were significantly decreased. TNF-α–induced nuclear factor-κB signaling was almost completely abolished. Consistent with the reduction in chronic inflammation and a significant increase in peroxisome proliferator–activated receptor-γ activity in the fat-1 liver tissue, hepatic insulin signaling was sharply elevated. The activities of prolipogenic regulators, such as liver X receptor, stearoyl-CoA desaturase-1, and sterol regulatory element binding protein-1 were sharply decreased, whereas the activity of peroxisome proliferator–activated receptor-α, a nuclear receptor that facilitates lipid β-oxidation, was markedly increased. Thus, endogenous conversion of ω-6 to ω-3 PUFAs via fat-1 strongly protects against obesity, diabetes, inflammation, and dyslipidemia and may represent a novel therapeutic modality to treat these prevalent

Prunus mume leaf extract lowers blood glucose level in diabetic mice.

PubMed

Lee, Min Woo; Kwon, Jung Eun; Lee, Young-Jong; Jeong, Yong Joon; Kim, Inhye; Cho, Young Mi; Kim, Yong-Min; Kang, Se Chan

2016-10-01

Context Diabetes is a common metabolic disease with long-term complications. Prunus mume Sieb. et Zucc. (Rosaceae) fruits have shown to ameliorate glucose intolerance. However, the antidiabetic effects of P. mume leaves have not been investigated. Objective This study evaluated the effects of P. mume leaf 70% ethanol extract (PMLE) on alleviating diabetes in vivo and in vitro. Materials and methods PMLE was fractionated into n-hexane, dichloromethane (CH2Cl2), ethyl acetate (EtOAc), n-butanol (BuOH) and water. Polyphenol and flavonoid contents in PMLE fractions were determined using Folin-Ciocalteu reagent and the aluminium chloride colorimetric method, respectively. We evaluated α-glucosidase inhibition using a microplate reader at 400 nm. Adipocyte differentiation by lipid accumulation was measured using Nile Red staining. Male imprinting control region (ICR) mice were injected with streptozotocin (STZ, 100 mg/kg, i.p.). High-fat diets were provided for three weeks prior to PMLE treatments to induce type 2 diabetes. PMLE (0, 5, 25 or 50 mg/kg) was administrated for four weeks with high-fat diets. Results The EtOAc fraction of PMLE inhibited α-glucosidase activity (IC50 = 68.2 μg/mL) and contained 883.5 ± 14.9 mg/g of polyphenols and 820.1 ± 7.7 mg/g of flavonoids. The 50 mg/kg PMLE supplement reduced 40% of blood glucose level compared to obese/diabetes mice. Obese/diabetic mice treated with 50 mg/kg PMLE showed a lower level of triacylglycerol (320.7 ± 20.73 mg/dL) compared to obese/diabetes mice (494.9 ± 14.80 mg/dL). Conclusion The data demonstrate that P. mume leaves exert antidiabetic effects that may be attributable to high concentrations of polyphenols and flavonoids.

Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice.

PubMed

Peris-Sampedro, Fiona; Cabré, Maria; Basaure, Pia; Reverte, Ingrid; Domingo, José L; Teresa Colomina, Maria

2015-10-01

Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Our recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Thus, we aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. We examined body weight status, food and water intake, lipid and glucose homeostasis, metabolic biomarkers concentrations, insulin levels and insulin resistance, and leptin and ghrelin profiles. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health. Copyright © 2015 Elsevier Inc. All rights reserved.

Saccharomyces boulardii Administration Changes Gut Microbiota and Reduces Hepatic Steatosis, Low-Grade Inflammation, and Fat Mass in Obese and Type 2 Diabetic db/db Mice

PubMed Central

Everard, Amandine; Matamoros, Sébastien; Geurts, Lucie; Delzenne, Nathalie M.

2014-01-01

ABSTRACT Growing evidence shows that gut microbes are key factors involved in the regulation of energy homeostasis, metabolic inflammation, lipid metabolism, and glucose metabolism. Therefore, gut microbiota modulations caused by selectively fermented oligosaccharides or probiotic bacteria constitute an interesting target in the physiopathology of obesity. However, to date, no probiotic yeast has been investigated in this context. Therefore, our study aimed to evaluate the impact of the most-studied probiotic yeast (i.e., Saccharomyces boulardii Biocodex) on obesity and associated metabolic features, such as fat mass development, hepatic steatosis, and low-grade inflammation, in obese mice. S. boulardii was administered daily by oral gavage to leptin-resistant obese and type 2 diabetic mice (db/db) for 4 weeks. We found that S. boulardii-treated mice exhibited reduced body weight, fat mass, hepatic steatosis, and inflammatory tone. Interestingly, these effects of S. boulardii on host metabolism were associated with local effects in the intestine. S. boulardii increased cecum weight and cecum tissue weight but also induced dramatic changes in the gut microbial composition at the phylum, family, and genus levels. These gut microbiota changes in response to S. boulardii may also be correlated with the host metabolism response. In conclusion, this study demonstrates for the first time that S. boulardii may act as a beneficial probiotic treatment in the context of obesity and type 2 diabetes. PMID:24917595

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

PubMed Central

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

2016-01-01

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

The selective peroxisome proliferator–activated receptor‐delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice

PubMed Central

Haczeyni, Fahrettin; Wang, Hans; Barn, Vanessa; Mridha, Auvro R.; Yeh, Matthew M.; Haigh, W. Geoffrey; Ioannou, George N.; Choi, Yun‐Jung; McWherter, Charles A.; Teoh, Narcissus C.‐H.

2017-01-01

Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator–activated receptor‐alpha/delta (PPAR‐α/δ) agonists show some efficacy. Seladelpar (MBX‐8025), a selective PPAR‐δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR‐δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild‐type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8‐12) were then randomized to receive MBX‐8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX‐8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300‐600 U/L in vehicle‐treated foz/foz mice; MBX‐8025 reduced alanine aminotransferase by 50%. In addition, MBX‐8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle‐treated foz/foz versus wild‐type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle‐treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX‐8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet–fed obese diabetic mice. Selective PPAR‐δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017

Extracts of black and brown rice powders improve hepatic lipid accumulation via the activation of PPARα in obese and diabetic model mice.

PubMed

Felix, Angelina Dr; Takahashi, Nobuyuki; Takahashi, Mami; Katsumata-Tsuboi, Rie; Satoh, Ryo; Soon Hui, Teoh; Miyajima, Katsuhiro; Nakae, Dai; Inoue, Hirofumi; Uehara, Mariko

2017-11-01

Rice powder extract (RPE) from black and brown rice (Oryza sativa L. indica) improves hepatic lipid accumulation in obese and diabetic model mice via peroxisomal fatty acid oxidation. RPE showed PPARα agonistic activity which did not differ between black and brown RPE despite a higher anthocyanin content in black RPE.

Folic acid consumption reduces resistin level and restores blunted acetylcholine-induced aortic relaxation in obese/diabetic mice.

PubMed

Seto, Sai Wang; Lam, Tsz Yan; Or, Penelope Mei Yu; Lee, Wayne Yuk Wai; Au, Alice Lai Shan; Poon, Christina Chui Wa; Li, Rachel Wai Sum; Chan, Shun Wan; Yeung, John Hok Keung; Leung, George Pak Heng; Lee, Simon Ming Yuen; Ngai, Sai Ming; Kwan, Yiu Wa

2010-09-01

Folic acid supplementation provides beneficial effects on endothelial functions in patients with hyperhomocysteinemia. However, its effects on vascular functions under diabetic conditions are largely unknown. Therefore, the effect(s) of folic acid (5.7 and 71 microg/kg/day for 4 weeks) on aortic relaxation was investigated using obese/diabetic (+db/+db) mice and lean littermate (+db/+m) mice. Acetylcholine-induced relaxation in +db/+db mice was less than that observed in +db/+m mice. The reduced relaxation in +db/+db mice was restored by consumption of 71 microg/kg folic acid. Acetylcholine-induced relaxation (with and without folic acid treatment) was sensitive to N(G)-nitro-L-arginine methyl ester, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one, geldanamycin and triciribine. In addition, acetylcholine-induced relaxation was attenuated by resistin. The plasma level of resistin in +db/+db mice was sevenfold higher than that measured in +db/+m mice, and the elevated plasma level of resistin in +db/+db mice was reduced by 25% after treatment with 71 microg/kg folic acid. Folic acid slightly increased the ratio of reduced glutathione to oxidized glutathione in +db/+db mice. Moreover, folic acid caused a reduction in PTEN (phosphatase and tensin homolog deleted on chromosome 10) expression, an increase in the phosphorylation of endothelial nitric oxide synthase (eNOS(Ser1177)) and Akt(Ser473), and an enhanced interaction of heat shock protein 90 (HSP90) with eNOS in both strains, with greater magnitude observed in +db/+db mice. In conclusion, folic acid consumption improved blunted acetylcholine-induced relaxation in +db/+db mice. The mechanism may be, at least partly, attributed to enhancement of PI3K/HSP90/eNOS/Akt cascade, reduction in plasma resistin level, down-regulation of PTEN and slight modification of oxidative state. Copyright 2010 Elsevier Inc. All rights reserved.

Dietary supplementation with branched-chain amino acids suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-db/db mice.

PubMed

Iwasa, Junpei; Shimizu, Masahito; Shiraki, Makoto; Shirakami, Yohei; Sakai, Hiroyasu; Terakura, Yoichi; Takai, Koji; Tsurumi, Hisashi; Tanaka, Takuji; Moriwaki, Hisataka

2010-02-01

Obesity and related metabolic abnormalities, including insulin resistance, are risk factors for hepatocellular carcinoma in non-alcoholic steatohepatitis as well as in chronic viral hepatitis. Branched-chain amino acids (BCAA), which improve insulin resistance, inhibited obesity-related colon carcinogenesis in a rodent model, and also reduced the incidence of hepatocellular carcinoma in obese patients with liver cirrhosis. In the present study, we determined the effects of BCAA on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in obese C57BL/KsJ-db/db (db/db) mice with diabetes mellitus. Male db/db mice were given tap water containing 40 ppm DEN for an initial 2 weeks and thereafter they received a basal diet containing 3.0% of BCAA or casein, which served as a nitrogen content-matched control of BCAA, throughout the experiment. Supplementation with BCAA significantly reduced the total number of foci of cellular alteration, a premalignant lesion of the liver, and the expression of insulin-like growth factor (IGF)-1, IGF-2, and IGF-1 receptor in the liver when compared to the casein supplementation. BCAA supplementation for 34 weeks also significantly inhibited both the development of hepatocellular neoplasms and the proliferation of hepatocytes in comparison to the basal diet or casein-fed groups. Supplementation with BCAA improved liver steatosis and fibrosis and inhibited the expression of alpha-smooth muscle actin in the DEN-treated db/db mice. The serum levels of glucose and leptin decreased by dietary BCAA, whereas the value of the quantitative insulin sensitivity check index increased by this agent, indicating the improvement of insulin resistance and hyperleptinemia. In conclusion, oral BCAA supplementation improves insulin resistance and prevents the development of liver tumorigenesis in obese and diabetic mice.

Ipragliflozin Improves Hepatic Steatosis in Obese Mice and Liver Dysfunction in Type 2 Diabetic Patients Irrespective of Body Weight Reduction.

PubMed

Komiya, Chikara; Tsuchiya, Kyoichiro; Shiba, Kumiko; Miyachi, Yasutaka; Furuke, Shunsaku; Shimazu, Noriko; Yamaguchi, Shinobu; Kanno, Kazuo; Ogawa, Yoshihiro

2016-01-01

Type 2 diabetes mellitus (T2DM) is associated with a high incidence of non-alcoholic fatty liver disease (NAFLD) related to obesity and insulin resistance. Currently, medical interventions for NAFLD have focused on diet control and exercise to reduce body weight, and there is a requirement for effective pharmacological therapies. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are oral antidiabetic drugs that promote the urinary excretion of glucose by blocking its reabsorption in renal proximal tubules. SGLT2 inhibitors lower blood glucose independent of insulin action and are expected to reduce body weight because of urinary calorie loss. Here we show that an SGLT2 inhibitor ipragliflozin improves hepatic steatosis in high-fat diet-induced and leptin-deficient (ob/ob) obese mice irrespective of body weight reduction. In the obese mice, ipragliflozin-induced hyperphagia occurred to increase energy intake, attenuating body weight reduction with increased epididymal fat mass. There is an inverse correlation between weights of liver and epididymal fat in ipragliflozin-treated obese mice, suggesting that ipragliflozin treatment promotes normotopic fat accumulation in the epididymal fat and prevents ectopic fat accumulation in the liver. Despite increased adiposity, ipragliflozin ameliorates obesity-associated inflammation and insulin resistance in epididymal fat. Clinically, ipragliflozin improves liver dysfunction in patients with T2DM irrespective of body weight reduction. These findings provide new insight into the effects of SGLT2 inhibitors on energy homeostasis and fat accumulation and indicate their potential therapeutic efficacy in T2DM-associated hepatic steatosis.

Molecular exploration of fecal microbiome in quinoa-supplemented obese mice.

PubMed

Garcia-Mazcorro, Jose F; Mills, David; Noratto, Giuliana

2016-07-01

Diet affects gut microorganisms and dietary interventions can help treat obesity and overweight. Our aim was to investigate the effect of quinoa supplementation on fecal microbial ecology of obese diabetic mice. Obese db/db mice were fed commercial diets with and without quinoa supplementation for eight weeks; non-obese mice consuming non-supplemented diet served as lean-control. Fecal bacterial communities were analyzed using marker gene sequencing of 16S rRNA genes. Over 300 000 good-quality sequences were studied and assigned to 5774 different bacterial species (Operational Taxonomic Units at 97% similarity). Significant differences in bacterial abundances were found among the treatment groups, including some associated specifically with quinoa consumption. Analysis of weighted UniFrac distances revealed a distinctive clustering of lean microbial communities independently from obese-control and quinoa-supplemented mice (Analysis of Similarities, P < 0.01). Predicted functional profiles showed significant differences in 38 metabolic functions but most were due to a difference between lean samples compared to both obese-control and quinoa. Quinoa supplementation was associated with lower butyrate and succinic acid concentrations in cecum that were not necessarily more similar to those concentrations in lean mice. This study provides insight into the complex interactions between nutritional supplements and the gut microbiota thus informing future molecular analysis of the health benefits. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Prolonged antibiotic treatment induces a diabetogenic intestinal microbiome that accelerates diabetes in NOD mice.

PubMed

Brown, Kirsty; Godovannyi, Artem; Ma, Caixia; Zhang, YiQun; Ahmadi-Vand, Zahra; Dai, Chaunbin; Gorzelak, Monika A; Chan, YeeKwan; Chan, Justin M; Lochner, Arion; Dutz, Jan P; Vallance, Bruce A; Gibson, Deanna L

2016-02-01

Accumulating evidence supports that the intestinal microbiome is involved in Type 1 diabetes (T1D) pathogenesis through the gut-pancreas nexus. Our aim was to determine whether the intestinal microbiota in the non-obese diabetic (NOD) mouse model played a role in T1D through the gut. To examine the effect of the intestinal microbiota on T1D onset, we manipulated gut microbes by: (1) the fecal transplantation between non-obese diabetic (NOD) and resistant (NOR) mice and (2) the oral antibiotic and probiotic treatment of NOD mice. We monitored diabetes onset, quantified CD4+T cells in the Peyer's patches, profiled the microbiome and measured fecal short-chain fatty acids (SCFA). The gut microbiota from NOD mice harbored more pathobionts and fewer beneficial microbes in comparison with NOR mice. Fecal transplantation of NOD microbes induced insulitis in NOR hosts suggesting that the NOD microbiome is diabetogenic. Moreover, antibiotic exposure accelerated diabetes onset in NOD mice accompanied by increased T-helper type 1 (Th1) and reduced Th17 cells in the intestinal lymphoid tissues. The diabetogenic microbiome was characterized by a metagenome altered in several metabolic gene clusters. Furthermore, diabetes susceptibility correlated with reduced fecal SCFAs. In an attempt to correct the diabetogenic microbiome, we administered VLS#3 probiotics to NOD mice but found that VSL#3 colonized the intestine poorly and did not delay diabetes. We conclude that NOD mice harbor gut microbes that induce diabetes and that their diabetogenic microbiome can be amplified early in life through antibiotic exposure. Protective microbes like VSL#3 are insufficient to overcome the effects of a diabetogenic microbiome.

Regulation of contact sensitivity in non-obese diabetic (NOD) mice by innate immunity.

PubMed

Szczepanik, Marian; Majewska-Szczepanik, Monika; Wong, Florence S; Kowalczyk, Paulina; Pasare, Chandrashekhar; Wen, Li

2018-06-25

Genetic background influences allergic immune responses to environmental stimuli. Non-obese diabetic (NOD) mice are highly susceptible to environmental stimuli. Little is known about the interaction of autoimmune genetic factors with innate immunity in allergies, especially skin hypersensitivity. To study the interplay of innate immunity and autoimmune genetic factors in contact hypersensitivity (CHS) by using various innate immunity-deficient NOD mice. Toll-like receptor (TLR) 2-deficient, TLR9-deficient and MyD88-deficient NOD mice were used to investigate CHS. The cellular mechanism was determined by flow cytometry in vitro and adoptive cell transfer in vivo. To investigate the role of MyD88 in dendritic cells (DCs) in CHS, we also used CD11c MyD88+  MyD88 -/- NOD mice, in which MyD88 is expressed only in CD11c + cells. We found that innate immunity negatively regulates CHS, as innate immunity-deficient NOD mice developed exacerbated CHS accompanied by increased numbers of skin-migrating CD11c + DCs expressing higher levels of major histocompatibility complex II and CD80. Moreover, MyD88 -/- NOD mice had increased numbers of CD11c +  CD207 -  CD103 + DCs and activated T effector cells in the skin-draining lymph nodes. Strikingly, re-expression of MyD88 in CD11c + DCs (CD11c MyD88+  MyD88 -/- NOD mice) restored hyper-CHS to a normal level in MyD88 -/- NOD mice. Our results suggest that the autoimmune-prone NOD genetic background aggravates CHS regulated by innate immunity, through DCs and T effector cells. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

PubMed

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

2016-04-01

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

Dietary Tuna Dark Muscle Protein Attenuates Hepatic Steatosis and Increases Serum High-Density Lipoprotein Cholesterol in Obese Type-2 Diabetic/Obese KK-Ay Mice.

PubMed

Maeda, Hayato; Hosomi, Ryota; Fukuda, Mari; Ikeda, Yuki; Yoshida, Munehiro; Fukunaga, Kenji

2017-05-01

Tuna muscle consists of light and dark muscle in approximately equal proportions. However, besides for the light muscle of tuna, cod, sardine, and salmon, few researches have assessed the health-promoting functions of fish protein. Therefore, we evaluated the mechanisms underlying the alteration of lipid storage and cholesterol metabolism following the intake of tuna dark muscle protein (TDMP) by obese type-2 diabetic/obese mice. Four-week-old male KK-A y mice were separated into 2 dietary groups, with one group receiving a casein-based diet and the other receiving a diet with the substitution of part of the protein (50%, w/w) by TDMP (TDMP diet) for 4 wk. The TDMP diet significantly increased the content of serum high-density lipoprotein cholesterol, partly due to the reduction of the expression of scavenger receptor class B member 1 in epididymal white adipose tissue. In addition, dietary TDMP decreased the content of hepatic triacylglycerol, which could be due to the enhancement of carnitine palmitoyltransferase-2 activity through the activation of the expression of the peroxisome proliferative activated receptor-α in the liver. These results suggest that TDMP could have the potential to prevent the development of obesity-related diseases by suppressing the storage of hepatic triacylglycerol and cholesterol. © 2017 Institute of Food Technologists®.

Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.

PubMed

Park, Sung Bum; Jung, Won Hoon; Kang, Nam Sook; Park, Ji Seon; Bae, Gyu Hwan; Kim, Hee Youn; Rhee, Sang Dal; Kang, Seung Kyu; Ahn, Jin Hee; Jeong, Hye Gwang; Kim, Ki Young

2013-12-05

It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity. © 2013 Elsevier B.V. All rights reserved.

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

PubMed

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

2000-10-01

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

Lamp-2 deficiency prevents high-fat diet-induced obese diabetes via enhancing energy expenditure

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

Yasuda-Yamahara, Mako; Kume, Shinji, E-mail: skume@belle.shiga-med.ac.jp; Yamahara, Kosuke

Autophagy process is essential for maintaining intracellular homeostasis and consists of autophagosome formation and subsequent fusion with lysosome for degradation. Although the role of autophagosome formation in the pathogenesis of diabetes has been recently documented, the role of the latter process remains unclear. This study analyzed high-fat diet (HFD)-fed mice lacking lysosome-associated membrane protein-2 (lamp-2), which is essential for the fusion with lysosome and subsequent degradation of autophagosomes. Although lamp-2 deficient mice showed little alteration in glucose metabolism under normal diet feeding, they showed a resistance against high-fat diet (HFD)-induced obesity, hyperinsulinemic hyperglycemia and tissues lipid accumulation, accompanied with highermore » energy expenditure. The expression levels of thermogenic genes in brown adipose tissue were significantly increased in HFD-fed lamp-2-deficient mice. Of some serum factors related to energy expenditure, the serum level of fibroblast growth factor (FGF) 21 and its mRNA expression level in the liver were significantly higher in HFD-fed lamp-2-deficient mice in an ER stress-, but not PPARα-, dependent manner. In conclusion, a lamp-2-depenedent fusion and degradation process of autophagosomes is involved in the pathogenesis of obese diabetes, providing a novel insight into autophagy and diabetes. - Highlights: • Lamp-2 is essential for autophagosome fusion with lysosome and its degradation. • Lamp-2 deficiency lead to a resistance to diet-induced obese diabetes in mice. • Lamp-2 deficiency increased whole body energy expenditure under HFD-feeding. • Lamp-2 deficiency elevated the serum level of FGF21 under HFD-feeding.« less

Acylcarnitine Profiles in Plasma and Tissues of Hyperglycemic NZO Mice Correlate with Metabolite Changes of Human Diabetes

PubMed Central

Daniel, Hannelore

2018-01-01

The New Zealand obese (NZO) mouse is a polygenic model for obesity and diabetes with obese females and obese, diabetes-prone males, used to study traits of the metabolic syndrome like type 2 diabetes mellitus (T2DM), obesity, and dyslipidaemia. By using LC-MS/MS, we here examine the suitability of this model to mirror tissue-specific changes in acylcarnitine (AC) and amino acid (AA) species preceding T2DM which may reflect patterns investigated in human metabolism. We observed high concentrations of fatty acid-derived ACs in 11 female mice, high abundance of branched-chain amino acid- (BCAA-) derived ACs in 6 male mice, and slight increases in BCAA-derived ACs in the remaining 6 males. Principal component analysis (PCA) including all ACs and AAs confirmed our hypothesis especially in plasma samples by clustering females, males with high BCAA-derived ACs, and males with slight increases in BCAA-derived ACs. Concentrations of insulin, blood glucose, NEFAs, and triacylglycerols (TAGs) further supported the hypothesis of high BCAA-derived ACs being able to mirror the onset of diabetic traits in male individuals. In conclusion, alterations in AC and AA profiles overlap with observations from human studies indicating the suitability of NZO mice to study metabolic changes preceding human T2DM. PMID:29854816

Activation of peroxisome proliferator-activated receptor-α (PPARα) in proximal intestine improves postprandial lipidemia in obese diabetic KK-Ay mice.

PubMed

Kimura, Rino; Takahashi, Nobuyuki; Goto, Tsuyoshi; Murota, Kaeko; Kawada, Teruo

2013-01-01

Postprandial lipidemia is a risk factor for cardiovascular diseases. Thus, the suppression of postprandial lipidemia is valuable for disease management. Peroxisome proliferator-activated receptor- (PPAR ) is a key regulator in the lipid metabolism of peripheral tissues such as the liver and skeletal muscle, whose activation enhances fatty acid oxidation and decreases circulating lipid level. Recently, we have shown that bezafibrate, an agonistic compound for PPAR , suppresses post-prandial lipidemia by enhancing fatty acid oxidation in intestinal epithelial cells under physiological conditions. However, it was not elucidated whether the effect of PPAR on postprandial lipidemia is also observed under obese conditions, which change lipid metabolisms in various tissues and cells. Here, we observed that bezafibrate enhanced fatty acid oxidation in intestinal epithelial cells of obese diabetic KK-Ay mice. Bezafibrate treatment increased the mRNA expression levels of fatty acid oxidation-related genes, which are targets of PPAR , and enhanced CO2 production from [14C]-palmitic acid. The bezafibrate-treated mice showed the suppression of increasing serum triacylglyceride level after the oral administration of olive oil. Moreover, the effects of bezafibrate on mRNA expression and fatty acid oxidation were shown in only the proximal intestinal epithelial cells. These findings indicate that PPAR activation suppresses postprandial lipidemia under obese conditions through the enhancement of fatty acid oxidation, and that only the proximal intestine con-tributes to the effects in mice, suggesting that intestinal PPAR can be a target for prevention of obese-induced postprandial lipidemia. © 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice.

PubMed

Stewart, Taryn P; Kim, Hyoung Yon; Saxton, Arnold M; Kim, Jung Han

2010-12-19

Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains Apoa2 gene. Sequencing analysis revealed polymorphisms of Apoa2 in TH mice, suggesting Apoa2 as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs. We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6 intercross. Polymorphisms in Apoa

Genetic and genomic analysis of hyperlipidemia, obesity and diabetes using (C57BL/6J × TALLYHO/JngJ) F2 mice

PubMed Central

2010-01-01

Background Type 2 diabetes (T2D) is the most common form of diabetes in humans and is closely associated with dyslipidemia and obesity that magnifies the mortality and morbidity related to T2D. The genetic contribution to human T2D and related metabolic disorders is evident, and mostly follows polygenic inheritance. The TALLYHO/JngJ (TH) mice are a polygenic model for T2D characterized by obesity, hyperinsulinemia, impaired glucose uptake and tolerance, hyperlipidemia, and hyperglycemia. Results In order to determine the genetic factors that contribute to these T2D related characteristics in TH mice, we interbred TH mice with C57BL/6J (B6) mice. The parental, F1, and F2 mice were phenotyped at 8, 12, 16, 20, and 24 weeks of age for 4-hour fasting plasma triglyceride, cholesterol, insulin, and glucose levels and body, fat pad and carcass weights. The F2 mice were genotyped genome-wide and used for quantitative trait locus (QTL) mapping. We also applied a genetical genomic approach using a subset of the F2 mice to seek candidate genes underlying the QTLs. Major QTLs were detected on chromosomes (Chrs) 1, 11, 4, and 8 for hypertriglyceridemia, 1 and 3 for hypercholesterolemia, 4 for hyperglycemia, 11 and 1 for body weight, 1 for fat pad weight, and 11 and 14 for carcass weight. Most alleles, except for Chr 3 and 14 QTLs, increased phenotypic values when contributed by the TH strain. Fourteen pairs of interacting loci were detected, none of which overlapped the major QTLs. The QTL interval linked to hypercholesterolemia and hypertriglyceridemia on distal Chr 1 contains Apoa2 gene. Sequencing analysis revealed polymorphisms of Apoa2 in TH mice, suggesting Apoa2 as the candidate gene for the hyperlipidemia QTL. Gene expression analysis added novel information and aided in selection of candidates underlying the QTLs. Conclusions We identified several genetic loci that affect the quantitative variations of plasma lipid and glucose levels and obesity traits in a TH × B6

Obesity/Type II diabetes alters macrophage polarization resulting in a fibrotic tendon healing response

PubMed Central

Ackerman, Jessica E.; Geary, Michael B.; Orner, Caitlin A.; Bawany, Fatima

2017-01-01

Type II Diabetes (T2DM) dramatically impairs the tendon healing response, resulting in decreased collagen organization and mechanics relative to non-diabetic tendons. Despite this burden, there remains a paucity of information regarding the mechanisms that govern impaired healing of diabetic tendons. Mice were placed on either a high fat diet (T2DM) or low fat diet (lean) and underwent flexor tendon transection and repair surgery. Healing was assessed via mechanical testing, histology and changes in gene expression associated with collagen synthesis, matrix remodeling, and macrophage polarization. Obese/diabetic tendons healed with increased scar formation and impaired mechanical properties. Consistent with this, prolonged and excess expression of extracellular matrix (ECM) components were observed in obese/T2DM tendons. Macrophages are involved in both inflammatory and matrix deposition processes during healing. Obese/T2DM tendons healed with increased expression of markers of pro-inflammatory M1 macrophages, and elevated and prolonged expression of M2 macrophages markers that are involved in ECM deposition. Here we demonstrate that tendons from obese/diabetic mice heal with increased scar formation and increased M2 polarization, identifying excess M2 macrophage activity and matrix synthesis as a potential mechanism of the fibrotic healing phenotype observed in T2DM tendons, and as such a potential target to improve tendon healing in T2DM. PMID:28686669

Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice.

PubMed

Tahara, Atsuo; Takasu, Toshiyuki; Yokono, Masanori; Imamura, Masakazu; Kurosaki, Eiji

2017-08-15

In this study, we investigated and compared the effects of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan on diabetes-related diseases and complications in type 2 diabetic mice. Following 4-week repeated administration to diabetic mice, all SGLT2 inhibitors showed significant improvement in diabetes-related diseases and complications, including obesity; abnormal lipid metabolism; steatohepatitis; inflammation; endothelial dysfunction; and nephropathy. While all SGLT2 inhibitors exerted comparable effects in reducing hyperglycemia, improvement of these diabetes-related diseases and complications was more potent with the two long-acting drugs (ipragliflozin and dapagliflozin) than with the four intermediate-acting four drugs (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin), albeit without statistical significance. These findings demonstrate that SGLT2 inhibitors alleviate various diabetic pathological conditions in type 2 diabetic mice, and suggest that SGLT2 inhibitors, particularly long-acting drugs, might be useful not only for hyperglycemia but also in diabetes-related diseases and complications, including nephropathy in type 2 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

Genetic identification of thiosulfate sulfurtransferase as an adipocyte-expressed anti-diabetic target in mice selected for leanness

PubMed Central

Morton, Nicholas M.; Beltram, Jasmina; Carter, Roderick N.; Michailidou, Zoi; Gorjanc, Gregor; Fadden, Clare Mc; Barrios-Llerena, Martin E.; Rodriguez-Cuenca, Sergio; Gibbins, Matthew T. G.; Aird, Rhona E.; Moreno-Navarrete, José Maria; Munger, Steven C.; Svenson, Karen L.; Gastaldello, Annalisa; Ramage, Lynne; Naredo, Gregorio; Zeyda, Maximilian; Wang, Zhao V.; Howie, Alexander F.; Saari, Aila; Sipilä, Petra; Stulnig, Thomas M.; Gudnason, Vilmundur; Kenyon, Christopher J.; Seckl, Jonathan R.; Walker, Brian R.; Webster, Scott P.; Dunbar, Donald R.; Churchill, Gary A.; Vidal-Puig, Antonio; Fernandez-Real, José Manuel; Emilsson, Valur; Horvat, Simon

2017-01-01

Discovery of genetic mechanisms for resistance to obesity and diabetes may illuminate new therapeutic strategies for the treatment of this global health challenge. We used the polygenic Lean mouse model, selected for low adiposity over 60 generations, to identify thiosulfate sulfurtransferase (Tst, Rhodanese) as a candidate obesity-resistance gene with selectively increased adipocyte expression. Elevated adipose Tst expression correlated with indices of metabolic health across diverse mouse strains. Transgenic overexpression of Tst in adipocytes protected mice from diet-induced obesity and insulin-resistant diabetes. Tst gene deficiency markedly exacerbated diabetes whereas pharmacological TST activation ameliorated diabetes in mice in vivo. Mechanistically, TST selectively augmented mitochondrial function combined with degradation of reactive oxygen species and sulfide. In humans, adipose TST mRNA correlated positively with adipose insulin sensitivity and negatively with fat mass. Genetic identification of Tst as a beneficial regulator of adipocyte mitochondrial function may have therapeutic significance for type 2 diabetes. PMID:27270587

Reduction of obesity, as induced by leptin, reverses endothelial dysfunction in obese (Lep(ob)) mice

NASA Technical Reports Server (NTRS)

Winters, B.; Mo, Z.; Brooks-Asplund, E.; Kim, S.; Shoukas, A.; Li, D.; Nyhan, D.; Berkowitz, D. E.

2000-01-01

Obesity is a major health care problem and is associated with significant cardiovascular morbidity. Leptin, a neuroendocrine hormone released by adipose tissue, is important in modulating obesity by signaling satiety and increasing metabolism. Moreover, leptin receptors are expressed on vascular endothelial cells (ECs) and mediate angiogenesis. We hypothesized that leptin may also play an important role in vasoregulation. We investigated vasoregulatory mechanisms in the leptin-deficient obese (ob/ob) mouse model and determined the influence of leptin replacement on endothelial-dependent vasorelaxant responses. The direct effect of leptin on EC nitric oxide (NO) production was also tested by using 4, 5-diaminofluorescein-2 diacetate staining and measurement of nitrate and nitrite concentrations. Vasoconstrictor responses to phenylephrine, norepinephrine, and U-46619 were markedly enhanced in aortic rings from ob/ob mice and were modulated by NO synthase inhibition. Vasorelaxant responses to ACh were markedly attenuated in mesenteric microvessels from ob/ob mice. Leptin replacement resulted in significant weight loss and reversal of the impaired endothelial-dependent vasorelaxant responses observed in ob/ob mice. Preincubation of ECs with leptin enhanced the release of NO production. Thus leptin-deficient ob/ob mice demonstrate marked abnormalities in vasoregulation, including impaired endothelial-dependent vasodilation, which is reversed by leptin replacement. These findings may be partially explained by the direct effect of leptin on endothelial NO production. These vascular abnormalities are similar to those observed in obese, diabetic, leptin-resistant humans. The ob/ob mouse may, therefore, be an excellent new model for the study of the cardiovascular effects of obesity.

Low Incidence of Spontaneous Type 1 Diabetes in Non-Obese Diabetic Mice Raised on Gluten-Free Diets Is Associated with Changes in the Intestinal Microbiome

PubMed Central

Marietta, Eric V.; Gomez, Andres M.; Yeoman, Carl; Tilahun, Ashenafi Y.; Clark, Chad R.; Luckey, David H.; Murray, Joseph A.; White, Bryan A.; Kudva, Yogish C.; Rajagopalan, Govindarajan

2013-01-01

Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of

Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome.

PubMed

Marietta, Eric V; Gomez, Andres M; Yeoman, Carl; Tilahun, Ashenafi Y; Clark, Chad R; Luckey, David H; Murray, Joseph A; White, Bryan A; Kudva, Yogish C; Rajagopalan, Govindarajan

2013-01-01

Human and animal studies strongly suggest that dietary gluten could play a causal role in the etiopathogenesis of type 1 diabetes (T1D). However, the mechanisms have not been elucidated. Recent reports indicate that the intestinal microbiome has a major influence on the incidence of T1D. Since diet is known to shape the composition of the intestinal microbiome, we investigated using non-obese diabetic (NOD) mice whether changes in the intestinal microbiome could be attributed to the pro- and anti-diabetogenic effects of gluten-containing and gluten-free diets, respectively. NOD mice were raised on gluten-containing chows (GCC) or gluten-free chows (GFC). The incidence of diabetes was determined by monitoring blood glucose levels biweekly using a glucometer. Intestinal microbiome composition was analyzed by sequencing 16S rRNA amplicons derived from fecal samples. First of all, GCC-fed NOD mice had the expected high incidence of hyperglycemia whereas NOD mice fed with a GFC had significantly reduced incidence of hyperglycemia. Secondly, when the fecal microbiomes were compared, Bifidobacterium, Tannerella, and Barnesiella species were increased (p = 0.03, 0.02, and 0.02, respectively) in the microbiome of GCC mice, where as Akkermansia species was increased (p = 0.02) in the intestinal microbiomes of NOD mice fed GFC. Thirdly, both of the gluten-free chows that were evaluated, either egg white based (EW-GFC) or casein based (C-GFC), significantly reduced the incidence of hyperglycemia. Interestingly, the gut microbiome from EW-GFC mice was similar to C-GFC mice. Finally, adding back gluten to the gluten-free diet reversed its anti-diabetogenic effect, reduced Akkermansia species and increased Bifidobacterium, Tannerella, and Barnesiella suggesting that the presence of gluten is directly responsible for the pro-diabetogenic effects of diets and it determines the gut microflora. Our novel study thus suggests that dietary gluten could modulate the incidence of

Significant obesity-associated gene expression changes occur in the stomach but not intestines in obese mice.

PubMed

Chen, Jing; Chen, Lihong; Sanseau, Philippe; Freudenberg, Johannes M; Rajpal, Deepak K

2016-05-01

The gastrointestinal (GI) tract can have significant impact on the regulation of the whole-body metabolism and may contribute to the development of obesity and diabetes. To systemically elucidate the role of the GI tract in obesity, we performed a transcriptomic analysis in different parts of the GI tract of two obese mouse models: ob/ob and high-fat diet (HFD) fed mice. Compared to their lean controls, significant changes in the gene expression were observed in both obese mouse groups in the stomach (ob/ob: 959; HFD: 542). In addition, these changes were quantitatively much higher than in the intestine. Despite the difference in genetic background, the two mouse models shared 296 similar gene expression changes in the stomach. Among those genes, some had known associations to obesity, diabetes, and insulin resistance. In addition, the gene expression profiles strongly suggested an increased gastric acid secretion in both obese mouse models, probably through an activation of the gastrin pathway. In conclusion, our data reveal a previously unknown dominant connection between the stomach and obesity in murine models extensively used in research. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Altered small intestinal absorptive enzyme activities in leptin-deficient obese mice: influence of bowel resection.

PubMed

Kiely, James M; Noh, Jae H; Svatek, Carol L; Pitt, Henry A; Swartz-Basile, Deborah A

2006-07-01

Residual bowel increases absorption after massive small bowel resection. Leptin affects intestinal adaptation, carbohydrate, peptide, and lipid handling. Sucrase, peptidase, and acyl coenzyme A:monoacylglycerol acyltransferase (MGAT) are involved in carbohydrate, protein, and lipid absorption. We hypothesized that leptin-deficient obese mice would have altered absorptive enzymes compared with controls before and after small bowel resection. Sucrase, peptidase (aminopeptidase N [ApN], dipeptidyl peptidase IV [DPPIV]), and MGAT activities were determined from lean control (C57BL/6J, n = 16) and leptin-deficient (Lep(ob), n = 16) mice small bowel before and after 50% resection. Ileal sucrase activity was greater in obese mice before and after resection. Jejunal ApN and DPPIV activities were lower for obese mice before resection; ileal ApN activity was unaltered after resection for both strains. Resection increased DPPIV activity in both strains. Jejunal MGAT in obese mice decreased postresection. In both strains, ileal MGAT activity decreased after resection, and obese mice had greater activity in remnant ileum. After small bowel resection, leptin-deficient mice have increased sucrase activity and diminished ileal ApN, DPPIV, and MGAT activity compared with controls. Therefore, we conclude that leptin deficiency alters intestinal enzyme activity in unresected animals and after small bowel resection. Altered handling of carbohydrate, protein, and lipid may contribute to obesity and diabetes in leptin-deficient mice.

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

PubMed

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

2005-01-01

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

Ganoderma lucidum reduces obesity in mice by modulating the composition of the gut microbiota.

PubMed

Chang, Chih-Jung; Lin, Chuan-Sheng; Lu, Chia-Chen; Martel, Jan; Ko, Yun-Fei; Ojcius, David M; Tseng, Shun-Fu; Wu, Tsung-Ru; Chen, Yi-Yuan Margaret; Young, John D; Lai, Hsin-Chih

2015-06-23

Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels-but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further show that high molecular weight polysaccharides (>300 kDa) isolated from the WEGL extract produce similar anti-obesity and microbiota-modulating effects. Our results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals.

A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice.

PubMed

Plovier, Hubert; Everard, Amandine; Druart, Céline; Depommier, Clara; Van Hul, Matthias; Geurts, Lucie; Chilloux, Julien; Ottman, Noora; Duparc, Thibaut; Lichtenstein, Laeticia; Myridakis, Antonis; Delzenne, Nathalie M; Klievink, Judith; Bhattacharjee, Arnab; van der Ark, Kees C H; Aalvink, Steven; Martinez, Laurent O; Dumas, Marc-Emmanuel; Maiter, Dominique; Loumaye, Audrey; Hermans, Michel P; Thissen, Jean-Paul; Belzer, Clara; de Vos, Willem M; Cani, Patrice D

2017-01-01

Obesity and type 2 diabetes are associated with low-grade inflammation and specific changes in gut microbiota composition. We previously demonstrated that administration of Akkermansia muciniphila to mice prevents the development of obesity and associated complications. However, the underlying mechanisms of this protective effect remain unclear. Moreover, the sensitivity of A. muciniphila to oxygen and the presence of animal-derived compounds in its growth medium currently limit the development of translational approaches for human medicine. We have addressed these issues here by showing that A. muciniphila retains its efficacy when grown on a synthetic medium compatible with human administration. Unexpectedly, we discovered that pasteurization of A. muciniphila enhanced its capacity to reduce fat mass development, insulin resistance and dyslipidemia in mice. These improvements were notably associated with a modulation of the host urinary metabolomics profile and intestinal energy absorption. We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium. Finally, we showed that administration of live or pasteurized A. muciniphila grown on the synthetic medium is safe in humans. These findings provide support for the use of different preparations of A. muciniphila as therapeutic options to target human obesity and associated disorders.

DGAT: novel therapeutic target for obesity and type 2 diabetes mellitus.

PubMed

Subauste, Angela; Burant, Charles F

2003-12-01

Obesity is currently an exceptionally common problem in humans. The last several years have produced a significant number of breakthroughs in obesity related areas of investigation. Triglycerides are considered the main form of storage of excess calories in fat. A key enzyme in the synthesis of triglycerides is acylCoA: diacylglycerol acyltransferase (DGAT). Recent studies have shown that mice deficient in this enzyme are resistant to diet induced obesity and have increased insulin and leptin sensitivity. These effects suggest that inhibition of DGAT in vivo may be a novel therapeutic target not only for obesity but also for diabetes.

Comparative study of peripheral neuropathy and nerve regeneration in NOD and ICR diabetic mice.

PubMed

Homs, Judit; Ariza, Lorena; Pagès, Gemma; Verdú, Enrique; Casals, Laura; Udina, Esther; Chillón, Miguel; Bosch, Assumpció; Navarro, Xavier

2011-09-01

The non-obese diabetic (NOD) mouse was suggested as an adequate model for diabetic autonomic neuropathy. We evaluated sensory-motor neuropathy and nerve regeneration following sciatic nerve crush in NOD males rendered diabetic by multiple low doses of streptozotocin, in comparison with similarly treated Institute for Cancer Research (ICR) mice, a widely used model for type I diabetes. Neurophysiological values for both strains showed a decline in motor and sensory nerve conduction velocity at 7 and 8 weeks after induction of diabetes in the intact hindlimb. However, amplitudes of compound muscle and sensory action potentials (CMAPs and CNAPs) were significantly reduced in NOD but not in ICR diabetic mice. Morphometrical analysis showed myelinated fiber loss in highly hyperglycemic NOD mice, but no significant changes in fiber size. There was a reduction of intraepidermal nerve fibers, more pronounced in NOD than in ICR diabetic mice. Interestingly, aldose reductase and poly(ADP-ribose) polymerase (PARP) activities were increased already at 1 week of hyperglycemia, persisting until the end of the experiment in both strains. Muscle and nerve reinnervation was delayed in diabetic mice following sciatic nerve crush, being more marked in NOD mice. Thus, diabetes of mid-duration induces more severe peripheral neuropathy and slower nerve regeneration in NOD than in ICR mice. © 2011 Peripheral Nerve Society.

High- and moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity.

PubMed

Hafstad, Anne D; Lund, Jim; Hadler-Olsen, Elin; Höper, Anje C; Larsen, Terje S; Aasum, Ellen

2013-07-01

Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8-10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders.

High- and Moderate-Intensity Training Normalizes Ventricular Function and Mechanoenergetics in Mice With Diet-Induced Obesity

PubMed Central

Hafstad, Anne D.; Lund, Jim; Hadler-Olsen, Elin; Höper, Anje C.; Larsen, Terje S.; Aasum, Ellen

2013-01-01

Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8–10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders. PMID:23493573

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

PubMed

Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

2016-05-27

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

Physical exercise reduces pyruvate carboxylase (PCB) and contributes to hyperglycemia reduction in obese mice.

PubMed

Muñoz, Vitor Rosetto; Gaspar, Rafael Calais; Crisol, Barbara Moreira; Formigari, Guilherme Pedron; Sant'Ana, Marcella Ramos; Botezelli, José Diego; Gaspar, Rodrigo Stellzer; da Silva, Adelino S R; Cintra, Dennys Esper; de Moura, Leandro Pereira; Ropelle, Eduardo Rochete; Pauli, José Rodrigo

2018-07-01

The present study evaluated the effects of exercise training on pyruvate carboxylase protein (PCB) levels in hepatic tissue and glucose homeostasis control in obese mice. Swiss mice were distributed into three groups: control mice (CTL), fed a standard rodent chow; diet-induced obesity (DIO), fed an obesity-inducing diet; and a third group, which also received an obesity-inducing diet, but was subjected to an exercise training protocol (DIO + EXE). Protocol training was carried out for 1 h/d, 5 d/wk, for 8 weeks, performed at an intensity of 60% of exhaustion velocity. An insulin tolerance test (ITT) was performed in the last experimental week. Twenty-four hours after the last physical exercise session, the animals were euthanized and the liver was harvested for molecular analysis. Firstly, DIO mice showed increased epididymal fat and serum glucose and these results were accompanied by increased PCB and decreased p-Akt in hepatic tissue. On the other hand, physical exercise was able to increase the performance of the mice and attenuate PCB levels and hyperglycemia in DIO + EXE mice. The above findings show that physical exercise seems to be able to regulate hyperglycemia in obese mice, suggesting the participation of PCB, which was enhanced in the obese condition and attenuated after a treadmill running protocol. This is the first study to be aimed at the role of exercise training in hepatic PCB levels, which may be a novel mechanism that can collaborate to reduce the development of hyperglycemia and type 2 diabetes in DIO mice.

Circulatory and Renal Consequences of Pregnancy in Diabetic NOD Mice

PubMed Central

Burke, S.D.; Barrette, V.F.; David, S.; Khankin, E. V.; Adams, M.A.; Croy, B.A.

2011-01-01

Objectives Women with diabetes have elevated gestational risks for severe hemodynamic complications, including preeclampsia in mid- to late pregnancy. This study employed continuous, chronic radiotelemetry to compare the hemodynamic patterns in non-obese diabetic (NOD) mice who were overtly diabetic or normoglycemic throughout gestation. We hypothesized that overtly diabetic, pregnant NOD mice would develop gestational hypertension and provide understanding of mechanisms in progression of this pathology. Study Design Telemeter-implanted, age-matched NOD females with and without diabetes were assessed for six hemodynamic parameters (mean, systolic, diastolic, pulse pressures, heart rate and activity) prior to mating, over pregnancy and over a 72 hr post-partum interval. Urinalysis, serum biochemistry and renal histopathology were also conducted. Results Pregnant, normoglycemic NOD mice had a hemodynamic profile similar to other inbred strains, despite insulitis. This pattern was characterized by an interval of pre-implantation stability, post implantation decline in arterial pressure to mid gestation, and then a rebound to pre-pregnancy baseline during later gestation. Overtly diabetic NOD mice had a blood pressure profile that was normal until mid-gestation then become mildly hypotensive (−7mmHg, P<0.05), severely bradycardic (−80bpm, P<0.01) and showed signs of acute kidney injury. Pups born to diabetic dams were viable but growth restricted, despite their mothers’ failing health, which did not rebound post-partum (−10% pre-pregnancy pressure and HR, P<0.05). Conclusions Pregnancy accelerates circulatory and renal pathologies in overtly diabetic NOD mice and is characterized by depressed arterial pressure from mid-gestation and birth of growth 45 restricted offspring. PMID:22014504

Systemic anti-TNFalpha treatment restores diabetes-impaired skin repair in ob/ob mice by inactivation of macrophages.

PubMed

Goren, Itamar; Müller, Elke; Schiefelbein, Dana; Christen, Urs; Pfeilschifter, Josef; Mühl, Heiko; Frank, Stefan

2007-09-01

To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)alpha (V1q) or monocyte/macrophage-expressed EGF-like module-containing mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFalpha- and anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFalpha therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting "activated" TNFalpha-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.

Obeticholic acid improves adipose morphometry and inflammation and reduces steatosis in dietary but not metabolic obesity in mice.

PubMed

Haczeyni, Fahrettin; Poekes, Laurence; Wang, Hans; Mridha, Auvro R; Barn, Vanessa; Geoffrey Haigh, W; Ioannou, George N; Yeh, Matthew M; Leclercq, Isabelle A; Teoh, Narcissus C; Farrell, Geoffrey C

2017-01-01

Nonalcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients but for unknown reasons does not resolve NASH pathology. This study therefore investigated OCA effects in Wt mice, which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet, which develop metabolic obesity and diabetes. OCA (1 mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. Adipose indices, glucose tolerance, and fatty liver pathology were studied. Experiments were repeated with OCA 10 mg/kg. OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favor of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure number in visceral adipose tissue. foz/foz mice showed more crown-like structures in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10 mg/kg. OCA improved adipose indices, glucose tolerance, and steatosis in a milder metabolic phenotype but failed to improve these factors in morbidly obese diabetic mice. These results help explain OCA's limited efficacy to reverse human NASH. © 2016 The Obesity Society.

Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes.

PubMed

Laeger, Thomas; Castaño-Martinez, Teresa; Werno, Martin W; Japtok, Lukasz; Baumeier, Christian; Jonas, Wenke; Kleuser, Burkhard; Schürmann, Annette

2018-06-01

Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.

Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes.

PubMed

Funda, David P; Kaas, Anne; Tlaskalová-Hogenová, Helena; Buschard, Karsten

2008-01-01

Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten-free, non-purified diet largely prevented diabetes in non-obese diabetic (NOD) mice. In this study we tested hypothesis that early introduction of gluten-enriched (gluten+) diet may increase diabetes incidence in NOD mice. Standard, gluten-free, gluten+ modified Altromin diets and hydrolysed-casein-based Pregestimil diet were fed to NOD females and diabetes incidence was followed for 310 days. Insulitis score and numbers of gut mucosal lymphocytes were determined in non-diabetic animals. A significantly lower diabetes incidence (p < 0.0001) was observed in NOD mice fed gluten-free diet (5.9%, n = 34) and Pregestimil diet (10%, n = 30) compared to mice on the standard Altromin diet (60.6%, n = 33). Surprisingly, gluten+ diet also prevented diabetes incidence, even at the level found with the gluten-free diet (p < 0.0001, 5.9%, n = 34). The minority of mice, which developed diabetes on all the three diabetes-protective (gluten+, gluten-free, Pregestimil) diets, did that slightly later compared to those on the standard diet. Lower insulitis score compared to control mice was found in non-diabetic NOD mice on the gluten-free, and to a lesser extent also gluten+ and Pregestimil diets. No substantial differences in the number of CD3(+), TCR-gammadelta(+), and IgA(+) cells in the small intestine were documented. Gluten+ diet prevents diabetes in NOD mice at the level found with the non-purified gluten-free diet. Possible mechanisms of the enigmatic, dual effect of dietary gluten on the development of T1D are discussed. 2007 John Wiley & Sons, Ltd

Comparative analysis of the intestinal flora in type 2 diabetes and nondiabetic mice

PubMed Central

Horie, Masanori; Miura, Takamasa; Hirakata, Satomi; Hosoyama, Akira; Sugino, Sakiko; Umeno, Aya; Murotomi, Kazutoshi; Yoshida, Yasukazu; Koike, Taisuke

2017-01-01

A relationship between type 2 diabetes mellitus (T2DM) and intestinal flora has been suggested since development of analysis technology for intestinal flora. An animal model of T2DM is important for investigation of T2DM. Although there are some animal models of T2DM, a comparison of the intestinal flora of healthy animals with that of T2DM animals has not yet been reported. The intestinal flora of Tsumura Suzuki Obese Diabetes (TSOD) mice was compared with that of Tsumura, Suzuki, Non Obesity (TSNO) mice in the present study. The TSOD mice showed typical type 2 diabetes symptoms, which were high-fat diet-independent. The TSOD and the TSNO mouse models were derived from the same strain, ddY. In this study, we compared the intestinal flora of TSOD mice with that if TSNO mice at 5 and 12 weeks of age. We determined that that the number of operational taxonomic units (OTUs) was significantly higher in the cecum of TSOD mice than in that of TSNO mice. The intestinal flora of the cecum and that of the feces were similar between the TSNO and the TSOD strains. The dominant bacteria in the cecum and feces were of the phyla Firmicutes and Bacteroidetes. However, the content of some bacterial species varied between the two strains. The percentage of Lactobacillus spp. within the general intestinal flora was higher in TSOD mice than in TSNO mice. In contrast, the percentages of order Bacteroidales and family Lachnospiraceae were higher in TSNO mice than in TSOD mice. Some species were observed only in TSOD mice, such as genera Turicibacter and SMB53 (family Clostridiaceae), the percentage of which were 3.8% and 2.0%, respectively. Although further analysis of the metabolism of the individual bacteria in the intestinal flora is essential, genera Turicibacter and SMB53 may be important for the abnormal metabolism of type 2 diabetes. PMID:28701620

Comparative analysis of the intestinal flora in type 2 diabetes and nondiabetic mice.

PubMed

Horie, Masanori; Miura, Takamasa; Hirakata, Satomi; Hosoyama, Akira; Sugino, Sakiko; Umeno, Aya; Murotomi, Kazutoshi; Yoshida, Yasukazu; Koike, Taisuke

2017-10-30

A relationship between type 2 diabetes mellitus (T2DM) and intestinal flora has been suggested since development of analysis technology for intestinal flora. An animal model of T2DM is important for investigation of T2DM. Although there are some animal models of T2DM, a comparison of the intestinal flora of healthy animals with that of T2DM animals has not yet been reported. The intestinal flora of Tsumura Suzuki Obese Diabetes (TSOD) mice was compared with that of Tsumura, Suzuki, Non Obesity (TSNO) mice in the present study. The TSOD mice showed typical type 2 diabetes symptoms, which were high-fat diet-independent. The TSOD and the TSNO mouse models were derived from the same strain, ddY. In this study, we compared the intestinal flora of TSOD mice with that if TSNO mice at 5 and 12 weeks of age. We determined that that the number of operational taxonomic units (OTUs) was significantly higher in the cecum of TSOD mice than in that of TSNO mice. The intestinal flora of the cecum and that of the feces were similar between the TSNO and the TSOD strains. The dominant bacteria in the cecum and feces were of the phyla Firmicutes and Bacteroidetes. However, the content of some bacterial species varied between the two strains. The percentage of Lactobacillus spp. within the general intestinal flora was higher in TSOD mice than in TSNO mice. In contrast, the percentages of order Bacteroidales and family Lachnospiraceae were higher in TSNO mice than in TSOD mice. Some species were observed only in TSOD mice, such as genera Turicibacter and SMB53 (family Clostridiaceae), the percentage of which were 3.8% and 2.0%, respectively. Although further analysis of the metabolism of the individual bacteria in the intestinal flora is essential, genera Turicibacter and SMB53 may be important for the abnormal metabolism of type 2 diabetes.

Type 2 diabetes and obesity in adults.

PubMed

Whitmore, Catherine

There are approximately 2.5 million people in the UK with diabetes; 85-95% of whom have type 2 diabetes. Type 2 diabetes mellitus is characterized by insulin resistance and impaired insulin secretion. As approximately 90% of people with type 2 diabetes are overweight or obese, obesity is seen as a significant contributory factor in its development. This article aims to examine some of the physiological mechanisms by which overweight and obesity contribute to the development of type 2 diabetes, and review some of the approaches to managing overweight and obesity in the person with established type 2 diabetes, including dietary management, the use of reduced carbohydrate diets on glycamic control, anti-diabetes and anti-obesity drugs both in use and in development, and bariatric surgery.

Ginsenoside Rb1 ameliorates liver fat accumulation by upregulating perilipin expression in adipose tissue of db/db obese mice

PubMed Central

Yu, Xizhong; Ye, Lifang; Zhang, Hao; Zhao, Juan; Wang, Guoqiang; Guo, Chao; Shang, Wenbin

2014-01-01

Background Ginsenoside Rb1 (G-Rb1), the major active constituent of ginseng, improves insulin sensitivity and exerts antidiabetic effects. We tested whether the insulin-sensitizing and antidiabetic effects of G-Rb1 results from a reduction in ectopic fat accumulation, mediated by inhibition of lipolysis in adipocytes. Methods Obese and diabetic db/db mice were treated with daily doses of 20 mg/kg G-Rb1 for 14 days. Hepatic fat accumulation was evaluated by measuring liver weight and triglyceride content. Levels of blood glucose and serum insulin were used to evaluate insulin sensitivity in db/db mice. Lipolysis in adipocytes was evaluated by measuring plasma-free fatty acids and glycerol release from 3T3-L1 adipocytes treated with G-Rb1. The expression of relevant genes was analyzed by western blotting, quantitative real-time polymerase chain reaction, and enzyme-linked immunosorbent assay kit. Results G-Rb1 increased insulin sensitivity and alleviated hepatic fat accumulation in obese diabetic db/db mice, and these effects were accompanied by reduced liver weight and hepatic triglyceride content. Furthermore, G-Rb1 lowered the levels of free fatty acids in obese mice, which may contribute to a decline in hepatic lipid accumulation. Corresponding to these results, G-Rb1 significantly suppressed lipolysis in 3T3-L1 adipocytes and upregulated the perilipin expression in both 3T3-L1 adipocytes and mouse epididymal fat pads. Moreover, G-Rb1 increased the level of adiponectin and reduced that of tumor necrosis factor-α in obese mice, and these effects were confirmed in 3T3-L1 adipocytes. Conclusion G-Rb1 may improve insulin sensitivity in obese and diabetic db/db mice by reducing hepatic fat accumulation and suppressing adipocyte lipolysis; these effects may be mediated via the upregulation of perilipin expression in adipocytes. PMID:26199550

Peripherally administered baclofen reduced food intake and body weight in db/db as well as diet-induced obese mice.

PubMed

Sato, Ikuko; Arima, Hiroshi; Ozaki, Noriyuki; Ozaki, Nobuaki; Watanabe, Minemori; Goto, Motomitsu; Shimizu, Hiroshi; Hayashi, Masayuki; Banno, Ryouichi; Nagasaki, Hiroshi; Oiso, Yutaka

2007-10-16

Peripheral administration of baclofen significantly reduced food intake and body weight increase in both diabetic (db/db) and diet-induced obese mice for 5 weeks, whereas it had no significant effects on energy balance in their lean control mice. Despite the decreased body weight, neuropeptide Y expression in the arcuate nucleus was significantly decreased, whereas pro-opiomelanocortin expression was significantly increased by baclofen treatment. These data demonstrate that the inhibitory effects of baclofen on body weight in the obese mice were mediated via the arcuate nucleus at least partially, and suggest that GABA(B) agonists could be a new therapeutic reagent for obesity.

Rotavirus Activates Lymphocytes from Non-Obese Diabetic Mice by Triggering Toll-Like Receptor 7 Signaling and Interferon Production in Plasmacytoid Dendritic Cells

PubMed Central

Pane, Jessica A.; Webster, Nicole L.; Coulson, Barbara S.

2014-01-01

It has been proposed that rotavirus infection promotes the progression of genetically-predisposed children to type 1 diabetes, a chronic autoimmune disease marked by infiltration of activated lymphocytes into pancreatic islets. Non-obese diabetic (NOD) mice provide a model for the human disease. Infection of adult NOD mice with rhesus monkey rotavirus (RRV) accelerates diabetes onset, without evidence of pancreatic infection. Rather, RRV spreads to the pancreatic and mesenteric lymph nodes where its association with antigen-presenting cells, including dendritic cells, induces cellular maturation. RRV infection increases levels of the class I major histocompatibility complex on B cells and proinflammatory cytokine expression by T cells at these sites. In autoimmunity-resistant mice and human mononuclear cells from blood, rotavirus-exposed plasmacytoid dendritic cells contribute to bystander polyclonal B cell activation through type I interferon expression. Here we tested the hypothesis that rotavirus induces bystander activation of lymphocytes from NOD mice by provoking dendritic cell activation and proinflammatory cytokine secretion. NOD mouse splenocytes were stimulated with rotavirus and assessed for activation by flow cytometry. This stimulation activated antigen-presenting cells and B cells independently of virus strain and replicative ability. Instead, activation depended on virus dose and was prevented by blockade of virus decapsidation, inhibition of endosomal acidification and interference with signaling through Toll-like receptor 7 and the type I interferon receptor. Plasmacytoid dendritic cells were more efficiently activated than conventional dendritic cells by RRV, and contributed to the activation of B and T cells, including islet-autoreactive CD8+ T cells. Thus, a double-stranded RNA virus can induce Toll-like receptor 7 signaling, resulting in lymphocyte activation. Our findings suggest that bystander activation mediated by type I interferon

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

PubMed Central

Trammell, Samuel A.J.; Weidemann, Benjamin J.; Chadda, Ankita; Yorek, Matthew S.; Holmes, Amey; Coppey, Lawrence J.; Obrosov, Alexander; Kardon, Randy H.; Yorek, Mark A.; Brenner, Charles

2016-01-01

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

Obeticholic Acid Improves Adipose Morphometry and Inflammation and Reduces Steatosis in Dietary but not Metabolic Obesity in Mice

PubMed Central

Haczeyni, Fahrettin; Poekes, Laurence; Wang, Hans; Mridha, Auvro R.; Barn, Vanessa; Haigh, W. Geoffrey; Ioannou, George N.; Yeh, Matthew M; Leclercq, Isabelle A.; Teoh, Narcissus C.; Farrell, Geoffrey C.

2018-01-01

Objective Non-alcoholic steatohepatitis (NASH) is the outcome of interactions between overnutrition, energy metabolism, and adipose function. Obeticholic acid (OCA) improves steatosis in patients, but for unknown reason does not resolve NASH pathology. We therefore investigated OCA effects in Wt mice which develop obesity with atherogenic dietary feeding, and appetite-dysregulated, Alms1 mutant foz/foz mice fed the same diet which develop metabolic obesity and diabetes. Methods OCA (1mg/kg) was administered orally to female foz/foz mice and Wt littermates from weaning until 28 weeks. We studied adipose indices, glucose tolerance and fatty liver pathology. Experiments were repeated with OCA 10mg/kg. Results OCA reduced body weight and hepatic lipids and improved glucose disposal only in Wt mice. OCA limited Wt adipose expansion, altered morphometry in favour of small adipocytes, enhanced expression of genes indicating adipose browning, and reduced crown-like structure (CLS) number in visceral adipose. foz/foz mice showed more CLSs in all compartments; OCA failed to alter adipose morphometry, browning, inflammation, or improve NASH severity, even at 10mg/kg. Conclusion OCA improves adipose indices, glucose tolerance and steatosis in milder metabolic phenotype, but fails to improve these factors in morbidly obese diabetic mice. These results help explain OCA’s limited efficacy to reverse human NASH. PMID:27804232

Protective effects of SGLT2 inhibitor luseogliflozin on pancreatic β-cells in obese type 2 diabetic db/db mice

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

Okauchi, Seizo, E-mail: okauchi@med.kawasaki-m.ac.jp; Shimoda, Masashi; Obata, Atsushi

It is well known that Sodium-Glucose Co-transporter 2 (SGLT2) inhibitors, new hypoglycemic agents, improve glycemic control by increasing urine glucose excretion, but it remained unclear how they exert protective effects on pancreatic β-cells. In this study, we examined the effects of SGLT2 inhibitor luseogliflozin on β-cell function and mass using obese type 2 diabetic db/db mice. Ten-week-old male diabetic db/db mice were treated with luseogliflozin 0.0025% or 0.01% in chow (Luse 0.0025% or Luse 0.01%) or vehicle (control) for 4 weeks. Urinary glucose excretion was increased in Luse groups (0.0025% and 0.01%) compared to control mice 3 days after themore » intervention. Fasting blood glucose levels were significantly lower in mice treated with Luse compared to control mice. Fasting serum insulin concentrations were significantly higher in mice treated with Luse compared to control mice. Triglyceride levels tended to be lower in Luse groups compared to control mice. In immunohistochemical study using pancreas tissues, β-cell mass was larger in Luse groups compared to control group which was due to the increase of β-cell proliferation and decrease of β-cell apoptosis. Furthermore, in gene analysis using isolated islets, insulin 1, insulin 2, MafA, PDX-1 and GLUT2 gene expression levels were significantly higher in Luse groups compared to control group. In contrast, expression levels of fibrosis-related gene such as TGFβ, fibronectin, collagen I and collagen III were significantly lower in Luse groups. In conclusion, SGLT2 inhibitor luseogliflozin ameliorates glycemic control and thus exerts protective effects on pancreatic β-cell mass and function. - Highlights: • SGLT2 inhibitor luseogliflozin ameliorates glycemic control in db/db mice. • Luseogliflozin increases β-cell proliferation and decreases β-cell apoptosis. • Luseogliflozin preserves various β-cell-specific gene expression. • Luseogliflozin decreases various fibrosis-related factors in

Mechanisms for antidiabetic effect of gingerol in cultured cells and obese diabetic model mice.

PubMed

Son, Myoung Jin; Miura, Yutaka; Yagasaki, Kazumi

2015-08-01

There have been studies on health beneficial effects of ginger and its components. However, there still remain certain aspects that are not well defined in their anti-hyperglycemic effects. Our aims were to find evidence of possible mechanisms for antidiabetic action of [6]-gingerol, a pungent component of ginger, employing a rat skeletal muscle-derived cell line, a rat-derived pancreatic β-cell line, and type 2 diabetic model animals. The antidiabetic effect of [6]-gingerol was investigated through studies on glucose uptake in L6 myocytes and on pancreatic β-cell protective ability from reactive oxygen species (ROS) in RIN-5F cells. Its in vivo effect was also examined using obese diabetic db/db mice. [6]-Gingerol increased glucose uptake under insulin absent condition and induced 5' adenosine monophosphate-activated protein kinase phosphorylation in L6 myotubes. Promotion by [6]-gingerol of glucose transporter 4 (GLUT4) translocation to plasma membrane was visually demonstrated by immunocytochemistry in L6 myoblasts transfected with glut4 cDNA-coding vector. [6]-Gingerol suppressed advanced glycation end product-induced rise of ROS levels in RIN-5F pancreatic β-cells. [6]-Gingerol feeding suppressed the increases in fasting blood glucose levels and improved glucose intolerance in db/db mice. [6]-Gingerol regulated hepatic gene expression of enzymes related to glucose metabolism toward decreases in gluconeogenesis and glycogenolysis as well as an increase in glycogenesis, thereby contributing to reductions in hepatic glucose production and hence blood glucose concentrations. These in vitro and in vivo results strongly suggest that [6]-gingerol has antidiabetic potential through multiple mechanisms.

Attenuation of obesity-induced inflammation in mice orally administered with salmon cartilage proteoglycan, a prophylactic agent.

PubMed

Hirose, Shouhei; Asano, Krisana; Nakane, Akio

2017-03-11

Obesity is associated with chronic inflammation of adipose tissue and causes development of type 2 diabetes. M1 macrophage population was increased in adipose tissue of obese mouse. M1 macrophages induce insulin resistance through the secretion of proinflammatory cytokines. Our previous studies demonstrated that salmon cartilage proteoglycan (PG) suppresses excess inflammation in various mouse inflammatory diseases. In this study, we examined the effect of PG on type 2 diabetes using high-fat-diet (HFD) induced obese mouse model. Oral PG administration enhanced the population of small adipocytes (area less than 1000 μm 2 ) without body and tissue weight gain. In addition, PG administration suppressed mRNA expression of TNF-α, IL-6 and CXCL2 in adipose tissue. The proportion of M1 macrophages was decreased by PG administration. In addition, PG administration suppressed hyperglycemia after intraperitoneal glucose injection. Fasted serum insulin level was decreased in PG-administered mice. Moreover, insulin-stimulated phosphorylation of Akt was enhanced in the liver and gastrocnemius skeletal muscle of PG-administered mice. These data suggested that PG administration improves hyperglycemia and insulin sensitivity in obese mice by modulation of M1 macrophages which secrete proinflammatory cytokines in adipose tissue and activation of Akt in liver and skeletal muscle. Copyright © 2017 Elsevier Inc. All rights reserved.

Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development.

PubMed

Mori, Yoshiko; Kodaka, Tetsuro; Kato, Takako; Kanagawa, Edith M; Kanagawa, Osami

2009-11-01

IFN-gamma signaling-deficient non-obese diabetic (NOD) mice develop diabetes with similar kinetics to those of wild-type NOD mice. However, the immunization of IFN-gamma signaling-deficient NOD mice with CFA failed to induce long-term protection, whereas wild-type NOD mice receiving CFA remained diabetes-free. CFA also failed to protect IFN-gamma receptor-deficient (IFN-gammaR(-/-)) NOD mice from the autoimmune rejection of transplanted islets, as it does in diabetic NOD mice, and from disease transfer by spleen cells from diabetic NOD mice. These data clearly show that the pro-inflammatory cytokine IFN-gamma is necessary for the CFA-mediated protection of NOD mice from diabetes. There is no difference in the T(h)1/T(h)17 balance between IFN-gammaR(-/-) NOD and wild-type NOD mice. There is also no difference in the total numbers and percentages of regulatory T (Treg) cells in the lymph node CD4(+) T-cell populations between IFN-gammaR(-/-) NOD and wild-type NOD mice. However, pathogenic T cells lacking IFN-gammaR are resistant to the suppressive effect of Treg cells, both in vivo and in vitro. Therefore, it is likely that CFA-mediated protection against diabetes development depends on a change in the balance between Treg cells and pathogenic T cells, and IFN-gamma signaling seems to control the susceptibility of pathogenic T cells to the inhibitory activity of Treg cells.

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

Daintain/AIF-1 (Allograft Inflammatory Factor-1) accelerates type 1 diabetes in NOD mice

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

Zhao, Yan-Ying, E-mail: biozyy@163.com; Huang, Xin-Yuan; Chen, Zheng-Wang

Highlights: Black-Right-Pointing-Pointer Daintain/AIF-1 is over-expressed in the blood of NOD mice suffering from insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 stimulates white blood cell proliferation in NOD mice. Black-Right-Pointing-Pointer Daintain/AIF-1 increases blood glucose levels and triggers type 1 diabetes. Black-Right-Pointing-Pointer Daintain/AIF-1 accelerates insulitis, while its antibody prevents insulitis. Black-Right-Pointing-Pointer Daintain/AIF-1 enhances the levels of nitric oxide in the pancreases of NOD mice. -- Abstract: A large body of experimental evidence suggests that cytokines trigger pancreatic {beta}-cell death in type 1 diabetes mellitus. Daintain/AIF-1 (Allograft Inflammatory Factor-1), a specific marker for activated macrophages, is accumulated in the pancreatic islets of pre-diabetic BB rats. In themore » present study, we demonstrate that daintain/AIF-1 is released into blood and the levels of daintain/AIF-1 in the blood of type 1 diabetes-prone non-obese diabetic (NOD) mice suffering from insulitis are significantly higher than that in healthy NOD mice. When injected intravenously into NOD mice, daintain/AIF-1 stimulates white blood cell proliferation, increases the concentrations of blood glucose, impairs insulin expression, up-regulates nitric oxide (NO) production in pancreases and accelerates diabetes in NOD mice, while the antibody against daintain/AIF-1 delays or prevents insulitis in NOD mice. These results imply daintain/AIF-1 triggers type 1 diabetes probably via arousing immune cells activation and induction of NO production in pancreas of NOD mice.« less

Lifelong obesity in a polygenic mouse model prevents age- and diet-induced glucose intolerance- obesity is no road to late-onset diabetes in mice.

PubMed

Renne, Ulla; Langhammer, Martina; Brenmoehl, Julia; Walz, Christina; Zeissler, Anja; Tuchscherer, Armin; Piechotta, Marion; Wiesner, Rudolf J; Bielohuby, Maximilian; Hoeflich, Andreas

2013-01-01

Visceral obesity holds a central position in the concept of the metabolic syndrome characterized by glucose intolerance in humans. However, until now it is unclear if obesity by itself is responsible for the development of glucose intolerance. We have used a novel polygenic mouse model characterized by genetically fixed obesity (DU6) and addressed age- and high fat diet-dependent glucose tolerance. Phenotype selection over 146 generations increased body weight by about 2.7-fold in male 12-week DU6 mice (P<0.0001) if compared to unselected controls (Fzt:DU). Absolute epididymal fat mass was particularly responsive to weight selection and increased by more than 5-fold (P<0.0001) in male DU6 mice. At an age of 6 weeks DU6 mice consumed about twice as much food if compared to unselected controls (P<0.001). Absolute food consumption was higher at all time points measured in DU6 mice than in Fzt:DU mice. Between 6 and 12 weeks of age, absolute food intake was reduced by 15% in DU6 mice (P<0.001) but not in Fzt:DU mice. In both mouse lines feeding of the high fat diet elevated body mass if compared to the control diet (P<0.05). In contrast to controls, DU6 mice did not display high fat diet-induced increases of epididymal and renal fat. Control mice progressively developed glucose intolerance with advancing age and even more in response to the high fat diet. In contrast, obese DU6 mice did neither develop a glucose intolerant phenotype with progressive age nor when challenged with a high fat diet. Our results from a polygenic mouse model demonstrate that genetically pre-determined and life-long obesity is no precondition of glucose intolerance later in life.

Exendin-4 improves resistance to Listeria monocytogenes infection in diabetic db/db mice

PubMed Central

Liu, Hsien Yueh; Chung, Chih-Yao; Yang, Wen-Chin; Liang, Chih-Lung; Wang, Chi-Young; Chang, Chih-Yu

2012-01-01

The incidence of diabetes mellitus is increasing among companion animals. This disease has similar characteristics in both humans and animals. Diabetes is frequently identified as an independent risk factor for infections associated with increased mortality. In the present study, homozygous diabetic (db/db) mice were infected with Listeria (L.) monocytogenes and then treated with the anti-diabetic drug exendin-4, a glucagon-like peptide 1 analogue. In aged db/db mice, decreased CD11b+ macrophage populations with higher lipid content and lower phagocytic activity were observed. Exendin-4 lowered high lipid levels and enhanced phagocytosis in macrophages from db/db mice infected with L. monocytogenes. Exendin-4 also ameliorated obesity and hyperglycemia, and improved ex vivo bacteria clearance by macrophages in the animals. Liver histology examined during L. monocytogenes infection indicated that abscess formation was much milder in exendin-4-treated db/db mice than in the control animals. Moreover, mechanistic studies demonstrated that expression of ATP binding cassette transporter 1, a sterol transporter, was higher in macrophages isolated from the exendin-4-treated db/db mice. Overall, our results suggest that exendin-4 decreases the risk of infection in diabetic animals by modifying the interaction between intracellular lipids and phagocytic macrophages. PMID:23000581

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice

PubMed Central

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-01-01

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes. PMID:25367288

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice

NASA Astrophysics Data System (ADS)

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-11-01

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.

Arsenic induces diabetic effects through beta-cell dysfunction and increased gluconeogenesis in mice.

PubMed

Liu, Su; Guo, Xuechao; Wu, Bing; Yu, Haiyan; Zhang, Xuxiang; Li, Mei

2014-11-04

Arsenic as a potential risk factor for type 2 diabetes has been received attention recently. However, the roles of arsenic on development of diabetes are unclear. In this study, we compared the influences of inorganic arsenic (iAs) on normal and diabetic mice by systems toxicology approaches. Although iAs exposure did not change glucose tolerance in normal mice, it caused the pancreatic β-cell dysfunction and increased gluconeogenesis and oxidative damages in liver. However, iAs exposure worsened the glucose tolerance in diabetic mice, which might be due to increased gluconeogenesis and impairment of pancreatic β-cell function. It is interesting that iAs exposure could improve the insulin sensitivity based on the insulin tolerance testing by the activation of glucose uptake-related genes and enzymes in normal and diabetic individuals. Our data suggested that iAs exposure could cause pre-diabetic effects by altering the lipid metabolism, gluconeogenesis and insulin secretion in normal individual, and worsen diabetic effects in diabetes individual by these processes. Insulin resistance might be not the reason of diabetic effects caused by iAs, indicating that mechanism of the diabetogenic effects of iAs exposure is different from the mechanism associated with traditional risk factors (such as obesity)-reduced type 2 diabetes.

miR-378 Activates the Pyruvate-PEP Futile Cycle and Enhances Lipolysis to Ameliorate Obesity in Mice

PubMed Central

Zhang, Yong; Li, Changyin; Li, Hu; Song, Yipeng; Zhao, Yixia; Zhai, Lili; Wang, Haixia; Zhong, Ran; Tang, Huiru; Zhu, Dahai

2016-01-01

Obesity has been linked to many health problems, such as diabetes. However, there is no drug that effectively treats obesity. Here, we reveal that miR-378 transgenic mice display reduced fat mass, enhanced lipolysis, and increased energy expenditure. Notably, administering AgomiR-378 prevents and ameliorates obesity in mice. We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism. This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1. Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. Thus, miR-378 may serve as a promising agent for preventing and treating obesity in humans. PMID:27077116

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

Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model.

PubMed

Koopman, F A; Vosters, J L; Roescher, N; Broekstra, N; Tak, P P; Vervoordeldonk, M J

2015-10-01

Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's syndrome and type 1 diabetes. The alpha-7 nicotinic acetylcholine receptor (α7nAChR) was stimulated with AR-R17779 or nicotine in NOD mice. In a second study, unilateral cervical vagotomy was performed. α7nAChR expression, focus scores, and salivary flow were evaluated in salivary glands (SG) and insulitis score in the pancreas. Cytokines were measured in serum and SG. α7nAChR was expressed on myoepithelial cells in SG. Monocyte chemotactic protein-1 levels were reduced in SG after AR-R17779 treatment and tumor necrosis factor production was increased in the SG of the vagotomy group compared to controls. Focus score and salivary flow were unaffected. NOD mice developed diabetes more rapidly after vagotomy, but at completion of the study there were no statistically significant differences in number of mice that developed diabetes or in insulitis scores. Intervention of the CAP in NOD mice leads to minimal changes in inflammatory cytokines, but did not affect overall inflammation and function of SG or development of diabetes. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Effects of pioglitazone mediated activation of PPAR-γ on CIDEC and obesity related changes in mice.

PubMed

Shamsi, Bilal Haider; Ma, Chaofeng; Naqvi, Saima; Xiao, Yanfeng

2014-01-01

Obesity is a metabolic disorder that can lead to high blood pressure, increased blood cholesterol and triglycerides, insulin resistance, and diabetes mellitus. The aim was to study the effects of pioglitazone mediated sensitization of peroxisome proliferator-activated receptor gamma (PPAR-γ) on the relationship of Cell death-inducing DFFA-like effector C (CIDEC) with obesity related changes in mice. Sixty C57B/L6 mice weighing 10-12g at 3 weeks of age were randomly divided into 3 groups. Mice in Group 1 were fed on normal diet (ND) while Group 2 mice were given high fat diet (HFD), and Group 3 mice were given high fat diet and treated with Pioglitazone (HFD+P). Body weight, length and level of blood sugar were measured weekly. Quantitative real-time PCR, fluorescence microscopy, and ELISA were performed to analyze the expression of CIDEC and PPAR-γ in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Body weight and length of mice increased gradually with time in all groups. Blood sugar in HFD mice started to increase significantly from the mid of late phase of obesity while pioglitazone attenuated blood sugar level in HFD+P mice. The mRNA expressions and protein levels of PPAR-γ and CIDEC genes started to increase in HFD mice as compared to ND mice and decreased gradually during the late phase of obesity in VAT. Pioglitazone enhanced the expression of PPAR-γ and CIDEC genes in HFD+P mice even during the late phase of obesity. It is insinuated that VAT is associated with late phase obesity CIDEC decrease and insulin resistance, while pioglitazone enhances CIDEC through activation of PPAR-γ, increases its expression, and decreases lipolysis, hence preventing an increase of blood sugar in mice exposed to HFD.

Deficiency in plasmacytoid dendritic cells and type I interferon signalling prevents diet-induced obesity and insulin resistance in mice.

PubMed

Hannibal, Tine D; Schmidt-Christensen, Anja; Nilsson, Julia; Fransén-Pettersson, Nina; Hansen, Lisbeth; Holmberg, Dan

2017-10-01

Obesity is associated with glucose intolerance and insulin resistance and is closely linked to the increasing prevalence of type 2 diabetes. In mouse models of diet-induced obesity (DIO) and type 2 diabetes, an increased fat intake results in adipose tissue expansion and the secretion of proinflammatory cytokines. The innate immune system not only plays a crucial role in obesity-associated chronic low-grade inflammation but it is also proposed to play a role in modulating energy metabolism. However, little is known about how the modulation of metabolism by the immune system may promote increased adiposity in the early stages of increased dietary intake. Here we aimed to define the role of type I IFNs in DIO and insulin resistance. Mice lacking the receptor for IFN-α (IFNAR -/- ) and deficient in plasmacytoid dendritic cells (pDCs) (B6.E2-2 fl/fl .Itgax-cre) were fed a diet with a high fat content or normal chow. The mice were analysed in vivo and in vitro using cellular, biochemical and molecular approaches. We found that the development of obesity was inhibited by an inability to respond to type I IFNs. Furthermore, the development of obesity and insulin resistance in this model was associated with pDC recruitment to the fatty tissues and liver of obese mice (a 4.3-fold and 2.7-fold increase, respectively). Finally, we demonstrated that the depletion of pDCs protects mice from DIO and from developing obesity-associated metabolic complications. Our results provide genetic evidence that pDCs, via type I IFNs, regulate energy metabolism and promote the development of obesity.

Diet-induced obesity in mice reduces the maintenance of influenza-specific CD8+ memory T cells.

PubMed

Karlsson, Erik A; Sheridan, Patricia A; Beck, Melinda A

2010-09-01

Obesity has been associated with increasing the risk for type 2 diabetes and heart disease, but its influence on the immune response to viral infection is understudied. Memory T cells generated during a primary influenza infection are important for protection against subsequent influenza exposures. Previously, we have demonstrated that diet-induced obese (DIO) mice have increased morbidity and mortality following secondary influenza infection compared with lean mice. To determine whether the problem resided in a failure to maintain functional, influenza-specific CD8(+) memory T cells, male DIO and lean mice were infected with influenza X-31. At 84 d postinfection, DIO mice had a 10% reduction in memory T cell numbers. This reduction may have resulted from significantly reduced memory T cell expression of interleukin 2 receptor beta (IL-2R beta, CD122), but not IL-7 receptor alpha (CD127), which are both required for memory cell maintenance. Peripheral leptin resistance in the DIO mice may be a contributing factor to the impairment. Indeed, leptin receptor mRNA expression was significantly reduced in the lungs of obese mice, whereas suppressor of cytokine signaling (Socs)1 and Socs3 mRNA expression were increased. It is imperative to understand how the obese state alters memory T cells, because impairment in maintenance of functional memory responses has important implications for vaccine efficacy in an obese population.

Pediatric obesity & type 2 diabetes.

PubMed

Dea, Tara L

2011-01-01

This article focuses on (a) identifying obesity and other risk factors for developing type 2 diabetes, (b) differentiating between pediatric type 1 diabetes and type 2 diabetes, and (c) treating pediatric type 2 diabetes. Obesity has significant implications on a child's health, including an increased risk for insulin resistance and progression to type 2 diabetes. Type 2 diabetes in children, characterized by insulin resistance and relative pancreatic b-cell failure due to the increased demand for insulin production, has now reached epidemic proportions. Longitudinal research on pediatric type 2 diabetes, however, is lacking because this epidemic is relatively new. Treatment of type 2 diabetes in children is focused on lifestyle modification with weight management/increased physical activity, and pharmacological management through oral medication or insulin therapy. Because children with type 2 diabetes are at risk for developing diabetes-related complications earlier in life, they need to be closely monitored for comorbidities.

Diet-induced obese mice retain endogenous leptin action.

PubMed

Ottaway, Nickki; Mahbod, Parinaz; Rivero, Belen; Norman, Lee Ann; Gertler, Arieh; D'Alessio, David A; Perez-Tilve, Diego

2015-06-02

Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. Copyright © 2015 Elsevier Inc. All rights reserved.

Fat aussie--a new Alström syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.

PubMed

Arsov, Todor; Silva, Diego G; O'Bryan, Moira K; Sainsbury, Amanda; Lee, Nicola J; Kennedy, Claire; Manji, Shehnaaz S M; Nelms, Keats; Liu, Conan; Vinuesa, Carola G; de Kretser, David M; Goodnow, Christopher C; Petrovsky, Nikolai

2006-07-01

Mutations in the human ALMS1 gene are responsible for Alström syndrome, a disorder in which key metabolic and endocrinological features include childhood-onset obesity, metabolic syndrome, and diabetes, as well as infertility. ALMS1 localizes to the basal bodies of cilia and plays a role in intracellular trafficking, but the biological functions of ALMS1 and how these relate to the pathogenesis of obesity, diabetes, and infertility remain unclear. Here we describe a new mouse model of Alström syndrome, fat aussie, caused by a spontaneous mutation in the Alms1 gene. Fat aussie (Alms1 foz/foz) mice are of normal weight when young but, by 120 d of age, they become obese and hyperinsulinemic. Diabetes develops in Alms1 foz/foz mice accompanied by pancreatic islet hyperplasia and islet cysts. Female mice are fertile before the onset of obesity and metabolic syndrome; however, male fat aussie mice are sterile due to a progressive germ cell loss followed by an almost complete block of development at the round-to-elongating spermatid stage of spermatogenesis. In conclusion, Alms1 foz/foz mouse is a new animal model in which to study the pathogenesis of the metabolic and fertility defects of Alström syndrome, including the role of ALMS1 in appetite regulation, pathogenesis of the metabolic syndrome, pancreatic islet physiology, and spermatogenesis.

Childhood obesity affects adult metabolic syndrome and diabetes.

PubMed

Liang, Yajun; Hou, Dongqing; Zhao, Xiaoyuan; Wang, Liang; Hu, Yuehua; Liu, Junting; Cheng, Hong; Yang, Ping; Shan, Xinying; Yan, Yinkun; Cruickshank, J Kennedy; Mi, Jie

2015-09-01

We seek to observe the association between childhood obesity by different measures and adult obesity, metabolic syndrome (MetS), and diabetes. Thousand two hundred and nine subjects from "Beijing Blood Pressure Cohort Study" were followed 22.9 ± 0.5 years in average from childhood to adulthood. We defined childhood obesity using body mass index (BMI) or left subscapular skinfold (LSSF), and adult obesity as BMI ≥ 28 kg/m(2). MetS was defined according to the joint statement of International Diabetes Federation and American Heart Association with modified waist circumference (≥ 90/85 cm for men/women). Diabetes was defined as fasting plasma glucose ≥ 7.0 mmol/L or blood glucose 2 h after oral glucose tolerance test ≥ 11.1 mmol/L or currently using blood glucose-lowering agents. Multiple linear and logistic regression models were used to assess the association. The incidence of adult obesity was 13.4, 60.0, 48.3, and 65.1 % for children without obesity, having obesity by BMI only, by LSSF only, and by both, respectively. Compared to children without obesity, children obese by LSSF only or by both had higher risk of diabetes. After controlling for adult obesity, childhood obesity predicted independently long-term risks of diabetes (odds ratio 2.8, 95 % confidence interval 1.2-6.3) or abdominal obesity (2.7, 1.6-4.7) other than MetS as a whole (1.2, 0.6-2.4). Childhood obesity predicts long-term risk of adult diabetes, and the effect is independent of adult obesity. LSSF is better than BMI in predicting adult diabetes.

SERPINE 1 Links Obesity and Diabetes: A Pilot Study

PubMed Central

Kaur, Punit; Reis, Michael D.; Couchman, Glen R.; Forjuoh, Samuel N.; Greene, John F.; Asea, Alexzander

2010-01-01

In the past decade there has been a dramatic increase in the number of Americans considered obese. Over this same period, the number of individuals diagnosed with diabetes has increased by over 40%. Interestingly, in a great number of cases individuals considered obese develop diabetes later on. Although a link between obesity and diabetes has been suggested, conclusive scientific evidence is thus far just beginning to emerge. The present pilot study is designed to identify a possible link between obesity and diabetes. The plasma proteome is a desirable biological sample due to their accessibility and representative complexity due, in part, to the wide dynamic range of protein concentrations, which lead to the discovery of new protein markers. Here we present the results for the specific depletion of 14 high-abundant proteins from the plasma samples of obese and diabetic patients. Comparative proteomic profiling of plasma from individuals with either diabetes or obesity and individuals with both obesity and diabetes revealed SERPINE 1 as a possible candidate protein of interest, which might be a link between obesity and diabetes. PMID:21113241

SERPINE 1 Links Obesity and Diabetes: A Pilot Study.

PubMed

Kaur, Punit; Reis, Michael D; Couchman, Glen R; Forjuoh, Samuel N; Greene, John F; Asea, Alexzander

2010-06-01

In the past decade there has been a dramatic increase in the number of Americans considered obese. Over this same period, the number of individuals diagnosed with diabetes has increased by over 40%. Interestingly, in a great number of cases individuals considered obese develop diabetes later on. Although a link between obesity and diabetes has been suggested, conclusive scientific evidence is thus far just beginning to emerge. The present pilot study is designed to identify a possible link between obesity and diabetes. The plasma proteome is a desirable biological sample due to their accessibility and representative complexity due, in part, to the wide dynamic range of protein concentrations, which lead to the discovery of new protein markers. Here we present the results for the specific depletion of 14 high-abundant proteins from the plasma samples of obese and diabetic patients. Comparative proteomic profiling of plasma from individuals with either diabetes or obesity and individuals with both obesity and diabetes revealed SERPINE 1 as a possible candidate protein of interest, which might be a link between obesity and diabetes.

Leptin Rapidly Improves Glucose Homeostasis in Obese Mice by Increasing Hypothalamic Insulin Sensitivity

PubMed Central

Koch, Christiane; Augustine, Rachael A.; Steger, Juliane; Ganjam, Goutham K.; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W.; Shepherd, Peter R.; Anderson, Greg M.; Grattan, David R.; Tups, Alexander

2013-01-01

Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lepob/ob mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes. PMID:21123564

Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.

PubMed

Koch, Christiane; Augustine, Rachael A; Steger, Juliane; Ganjam, Goutham K; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W; Shepherd, Peter R; Anderson, Greg M; Grattan, David R; Tups, Alexander

2010-12-01

Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

Diabetes Associated Metabolomic Perturbations in NOD Mice

PubMed Central

Hwang, Jessica; Poudel, Ananta; Jo, Junghyo; Periwal, Vipul; Fiehn, Oliver; Hara, Manami

2014-01-01

Non-obese diabetic (NOD) mice are a widely-used model oftype1 diabetes (T1D). However, not all animals develop overt diabetes. This study examined the circulating metabolomic profiles of NOD mice progressing or not progressing to T1D. Total beta-cell mass was quantified in the intact pancreas using transgenic NOD mice expressinggreen fluorescent protein under the control of mouse insulin I promoter.While both progressor and non-progressor animals displayed lymphocyte infiltration and endoplasmic reticulum stress in the pancreas tissue;overt T1D did not develop until animals lost ~70% of the total beta-cell mass.Gas chromatography time of flight mass spectrometry (GC-TOF) was used to measure >470 circulating metabolites in male and female progressor and non-progressor animals (n=76) across a wide range of ages (neonates to >40-wk).Statistical and multivariate analyses were used to identify age and sex independent metabolic markers which best differentiated progressor and non-progressor animals’ metabolic profiles. Key T1D-associated perturbations were related with: (1) increased plasma glucose and reduced 1,5-anhydroglucitol markers of glycemic control; (2) increased allantoin, gluconic acid and nitric oxide-derived saccharic acid markers of oxidative stress; (3) reduced lysine, an insulin secretagogue; (4) increased branched-chain amino acids, isoleucine and valine; (5) reduced unsaturated fatty acids including arachidonic acid; and (6)perturbations in urea cycle intermediates suggesting increased arginine-dependent NO synthesis. Together these findings highlight the strength of the unique approach of comparing progressor and non-progressor NOD mice to identify metabolic perturbations involved in T1D progression. PMID:25755629

Smad3 Deficiency in Mice Protects Against Insulin Resistance and Obesity Induced by a High-Fat Diet

PubMed Central

Tan, Chek Kun; Leuenberger, Nicolas; Tan, Ming Jie; Yan, Yew Wai; Chen, Yinghui; Kambadur, Ravi; Wahli, Walter; Tan, Nguan Soon

2011-01-01

OBJECTIVE Obesity and associated pathologies are major global health problems. Transforming growth factor-β/Smad3 signaling has been implicated in various metabolic processes, including adipogenesis, insulin expression, and pancreatic β-cell function. However, the systemic effects of Smad3 deficiency on adiposity and insulin resistance in vivo remain elusive. This study investigated the effects of Smad3 deficiency on whole-body glucose and lipid homeostasis and its contribution to the development of obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS We compared various metabolic profiles of Smad3-knockout and wild-type mice. We also determined the mechanism by which Smad3 deficiency affects the expression of genes involved in adipogenesis and metabolism. Mice were then challenged with a high-fat diet to study the impact of Smad3 deficiency on the development of obesity and insulin resistance. RESULTS Smad3-knockout mice exhibited diminished adiposity with improved glucose tolerance and insulin sensitivity. Chromatin immunoprecipitation assay revealed that Smad3 deficiency increased CCAAT/enhancer-binding protein β-C/EBP homologous protein 10 interaction and exerted a differential regulation on proliferator-activated receptor β/δ and proliferator-activated receptor γ expression in adipocytes. Focused gene expression profiling revealed an altered expression of genes involved in adipogenesis, lipid accumulation, and fatty acid β-oxidation, indicative of altered adipose physiology. Despite reduced physical activity with no modification in food intake, these mutant mice were resistant to obesity and insulin resistance induced by a high-fat diet. CONCLUSIONS Smad3 is a multifaceted regulator in adipose physiology and the pathogenesis of obesity and type 2 diabetes, suggesting that Smad3 may be a potential target for the treatment of obesity and its associated disorders. PMID:21270259

Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence

PubMed Central

Farnsworth, Christopher W.; Schott, Eric M.; Jensen, Sarah E.; Zukoski, Jacob; Benvie, Abigail M.; Refaai, Majed A.; Kates, Stephen L.; Schwarz, Edward M.; Zuscik, Michael J.; Gill, Steven R.

2017-01-01

ABSTRACT Obesity and associated type 2 diabetes (T2D) are important risk factors for infection following orthopedic implant surgery. Staphylococcus aureus, the most common pathogen in bone infections, adapts to multiple environments to survive and evade host immune responses. Whether adaptation of S. aureus to the unique environment of the obese/T2D host accounts for its increased virulence and persistence in this population is unknown. Thus, we assessed implant-associated osteomyelitis in normal versus high-fat-diet obese/T2D mice and found that S. aureus infection was more severe, including increases in bone abscesses relative to nondiabetic controls. S. aureus isolated from bone of obese/T2D mice displayed marked upregulation of four adhesion genes (clfA, clfB, bbp, and sdrC), all with binding affinity for fibrin(ogen). Immunostaining of infected bone revealed increased fibrin deposition surrounding bacterial abscesses in obese/T2D mice. In vitro coagulation assays demonstrated a hypercoagulable state in obese/T2D mice that was comparable to that of diabetic patients. S. aureus with an inactivating mutation in clumping factor A (clfA) showed a reduction in bone infection severity that eliminated the effect of obesity/T2D, while infections in control mice were unchanged. In infected mice that overexpress plasminogen activator inhibitor-1 (PAI-1), S. aureus clfA expression and fibrin-encapsulated abscess communities in bone were also increased, further linking fibrin deposition to S. aureus expression of clfA and infection severity. Together, these results demonstrate an adaptation by S. aureus to obesity/T2D with increased expression of clfA that is associated with the hypercoagulable state of the host and increased virulence of S. aureus. PMID:28320836

Effects of Korean red ginseng (Panax ginseng) on obesity and adipose inflammation in ovariectomized mice.

PubMed

Lee, Hyunghee; Choi, Jeonghyun; Shin, Soon Shik; Yoon, Michung

2016-02-03

Korean red ginseng (ginseng, Panax ginseng C.A. Meyer) is a famous traditional drug used in Korea for the treatment and prevention of obesity, type 2 diabetes, cancer, and liver and cardiovascular diseases. Menopause is strongly associated with many of the aforementioned metabolic diseases and increased visceral obesity. The aims of this study were to investigate whether ginseng inhibits obesity and related disorders in ovariectomized (OVX) C57BL/6J mice, which is a mouse model of postmenopausal women, and to determine the mechanism of action involved in this process. After OVX mice were treated with 5% (w/w) ginseng for 15 weeks, we determined the effects of ginseng on obesity and adipose inflammation, angiogenesis, metalloproteinase (MMP) activity and metabolic parameters. OVX mice had higher body weight, adipose tissue mass and adipocyte size when fed a high fat diet (HFD) compared with HFD-fed sham-operated mice. All of these parameters were significantly reduced in OVX mice fed a HFD supplemented with ginseng. Ginseng treatment also decreased blood vessel density, MMP activity, and mRNA levels of angiogenic factors (e.g., VEGF-A and FGF-2) and MMPs (e.g., MMP-2 and MMP-9) in adipose tissues of OVX mice. Infiltrating inflammatory cells and expression of inflammatory cytokines (e.g., CD68, TNFα and MCP-1) in adipose tissue were reduced by ginseng. Ginseng not only reduced the circulating levels of free fatty acids and triglycerides, but also normalized hyperinsulinemia and hyperglycemia in OVX mice. Hepatic lipid droplets were almost completely abolished by ginseng. These results suggest that ginseng inhibited ovariectomy-induced obesity, adiposity, and adipocyte hypertrophy by modulating angiogenesis and MMP activity. Ginseng also suppressed adipose inflammation, insulin resistance, and hepatic steatosis in OVX mice. Thus, it is likely that ginseng may be a promising drug for the prevention and treatment of obesity and related disorders in obese postmenopausal

Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability.

PubMed

Cani, P D; Possemiers, S; Van de Wiele, T; Guiot, Y; Everard, A; Rottier, O; Geurts, L; Naslain, D; Neyrinck, A; Lambert, D M; Muccioli, G G; Delzenne, N M

2009-08-01

Obese and diabetic mice display enhanced intestinal permeability and metabolic endotoxaemia that participate in the occurrence of metabolic disorders. Our recent data support the idea that a selective increase of Bifidobacterium spp. reduces the impact of high-fat diet-induced metabolic endotoxaemia and inflammatory disorders. Here, we hypothesised that prebiotic modulation of gut microbiota lowers intestinal permeability, by a mechanism involving glucagon-like peptide-2 (GLP-2) thereby improving inflammation and metabolic disorders during obesity and diabetes. Study 1: ob/ob mice (Ob-CT) were treated with either prebiotic (Ob-Pre) or non-prebiotic carbohydrates as control (Ob-Cell). Study 2: Ob-CT and Ob-Pre mice were treated with GLP-2 antagonist or saline. Study 3: Ob-CT mice were treated with a GLP-2 agonist or saline. We assessed changes in the gut microbiota, intestinal permeability, gut peptides, intestinal epithelial tight-junction proteins ZO-1 and occludin (qPCR and immunohistochemistry), hepatic and systemic inflammation. Prebiotic-treated mice exhibited a lower plasma lipopolysaccharide (LPS) and cytokines, and a decreased hepatic expression of inflammatory and oxidative stress markers. This decreased inflammatory tone was associated with a lower intestinal permeability and improved tight-junction integrity compared to controls. Prebiotic increased the endogenous intestinotrophic proglucagon-derived peptide (GLP-2) production whereas the GLP-2 antagonist abolished most of the prebiotic effects. Finally, pharmacological GLP-2 treatment decreased gut permeability, systemic and hepatic inflammatory phenotype associated with obesity to a similar extent as that observed following prebiotic-induced changes in gut microbiota. We found that a selective gut microbiota change controls and increases endogenous GLP-2 production, and consequently improves gut barrier functions by a GLP-2-dependent mechanism, contributing to the improvement of gut barrier functions

IL-33 induces protective effects in adipose tissue inflammation during obesity in mice

PubMed Central

Miller, Ashley M.; Asquith, Darren L.; Hueber, Axel J.; Anderson, Lesley A.; Holmes, William M.; McKenzie, Andrew N.; Xu, Damo; Sattar, Naveed; McInnes, Iain B.; Liew, Foo Y.

2014-01-01

Rationale Chronic low-grade inflammation involving adipose tissue likely contributes to the metabolic consequences of obesity. The cytokine IL-33 and its receptor ST2 are expressed in adipose tissue but their role in adipose tissue inflammation during obesity is unclear. Objective To examine the functional role of IL-33 in adipose tissues, and investigate the effects on adipose tissue inflammation and obesity in vivo. Methods and Results We demonstrate that treatment of adipose tissue cultures in vitro with IL-33 induced production of Th2 cytokines (IL-5, IL-13, IL-10), and reduced expression of adipogenic and metabolic genes. Administration of recombinant IL-33 to genetically obese diabetic (ob/ob) mice led to reduced adiposity, reduced fasting glucose and improved glucose and insulin tolerance. IL-33 also induced accumulation of Th2 cells in adipose tissue and polarization of adipose tissue macrophages towards an M2 alternatively activated phenotype (CD206+), a lineage associated with protection against obesity-related metabolic events. Furthermore, mice lacking endogenous ST2 fed HFD had increased body weight and fat mass, impaired insulin secretion and glucose regulation compared to WT controls fed HFD. Conclusions In conclusion, IL-33 may play a protective role in the development of adipose tissue inflammation during obesity. PMID:20634488

Structure-guided design of an invariant natural killer T cell agonist for optimum protection from type 1 diabetes in non-obese diabetic mice

PubMed Central

Blumenfeld, H J; Tohn, R; Haeryfar, S M M; Liu, Y; Savage, P B; Delovitch, T L

2011-01-01

Because invariant natural killer T (iNK T) cells link innate and adaptive immunity, the structure-dependent design of iNK T cell agonists may have therapeutic value as vaccines for many indications, including autoimmune disease. Previously, we showed that treatment of non-obese diabetic (NOD) mice with the iNK T cell activating prototypic glycolipid α-galactosylceramide (α-GalCer) protects them from type 1 diabetes (T1D). However, α-GalCer is a strong agonist that can hyperactivate iNK T cells, elicit several side effects and has shown only limited success in clinical trials. Here, we used a structure-guided design approach to identify an iNK T cell agonist that optimally protects from T1D with minimal side effects. Analyses of the kinetics and function of a panel of synthetic α-GalCer fatty acyl chain derivatives (C8:0-C16:0) were performed in NOD mice. C16:0 elicited the highest protection from insulitis and T1D, which was associated with a higher frequency and survival of iNK T cells and enhanced activity of tolerogenic dendritic cells (DCs) in draining pancreatic lymph nodes (PLN), inability to transactivate NK cells and a more rapid kinetics of induction and recovery of iNK T cells from anergy. We conclude that the length and structure of the acyl chain of α-GalCer regulates the level of protection against T1D in mice, and propose that the extent of this protection depends on the relative capacity of the acyl chain to accommodate an endogenous spacer lipid of appropriate length and structure. Thus, our findings with the α-GalCer C16:0 derivative suggest strongly that it be considered as a lead glycolipid candidate in clinical trials of T1D. PMID:21910729

Assessment of gastric emptying in non-obese diabetic mice using a [13C]-octanoic acid breath test.

PubMed

Creedon, Christopher T; Verhulst, Pieter-Jan; Choi, Kyoung M; Mason, Jessica E; Linden, David R; Szurszewski, Joseph H; Gibbons, Simon J; Farrugia, Gianrico

2013-03-23

Gastric emptying studies in mice have been limited by the inability to follow gastric emptying changes in the same animal since the most commonly used techniques require killing of the animals and postmortem recovery of the meal(1,2). This approach prevents longitudinal studies to determine changes in gastric emptying with age and progression of disease. The commonly used [(13)C]-octanoic acid breath test for humans(3) has been modified for use in mice(4-6) and rats(7) and we previously showed that this test is reliable and responsive to changes in gastric emptying in response to drugs and during diabetic disease progression(8). In this video presentation the principle and practical implementation of this modified test is explained. As in the previous study, NOD LtJ mice are used, a model of type 1 diabetes(9). A proportion of these mice develop the symptoms of gastroparesis, a complication of diabetes characterized by delayed gastric emptying without mechanical obstruction of the stomach(10). This paper demonstrates how to train the mice for testing, how to prepare the test meal and obtain 4 hr gastric emptying data and how to analyze the obtained data. The carbon isotope analyzer used in the present study is suitable for the automatic sampling of the air samples from up to 12 mice at the same time. This technique allows the longitudinal follow-up of gastric emptying from larger groups of mice with diabetes or other long-standing diseases.

Sodium meta-arsenite prevents the development of autoimmune diabetes in NOD mice

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

Lee, Y.S.; Kim, D.; Lee, E.K.

Sodium meta-arsenite (SA) is an orally available arsenic compound. We investigated the effects of SA on the development of autoimmune type 1 diabetes. Female non-obese diabetic (NOD) mice were orally intubated with SA (5 mg/kg/day) from 8 weeks of age for 8 weeks. The cumulative incidence of diabetes was monitored until 30 weeks of age, islet histology was examined, and lymphocytes including T cells, B cells, CD4+ IFN-γ+ cells, CD8+ IFN-γ+ cells, CD4+ IL-4+ cells, and regulatory T cells were analyzed. We also investigated the diabetogenic ability of splenocytes using an adoptive transfer model and the effect of SA onmore » the proliferation, activation, and expression of glucose transporter 1 (Glut1) in splenocytes treated with SA in vitro and splenocytes isolated from SA-treated mice. SA treatment decreased the incidence of diabetes and delayed disease onset. SA treatment reduced the infiltration of immunocytes in islets, and splenocytes from SA-treated mice showed a reduced ability to transfer diabetes. The number of total splenocytes and T cells and both the number and the proportion of CD4+ IFN-γ+ and CD8+ IFN-γ+ T cells in the spleen were significantly reduced in SA-treated NOD mice compared with controls. The number, but not the proportion, of regulatory T cells was decreased in SA-treated NOD mice. Treatment with SA either in vitro or in vivo inhibited proliferation of splenocytes. In addition, the expression of Glut1 and phosphorylated ERK1/2 was decreased by SA treatment. These results suggest that SA reduces proliferation and activation of T cells, thus preventing autoimmune diabetes in NOD mice. - Highlights: • SA prevents the development of diabetes and delays the age of onset in NOD mice. • SA decreases the number but not the proportion of T lymphocytes in NOD mice. • SA reduces IFN-γ-producing T lymphocytes in NOD mice. • SA reduces proliferation and activation of T lymphocytes in vitro and in vivo. • SA reduces the expression of

Serum N(1)-Methylnicotinamide Is Associated With Obesity and Diabetes in Chinese.

PubMed

Liu, Ming; Li, Lihua; Chu, Jihong; Zhu, Boyu; Zhang, Qingtao; Yin, Xueyan; Jiang, Weimin; Dai, Guoliang; Ju, Wenzheng; Wang, Zhenxing; Yang, Qin; Fang, Zhuyuan

2015-08-01

Nicotinamide N-methyltransferase (NNMT) is a novel histone methylation modulator that regulates energy metabolism, and NNMT knockdown prevents diet-induced obesity in mice. However, whether NNMT plays a role in human obesity and type 2 diabetes (T2DM) remains to be elucidated. NNMT catalyzes methylation of nicotinamide to generate N(1)-methylnicotinamide (me-NAM). We aimed to investigate the associations of serum me-NAM with obesity and T2DM in Chinese. The study subjects (n = 1160) were recruited from Dali, a city of Yunnan Province, in southwest China. Anthropometric phenotypes, fasting glucose, and serum lipids were measured. Serum me-NAM was measured by liquid chromatography-mass spectrometry. Serum me-NAM was positively correlated with body mass index and waist circumference and negatively with high-density lipoprotein (P ≤ .03). The correlations remained highly significant in the multivariate adjusted correlation analyses. In men (n = 691), positive correlations between me-NAM and fasting glucose, low-density lipoprotein, liver function, and serum creatinine levels were also observed in both simple and multivariate adjusted correlation analyses. In multiple logistic regression analyses, elevated serum me-NAM was associated with higher risks for overweight/obesity (odds ratios, 2.36 and 5.78; 95% confidence intervals, 1.10-5.08 and 1.78-18.76 for men and women, respectively; P ≤ .03) and diabetes (odds ratios, 1.56 and 1.86; 95% confidence intervals, 1.10-2.22 and 1.05-3.31 for men and women, respectively; P ≤ .03). This first large-scale population study shows that me-NAM, as an indicator of NNMT activity, is strongly associated with obesity and diabetes, supporting NNMT as a potential target for treating obesity and diabetes in humans.

Dynamics of Diabetes and Obesity: Epidemiological Perspective

PubMed Central

Boles, Annette; Kandimalla, Ramesh; Reddy, P. Hemachandra

2017-01-01

The purpose of this review article is to understand the current literature on obesity, diabetes and therapeutic avenues across the world. Diabetes is a chronic lifestyle condition that affects millions of people worldwide and it is a major health concern in our society. Diabetes and obesity are associated with various conditions, including non-modifiable and modifiable risk factors. Early detectable markers are not well established to detect pre-diabetes and as a result, it becomes diabetes. Several published epidemiological studies were assessed and the findings were summarized. Resources from published studies were used to identify criteria used for pre-diabetes, the role of diet in pre-diabetics and potential risks and characteristics associated with pre-diabetes. Preventive strategies are needed to combat diabetes. Individuals diagnosed with pre-diabetes need detailed education, need to fully understand the risk factors and have the ability to manage diabetes. Interventions exist that include chronic disease self-management programs, lifestyle interventions and pharmacological strategies. Obesity plays a large role in causing pre-diabetes and diabetes. Critical analysis of existing epidemiological research data suggests that additional research is needed to determine the efficacy of interventions. PMID:28130199

Serum trace elements in obese women with or without diabetes

PubMed Central

Yerlikaya, F. Hümeyra; Toker, Aysun; Arıbaş, Alpay

2013-01-01

Background & objectives: Relationship of trace elements with obesity and diabetes is complex, alterations in their metabolism can be induced by the diseases and their complications. To study the role of the trace elements in diabetes and obesity, serum trace elements levels (Cr, Se, Fe, Zn, Cu and Mn) were measured in obese women with or without diabetes as well as healthy women. Further, correlation between serum trace elements levels and glucose, insulin, homeostasis model assessment (HOMA-IR), glycated haemoglobin (HbA1c), body mass index (BMI), waist circumferences, waist -to -hip ratio and high-sensitivity C-reactive protein(hsCRP) were also determined in these women. Methods: This study was performed with morbidly obese (BMI >40 kg/m2) women with diabetes (n=41), without diabetes (n=45) and 50 healthly non obese women. Anthropometric measurements were taken and levels of serum Zn, Cr, Fe Cu and Mn were determined. Biochemical parameters included serum glucose, insulin, lipids, haemoglobin, hsCRP and HbA1C. Results: The levels of Zn (P<0.001), Mn (P<0.05), Fe (P<0.05) were significantly lower and the level of Cu (P<0.001) and Cu / Zn ratio (P<0.05) were significantly higher in the diabetic obese women than those of the healthy women. Also, the levels of Zn and Fe were significantly lower and the levels of Cu were significantly higher in the non diabetic obese women than those of the healthy group. Serum Zn levels negatively and serum Cu levels positively correlated with anthropometric values in diabetic and non diabetic obese women. Further, serum Zn, Mn and Cr levels negatively correlated and serum Se levels positively correlated glycaemia control parameters in diabetic obese women. In addition, serum Zn levels negatively correlated with hsCRP in diabetic and nondiabetic obese females. Interpretation & conclusions: Our findings showed significant association between Zn and Fe deficiencies and obesity. Also, obese women with diabetes may be at a greater risk

Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation

PubMed Central

Dong, Huansheng; Huang, Hu; Yun, Xinxu; Kim, Do-sung; Yue, Yinan; Wu, Hongju; Sutter, Alton; Chavin, Kenneth D.; Otterbein, Leo E.; Adams, David B.; Kim, Young-Bum

2014-01-01

Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-α, IL-1β, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties. PMID

Enhanced anorexigenic signaling in lean obesity resistant syndecan-3 null mice

PubMed Central

Zheng, Qiao; Zhu, Jinling; Shanabrough, Marya; Borok, Erzsebet; Benoit, Stephen C.; Horvath, Tamas L.; Clegg, Deborah J.; Reizes, Ofer

2010-01-01

Obesity is associated with increased risk of diabetes, cardiovascular disease and several types of cancers. The hypothalamus is a region of the brain critical in the regulation of body weight. One of the critical and best studied hypothalamic circuits is comprised of the melanocortinergic orexigenic agouti -related protein (AgRP) and anorexigenic α-melanocyte stimulating hormone (α-MSH) neurons. These neurons project axons to the same hypothalamic target neurons and balance each other’s activity leading to body weight regulation. We previously showed that the brain proteoglycan syndecan-3 regulates feeding behavior and body weight, and syndecan-3 null (SDC-3−/−) mice are lean and obesity resistant. Here we show that the melanocortin agonist MTII potently suppresses food intake and activates the hypothalamic paraventricular nuclei (PVN) in SDC-3−/− mice based on c-fos immunoreactivity. Interestingly, we determined that the AgRP neuropeptide is reduced in the PVN of SDC-3−/− mice compared to wild type mice. In contrast, neuropeptide Y, coexpressed in the AgRP neuron, is not differentially expressed nor is the counteracting neuropeptide αMSH. These findings are unprecedented and indicate that AgRP protein localization can be selectively regulated within the hypothalamus resulting in altered neuropeptide response and tone. PMID:20923696

Exercise Improves Host Response to Influenza Viral Infection in Obese and Non-Obese Mice through Different Mechanisms

PubMed Central

Warren, Kristi J.; Olson, Molly M.; Thompson, Nicholas J.; Cahill, Mackenzie L.; Wyatt, Todd A.; Yoon, Kyoungjin J.; Loiacono, Christina M.; Kohut, Marian L.

2015-01-01

Obesity has been associated with greater severity of influenza virus infection and impaired host defense. Exercise may confer health benefits even when weight loss is not achieved, but it has not been determined if regular exercise improves immune defense against influenza A virus (IAV) in the obese condition. In this study, diet-induced obese mice and lean control mice exercised for eight weeks followed by influenza viral infection. Exercise reduced disease severity in both obese and non-obese mice, but the mechanisms differed. Exercise reversed the obesity-associated delay in bronchoalveolar-lavage (BAL) cell infiltration, restored BAL cytokine and chemokine production, and increased ciliary beat frequency and IFNα-related gene expression. In non-obese mice, exercise treatment reduced lung viral load, increased Type-I-IFN-related gene expression early during infection, but reduced BAL inflammatory cytokines and chemokines. In both obese and non-obese mice, exercise increased serum anti-influenza virus specific IgG2c antibody, increased CD8+ T cell percentage in BAL, and reduced TNFα by influenza viral NP-peptide-responding CD8+ T cells. Overall, the results suggest that exercise “restores” the immune response of obese mice to a phenotype similar to non-obese mice by improving the delay in immune activation. In contrast, in non-obese mice exercise treatment results in an early reduction in lung viral load and limited inflammatory response. PMID:26110868

Hepatic gluconeogenesis and the activity of PDH in individual tissues of GTG-obese mice following adrenalectomy.

PubMed

Blair, S C; Greenaway, T M; Bryson, J M; Phuyal, J L; Wensley, V R; Caterson, I D; Cooney, G J

1996-07-01

Adrenalectomy (ADX) lowers circulating glucose levels in animal models of non-insulin dependent diabetes (NIDDM) and obesity. To investigate the role of hepatic glucose production (HGP) and tissue glucose oxidation in the improvement in glucose tolerance, hepatocyte gluconeogenesis and the activity of pyruvate dehydrogenase (PDH) were examined in different tissues of gold thioglucose (GTG) obese mice 2 weeks after ADX or sham ADX. GTG-obese mice which had undergone ADX weighed significantly less than their adrenal intact counterparts (GTG ADX: 37.5 +/- 0.7 g; GTG: 44.1 +/- 0.4; p < 0.05), and demonstrated lower serum glucose (GTG ADX: 22.5 +/- 1.6 mmol/L; GTG: 29.4 +/- 1.9 mmol/L; p < 0.05) and serum insulin levels (GTG ADX: 76 +/- 10 microU/mL; GTG: 470 +/- 63 microU/mL; p < 0.05). Lactate conversion to glucose by hepatocytes isolated from ADX GTG mice was significantly reduced compared with that of hepatocytes from GTG mice (GTG ADX: 125 +/- 10 nmol glucose/10(6) cells; GTG: 403 +/- 65 nmol glucose/10(6) cells; p < 0.05). ADX also significantly reduced both the glycogen (GTG ADX: 165 +/- 27 mumol/liver; GTG: 614 +/- 60 mumol/liver; p < 0.05) and fatty acid content (GTG ADX: 101 +/- 9 mg fatty acid/g liver; GTG: 404 +/- 40 mg fatty acid/g liver; p < 0.05) of the liver of GTG-obese mice. ADX of GTG-obese mice reduced PDH activity by varying degrees in all tissues, except quadriceps muscle. These observations are consistent with an ADX induced decrease in hepatic lipid stores removing fatty acid-induced increases in gluconeogenesis and increased peripheral availability of fatty acids inhibiting PDH activity via the glucose/fatty acid cycle. It is also evident that the improvement in glucose tolerance which accompanies ADX of GTG-obese mice is not due to increased PDH activity resulting in enhanced peripheral glucose oxidation. Instead, it is more likely that reduced blood glucose levels after ADX of GTG-obese mice are the result of decreased gluconeogenesis in the

The importance of the Non Obese Diabetic (NOD) mouse model in autoimmune diabetes

PubMed Central

Pearson, James A; Wong, F. Susan; Wen, Li

2016-01-01

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the pancreatic infiltration of immune cells resulting in T cell-mediated destruction of the insulin-producing beta cells. The successes of the Non Obese Diabetic (NOD) mouse model have come in multiple forms including identifying key genetic and environmental risk factors e.g. Idd loci and effects of microorganisms including the gut microbiota, respectively, and how they may contribute to disease susceptibility and pathogenesis. Furthermore, the NOD model also provides insights into the roles of the innate immune cells as well as the B cells in contributing to the T cell-mediated disease. Unlike many autoimmune disease models, the NOD mouse develops spontaneous disease and has many similarities to human T1D. Through exploiting these similarities many targets have been identified for immune-intervention strategies. Although many of these immunotherapies did not have a significant impact on human T1D, they have been shown to be effective in the NOD mouse in early stage disease, which is not equivalent to trials in newly-diagnosed patients with diabetes. However, the continued development of humanized NOD mice would enable further clinical developments, bringing T1D research to a new translational level. Therefore, it is the aim of this review to discuss the importance of the NOD model in identifying the roles of the innate immune system and the interaction with the gut microbiota in modifying diabetes susceptibility. In addition, the role of the B cells will also be discussed with new insights gained through B cell depletion experiments and the impact on translational developments. Finally, this review will also discuss the future of the NOD mice and the development of humanized NOD mice, providing novel insights into human T1D. PMID:26403950

Increasing Muscle Mass Improves Vascular Function in Obese (db/db) Mice

PubMed Central

Qiu, Shuiqing; Mintz, James D.; Salet, Christina D.; Han, Weihong; Giannis, Athanassios; Chen, Feng; Yu, Yanfang; Su, Yunchao; Fulton, David J.; Stepp, David W.

2014-01-01

Background A sedentary lifestyle is an independent risk factor for cardiovascular disease and exercise has been shown to ameliorate this risk. Inactivity is associated with a loss of muscle mass, which is also reversed with isometric exercise training. The relationship between muscle mass and vascular function is poorly defined. The aims of the current study were to determine whether increasing muscle mass by genetic deletion of myostatin, a negative regulator of muscle growth, can influence vascular function in mesenteric arteries from obese db/db mice. Methods and Results Myostatin expression was elevated in skeletal muscle of obese mice and associated with reduced muscle mass (30% to 50%). Myostatin deletion increased muscle mass in lean (40% to 60%) and obese (80% to 115%) mice through increased muscle fiber size (P<0.05). Myostatin deletion decreased adipose tissue in lean mice, but not obese mice. Markers of insulin resistance and glucose tolerance were improved in obese myostatin knockout mice. Obese mice demonstrated an impaired endothelial vasodilation, compared to lean mice. This impairment was improved by superoxide dismutase mimic Tempol. Deletion of myostatin improved endothelial vasodilation in mesenteric arteries in obese, but not in lean, mice. This improvement was blunted by nitric oxide (NO) synthase inhibitor l‐NG‐nitroarginine methyl ester (l‐NAME). Prostacyclin (PGI2)‐ and endothelium‐derived hyperpolarizing factor (EDHF)‐mediated vasodilation were preserved in obese mice and unaffected by myostatin deletion. Reactive oxygen species) was elevated in the mesenteric endothelium of obese mice and down‐regulated by deletion of myostatin in obese mice. Impaired vasodilation in obese mice was improved by NADPH oxidase inhibitor (GKT136901). Treatment with sepiapterin, which increases levels of tetrahydrobiopterin, improved vasodilation in obese mice, an improvement blocked by l‐NAME. Conclusions Increasing muscle mass by genetic

High fat diet attenuates hyperglycemia, body composition changes, and bone loss in male streptozotocin-induced type 1 diabetic mice.

PubMed

Carvalho, Adriana Lelis; DeMambro, Victoria E; Guntur, Anyonya R; Le, Phuong; Nagano, Kenichi; Baron, Roland; de Paula, Francisco José Albuquerque; Motyl, Katherine J

2018-02-01

There is a growing and alarming prevalence of obesity and the metabolic syndrome in type I diabetic patients (T1DM), particularly in adolescence. In general, low bone mass, higher fracture risk, and increased marrow adipose tissue (MAT) are features of diabetic osteopathy in insulin-deficient subjects. On the other hand, type 2 diabetes (T2DM) is associated with normal or high bone mass, a greater risk of peripheral fractures, and no change in MAT. Therefore, we sought to determine the effect of weight gain on bone turnover in insulin-deficient mice. We evaluated the impact of a 6-week high-fat (HFD) rich in medium chain fatty acids or low-fat diet (LFD) on bone mass and MAT in a streptozotocin (STZ)-induced model using male C57BL/6J mice at 8 weeks of age. Dietary intervention was initiated after diabetes confirmation. At the endpoint, lower non-fasting glucose levels were observed in diabetic mice fed with high fat diet compared to diabetic mice fed the low fat diet (STZ-LFD). Compared to euglycemic controls, the STZ-LFD had marked polydipsia and polyphagia, as well as reduced lean mass, fat mass, and bone parameters. Interestingly, STZ-HFD mice had higher bone mass, namely less cortical bone loss and more trabecular bone than STZ-LFD. Thus, we found that a HFD, rich in medium chain fatty acids, protects against bone loss in a T1DM mouse model. Whether this may also translate to T1DM patients who are overweight or obese in respect to maintenance of bone mass remains to be determined through longitudinal studies. © 2017 Wiley Periodicals, Inc.

Plasminogen activator inhibitor-1 deficiency ameliorates insulin resistance and hyperlipidemia but not bone loss in obese female mice.

PubMed

Tamura, Yukinori; Kawao, Naoyuki; Yano, Masato; Okada, Kiyotaka; Matsuo, Osamu; Kaji, Hiroshi

2014-05-01

We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is involved in type 1 diabetic bone loss in female mice. PAI-1 is well known as an adipogenic factor induced by obesity. We therefore examined the effects of PAI-1 deficiency on bone and glucose and lipid metabolism in high-fat and high-sucrose diet (HF/HSD)-induced obese female mice. Female wild-type (WT) and PAI-1-deficient mice were fed with HF/HSD or normal diet for 20 weeks from 10 weeks of age. HF/HSD increased the levels of plasma PAI-1 in WT mice. PAI-1 deficiency suppressed the levels of blood glucose, plasma insulin, and total cholesterol elevated by obesity. Moreover, PAI-1 deficiency improved glucose intolerance and insulin resistance induced by obesity. Bone mineral density (BMD) at trabecular bone as well as the levels of osterix, alkaline phosphatase, and receptor activator of nuclear factor κB ligand mRNA in tibia were decreased by HF/HSD in WT mice, and those changes by HF/HSD were not affected by PAI-1 deficiency. HF/HSD increased the levels of plasma TNF-α in both WT and PAI-1-deficient mice, and the levels of plasma TNF-α were negatively correlated with trabecular BMD in tibia of female mice. In conclusion, we revealed that PAI-1 deficiency does not affect the trabecular bone loss induced by obesity despite the amelioration of insulin resistance and hyperlipidemia in female mice. Our data suggest that the changes of BMD and bone metabolism by obesity might be independent of PAI-1 as well as glucose and lipid metabolism.

Sodium Meta-Arsenite Ameliorates Hyperglycemia in Obese Diabetic db/db Mice by Inhibition of Hepatic Gluconeogenesis

PubMed Central

Lee, Eun-Kyu; Oh, Hyun-Hee; Choi, Cheol Soo; Kim, Sujong; Jun, Hee-Sook

2014-01-01

Sodium meta-arsenite (SA) is implicated in the regulation of hepatic gluconeogenesis-related genes in vitro; however, the effects in vivo have not been studied. We investigated whether SA has antidiabetic effects in a type 2 diabetic mouse model. Diabetic db/db mice were orally intubated with SA (10 mg kg−1 body weight/day) for 8 weeks. We examined hemoglobin A1c (HbA1c), blood glucose levels, food intake, and body weight. We performed glucose, insulin, and pyruvate tolerance tests and analyzed glucose production and the expression of gluconeogenesis-related genes in hepatocytes. We analyzed energy metabolism using a comprehensive animal metabolic monitoring system. SA-treated diabetic db/db mice had reduced concentrations of HbA1c and blood glucose levels. Exogenous glucose was quickly cleared in glucose tolerance tests. The mRNA expressions of genes for gluconeogenesis-related enzymes, glucose 6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase (PEPCK) were significantly reduced in the liver of SA-treated diabetic db/db mice. In primary hepatocytes, SA treatment decreased glucose production and the expression of G6Pase, PEPCK, and hepatocyte nuclear factor 4 alpha (HNF-4α) mRNA. Small heterodimer partner (SHP) mRNA expression was increased in hepatocytes dependent upon the SA concentration. The expression of Sirt1 mRNA and protein was reduced, and acetylated forkhead box protein O1 (FoxO1) was induced by SA treatment in hepatocytes. In addition, SA-treated diabetic db/db mice showed reduced energy expenditure. Oral intubation of SA ameliorates hyperglycemia in db/db mice by reducing hepatic gluconeogenesis through the decrease of Sirt1 expression and increase in acetylated FoxO1. PMID:25610880

Obesity-Associated Alterations in Inflammation, Epigenetics, and Mammary Tumor Growth Persist in Formerly Obese Mice.

PubMed

Rossi, Emily L; de Angel, Rebecca E; Bowers, Laura W; Khatib, Subreen A; Smith, Laura A; Van Buren, Eric; Bhardwaj, Priya; Giri, Dilip; Estecio, Marcos R; Troester, Melissa A; Hair, Brionna Y; Kirk, Erin L; Gong, Ting; Shen, Jianjun; Dannenberg, Andrew J; Hursting, Stephen D

2016-05-01

Using a murine model of basal-like breast cancer, we tested the hypothesis that chronic obesity, an established breast cancer risk and progression factor in women, induces mammary gland epigenetic reprogramming and increases mammary tumor growth. Moreover, we assessed whether the obesity-induced epigenetic and protumor effects are reversed by weight normalization. Ovariectomized female C57BL/6 mice were fed a control diet or diet-induced obesity (DIO) regimen for 17 weeks, resulting in a normal weight or obese phenotype, respectively. Mice on the DIO regimen were then randomized to continue the DIO diet or were switched to the control diet, resulting in formerly obese (FOb) mice with weights comparable with control mice. At week 24, all mice were orthotopically injected with MMTV-Wnt-1 mouse mammary tumor cells. Mean tumor volume, serum IL6 levels, expression of proinflammatory genes in the mammary fat pad, and mammary DNA methylation profiles were similar in DIO and FOb mice and higher than in controls. Many of the genes found to have obesity-associated hypermethylation in mice were also found to be hypermethylated in the normal breast tissue of obese versus nonobese human subjects, and nearly all of these concordant genes remained hypermethylated after significant weight loss in the FOb mice. Our findings suggest that weight normalization may not be sufficient to reverse the effects of chronic obesity on epigenetic reprogramming and inflammatory signals in the microenvironment that are associated with breast cancer progression. Cancer Prev Res; 9(5); 339-48. ©2016 AACR. ©2016 American Association for Cancer Research.

Effects of a treatment with Se-rich rice flour high in resistant starch on enteric dysbiosis and chronic inflammation in diabetic ICR mice.

PubMed

Yuan, Huaibo; Wang, Wenjuan; Chen, Deyi; Zhu, Xiping; Meng, Lina

2017-05-01

Enteric dysbiosis is associated with chronic inflammation and interacts with obesity and insulin resistance. Obesity and diabetes are induced in ICR (Institute of Cancer Research) mice fed a high-fat diet and administered a streptozocin injection. These mice were treated with normal rice (NR), normal rice with a high resistant starch content (NRRS) or Se-rich rice (selenium-enriched rice) with a high resistant starch content (SRRS). Faecal cell counts of Bifidobacterium, Lactobacillus and Enterococcus were significantly higher in SRRS-treated mice than in diabetic controls, while Enterobacter cloacae were lower. Similar results were also found in NRRS-treated mice. In contrast, no significant difference was found between NR-treated and diabetic control groups. The treatments with SRRS and NRRS reduced the faecal pH values of the diabetic mice. Regarding the inflammatory factor levels, lower levels of serum C-reactive protein (CRP), tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), nuclear factor-k-gene binding (NF-κB) and leptin (LEP) and higher adiponutrin (ADPN) levels were found in the SRRS and NRRS-treated mice compared with the diabetic and NR-treated mice. In addition, the CRP, IL-6 and NF-κB levels in the SRRS-treated mice were significantly reduced compared with those observed in the NRRS-treated mice. The reverse transcription-PCR (RT-PCR) results showed that the SRRS and NRRS-treated mice presented higher expression levels of orphan G protein-coupled receptor 41 (GPR41) and orphan G protein-coupled receptor 43 (GPR43) proteins compared with diabetic mice and NR-treated mice. These results indicate that treatments with rice high in RS exert beneficial effects by improving enteric dysbiosis and chronic inflammation. In addition, selenium and RS may exert synergistic effects on chronic inflammation. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Leptin replacement restores supraspinal cholinergic antinociception in leptin-deficient obese mice.

PubMed

Wang, Wenfei; Baghdoyan, Helen A; Lydic, Ralph

2009-08-01

A single gene deletion causes lack of leptin and obesity in B6.V-Lep(ob) (obese; ob) mice compared with wild-type C57BL/6J (B6) mice. This study compared the phenotype of nociception and supraspinal antinociception in obese and B6 mice by testing 2 hypotheses: (1) microinjection of cholinomimetics or an adenosine receptor agonist, but not morphine, into the pontine reticular formation (PRF) is antinociceptive in B6 but not obese mice, and (2) leptin replacement in obese mice attenuates differences in nociceptive responses between obese and B6 mice. Adult male mice (n = 22) were implanted with microinjection guide tubes aimed for the PRF. The PRF was injected with neostigmine, carbachol, nicotine, N(6)-p-sulfophenyladenosine (SPA), morphine, or saline (control), and latency to paw withdrawal (PWL) from a thermal stimulus was recorded. B6 and ob mice did not differ in PWL after saline microinjection into the PRF. Neostigmine, carbachol, and SPA caused PWL to increase significantly in B6 but not obese mice. An additional 15 obese mice were implanted with osmotic pumps that delivered leptin for 7 days. Leptin replacement in obese mice restored the analgesic effect of PRF neostigmine to the level displayed by B6 mice. The results show for the first time that leptin significantly alters supraspinal cholinergic antinociception. This study specifies a brain region (the pontine reticular formation), cholinergic neurotransmission, and a protein (leptin) modulating thermal nociception. The results are relevant for efforts to understand the association between obesity, disordered sleep, and hyperalgesia.

Prioritizing Environmental Chemicals for Obesity and Diabetes ...

EPA Pesticide Factsheets

Background: Diabetes and obesity are major threats to public health in the US and abroad. Understanding the role chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is a challenge. This review is intended to help researchers generate hypotheses about chemicals potentially contributing to diabetes and obesity-related health outcomes by summarizing relevant findings from the US Environmental Protection Agency (EPA) ToxCast high-throughput screening (HTS) program. Objectives: To develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high throughput screening data. Methods: Identify ToxCast assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte dierentiation, and feeding behavior) and present chemical screening data against those assay targets to identify chemicals of potential interest. Discussion: Results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated from research papers and reviews published in the peer-reviewed literature. Testing of hypotheses based on ToxCast data will a

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

PubMed

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

2014-12-01

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

Glyoxalase 1 Modulation in Obesity and Diabetes.

PubMed

Rabbani, Naila; Thornalley, Paul J

2018-01-02

Obesity and type 2 diabetes mellitus are increasing globally. There is also increasing associated complications, such as non-alcoholic fatty liver disease (NAFLD) and vascular complications of diabetes. There is currently no licensed treatment for NAFLD and no recent treatments for diabetic complications. New approaches are required, particularly those addressing mechanism-based risk factors for health decline and disease progression. Recent Advances: Dicarbonyl stress is the abnormal accumulation of reactive dicarbonyl metabolites such as methylglyoxal (MG) leading to cell and tissue dysfunction. It is a potential driver of obesity, diabetes, and related complications that are unaddressed by current treatments. Increased formation of MG is linked to increased glyceroneogenesis and hyperglycemia in obesity and diabetes and also down-regulation of glyoxalase 1 (Glo1)-which provides the main enzymatic detoxification of MG. Glo1 functional genomics studies suggest that increasing Glo1 expression and activity alleviates dicarbonyl stress; slows development of obesity, related insulin resistance; and prevents development of diabetic nephropathy and other microvascular complications of diabetes. A new therapeutic approach constitutes small-molecule inducers of Glo1 expression-Glo1 inducers-exploiting a regulatory antioxidant response element in the GLO1 gene. A prototype Glo1 inducer, trans-resveratrol (tRES)-hesperetin (HESP) combination, in corrected insulin resistance, improved glycemic control and vascular inflammation in healthy overweight and obese subjects in clinical trial. tRES and HESP synergize pharmacologically, and HESP likely overcomes the low bioavailability of tRES by inhibition of intestinal glucuronosyltransferases. Glo1 inducers may now be evaluated in Phase 2 clinical trials for treatment of NAFLD and vascular complications of diabetes. Antioxid. Redox Signal. 00, 000-000.

Whole-Mount Adult Ear Skin Imaging Reveals Defective Neuro-Vascular Branching Morphogenesis in Obese and Type 2 Diabetic Mouse Models.

PubMed

Yamazaki, Tomoko; Li, Wenling; Yang, Ling; Li, Ping; Cao, Haiming; Motegi, Sei-Ichiro; Udey, Mark C; Bernhard, Elise; Nakamura, Takahisa; Mukouyama, Yoh-Suke

2018-01-11

Obesity and type 2 diabetes are frequently associated with peripheral neuropathy. Though there are multiple methods for diagnosis and analysis of morphological changes of peripheral nerves and blood vessels, three-dimensional high-resolution imaging is necessary to appreciate the pathogenesis with an anatomically recognizable branching morphogenesis and patterning. Here we established a novel technique for whole-mount imaging of adult mouse ear skin to visualize branching morphogenesis and patterning of peripheral nerves and blood vessels. Whole-mount immunostaining of adult mouse ear skin showed that peripheral sensory and sympathetic nerves align with large-diameter blood vessels. Diet-induced obesity (DIO) mice exhibit defective vascular smooth muscle cells (VSMCs) coverage, while there is no significant change in the amount of peripheral nerves. The leptin receptor-deficient db/db mice, a severe obese and type 2 diabetic mouse model, exhibit defective VSMC coverage and a large increase in the amount of smaller-diameter nerve bundles with myelin sheath and unmyelinated nerve fibers. Interestingly, an increase in the amount of myeloid immune cells was observed in the DIO but not db/db mouse skin. These data suggest that our whole-mount imaging method enables us to investigate the neuro-vascular and neuro-immune phenotypes in the animal models of obesity and diabetes.

IL-33 Drives Augmented Responses to Ozone in Obese Mice

PubMed Central

Mathews, Joel A.; Krishnamoorthy, Nandini; Kasahara, David Itiro; Cho, Youngji; Wurmbrand, Allison Patricia; Ribeiro, Luiza; Smith, Dirk; Umetsu, Dale; Levy, Bruce D.; Shore, Stephanie Ann

2016-01-01

Background: Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure. Objectives: We assessed the role of IL-33 in the augmented effects of ozone observed in obese mice. Methods: Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in γδ T cells and their wildtype controls. Results and Discussion: Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ γδ T cells. Ozone increased ST2+ γδ T cells, indicating that these cells can be targets of IL-33, and γδ T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines. Conclusions: Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in γδ T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246–253; http://dx.doi.org/10.1289/EHP272 PMID:27472835

Assessment of DNA damage and lipid peroxidation in diabetic mice: effects of propolis and epigallocatechin gallate (EGCG).

PubMed

Oršolić, Nada; Sirovina, Damir; Gajski, Goran; Garaj-Vrhovac, Vera; Jazvinšćak Jembrek, Maja; Kosalec, Ivan

2013-09-18

There is growing recognition that polyphenolic compounds present in many plants and natural products may have beneficial effects on human health. Propolis - a substance produced by honeybees - and catechins in tea, in particular (-)-epigallocatechin gallate (EGCG), are strong antioxidants that appear to have anti-obesity and anti-diabetic effects. The present study was designed to elucidate the anti-diabetic effect of the water-soluble derivative of propolis (WSDP), which contains phenolic acids as the main compounds, and EGCG in alloxan-induced (75mg/kg, iv) diabetes in mice. Intraperitoneal administration of EGCG or propolis at doses of 50mg/kg body weight (bw) to diabetic mice for a period of 7 days resulted in a significant increase in body weight and in haematological/immunological blood parameters, as well as in 100% survival of the mice. A significant decrease in lipid peroxidation in liver, kidney and brain tissue was also observed in diabetic mice treated with these two agents. Additionally, EGCG and propolis clearly reduced DNA damage in peripheral lymphocytes of diabetic mice. Our studies demonstrate the anti-oxidative and anti-inflammatory potential of WSDP and EGCG, which could exert beneficial effects against diabetes and the associated consequences of free-radical formation in kidney, liver, spleen and brain tissue. The results suggest that dietary supplementation with WSDP or EGCG could potentially contribute to nutritional strategies for the prevention and treatment of diabetes mellitus. Copyright © 2013 Elsevier B.V. All rights reserved.

CCR2 antagonist CCX140-B provides renal and glycemic benefits in diabetic transgenic human CCR2 knockin mice

PubMed Central

Sullivan, Timothy; Miao, Zhenhua; Dairaghi, Daniel J.; Krasinski, Antoni; Wang, Yu; Zhao, Bin N.; Baumgart, Trageen; Ertl, Linda S.; Pennell, Andrew; Seitz, Lisa; Powers, Jay; Zhao, Ruiping; Ungashe, Solomon; Wei, Zheng; Boring, Landin; Tsou, Chia-Lin; Charo, Israel; Schall, Thomas J.; Jaen, Juan C.

2013-01-01

Chemokine (C-C motif) receptor 2 (CCR2) is central for the migration of monocytes into inflamed tissues. The novel CCR2 antagonist CCX140-B, which is currently in two separate phase 2 clinical trials in diabetic nephropathy, has recently been shown to reduce hemoglobin A1c and fasting blood glucose levels in type 2 diabetics. In this report, we describe the effects of this compound on glycemic and renal function parameters in diabetic mice. Since CCX140-B has a low affinity for mouse CCR2, transgenic human CCR2 knockin mice were generated and rendered diabetic with either a high-fat diet (diet-induced obesity) or by deletion of the leptin receptor gene (db/db). CCX140-B treatment in both models resulted in decreased albuminuria, which was associated with decreased glomerular hypertrophy and increased podocyte density. Moreover, treatment of diet-induced obese mice with CCX140-B resulted in decreased levels of fasting blood glucose and insulin, normalization of homeostatic model assessment of insulin resistance values, and decreased numbers of adipose tissue inflammatory macrophages. Unlike other CCR2 antagonists, CCX140-B had no effect on plasma levels of the CCR2 ligand CCL2 or on the numbers of blood monocytes. These results support the ongoing evaluation of this molecule in diabetic subjects with impaired renal function. PMID:23986513

Dietary Aloe Reduces Adipogenesis via the Activation of AMPK and Suppresses Obesity-related Inflammation in Obese Mice.

PubMed

Shin, Eunju; Shin, Seulmee; Kong, Hyunseok; Lee, Sungwon; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil; Hwang, In-Kyeong; Kim, Kyungjae

2011-04-01

Metabolic disorders, including type II diabetes and obesity, present major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes. In this study, we evaluated whether dietary aloe could reduce obesity-induced inflammation and adipogenesis. Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) 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. Aloe QDM complex down-regulated fat size through suppressed expression of scavenger receptors on adipose tissue macrophages (ATMs) compared with HFD. Both white adipose tissue (WATs) and muscle exhibited increased AMPK activation through aloe supplementation, and in particular, the Aloe QDM complex. Obesity-induced inflammatory cytokines (IL-1β and -6) and HIF1α mRNA and protein were decreased markedly, as was macrophage infiltration by the Aloe QDM complex. Further, the Aloe QDM complex decreased the translocation of NF-κB p65 from the cytosol in the WAT. Dietary aloe formula reduced obesity-induced inflammatory responses by activation of AMPK in muscle and suppression of proinflammatory cytokines in the WAT. Additionally, the expression of scavenger receptors in the ATM and activation of AMPK in WAT led to reduction in the percent of body fat. Thus, we suggest that the effect of the Aloe QDM complex in the WAT and muscle are related to activation of AMPK and its use as a nutritional intervention against T2D and obesity-related inflammation.

Dietary Aloe Reduces Adipogenesis via the Activation of AMPK and Suppresses Obesity-related Inflammation in Obese Mice

PubMed Central

Shin, Eunju; Shin, Seulmee; Kong, Hyunseok; Lee, Sungwon; Do, Seon-Gil; Jo, Tae Hyung; Park, Young-In; Lee, Chong-Kil; Hwang, In-Kyeong

2011-01-01

Background Metabolic disorders, including type II diabetes and obesity, present major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes. In this study, we evaluated whether dietary aloe could reduce obesity-induced inflammation and adipogenesis. Methods Male C57BL/6 obese mice fed a high-fat diet for 54 days received a supplement of aloe formula (PAG, ALS, Aloe QDM, and Aloe QDM complex) or pioglitazone (PGZ) 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. Results Aloe QDM complex down-regulated fat size through suppressed expression of scavenger receptors on adipose tissue macrophages (ATMs) compared with HFD. Both white adipose tissue (WATs) and muscle exhibited increased AMPK activation through aloe supplementation, and in particular, the Aloe QDM complex. Obesity-induced inflammatory cytokines (IL-1β and -6) and HIF1α mRNA and protein were decreased markedly, as was macrophage infiltration by the Aloe QDM complex. Further, the Aloe QDM complex decreased the translocation of NF-κB p65 from the cytosol in the WAT. Conclusion Dietary aloe formula reduced obesity-induced inflammatory responses by activation of AMPK in muscle and suppression of proinflammatory cytokines in the WAT. Additionally, the expression of scavenger receptors in the ATM and activation of AMPK in WAT led to reduction in the percent of body fat. Thus, we suggest that the effect of the Aloe QDM complex in the WAT and muscle are related to activation of AMPK and its use as a nutritional intervention against T2D and obesity-related inflammation. PMID:21637388

Management of obesity in non- insulin- dependent diabetes mellitus.

PubMed

Cheah, J S

1998-12-01

Obesity is common in non-insulin-dependent diabetes mellitus (NIDDM) patients; in Singapore in a cohort of 314 diabetics, 44.3% were overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. However, like in the non-diabetic, management of obesity in the diabetic requires a pragmatic and realistic approach. A team approach is required: the help of a nurse educator, a dietitian, behaviour modification therapist, exercise therapist and others are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM patient. Weight loss is urgent in the obese NIDDM patient, especially for those with android obesity. There must be a reduction in energy intake. Weight loss leads to an improvement in glucose tolerance and in insulin sensitivity, as well as to a reduction in lipid levels and to a fall in blood pressure in the hypertensive. Exercise is of limited short-term value measured in terms of weight reduction, except in the younger obese NIDDM patient; but it does allow improvement in overall metabolic control and, long-term, is critical for preferred weight maintenance. The biguanide, Metformin, is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM patient; a widely

The role of cadmium in obesity and diabetes.

PubMed

Tinkov, Alexey A; Filippini, Tommaso; Ajsuvakova, Olga P; Aaseth, Jan; Gluhcheva, Yordanka G; Ivanova, Juliana M; Bjørklund, Geir; Skalnaya, Margarita G; Gatiatulina, Eugenia R; Popova, Elizaveta V; Nemereshina, Olga N; Vinceti, Marco; Skalny, Anatoly V

2017-12-01

Multiple studies have shown an association between environmental exposure to hazardous chemicals including toxic metals and obesity, diabetes, and metabolic syndrome. At the same time, the existing data on the impact of cadmium exposure on obesity and diabetes are contradictory. Therefore, the aim of the present work was to review the impact of cadmium exposure and status on the risk and potential etiologic mechanisms of obesity and diabetes. In addition, since an effect of cadmium exposure on incidence of diabetes mellitus and insulin resistance was suggested by several epidemiologic studies, we carried out a meta-analysis of all studies assessing risk of prevalence and incidence of diabetes. By comparing the highest versus the lowest cadmium exposure category, we found a high risk of diabetes incidence (odds ratio=1.38, 95% confidence interval 1.12-1.71), which was higher for studies using urine as exposure assessment. On the converse, results of epidemiologic studies linking cadmium exposure and overweight or obesity are far less consistent and even conflicting, also depending on differences in exposure levels and the specific marker of exposure (blood, urine, hair, nails). In turn, laboratory studies demonstrated that cadmium adversely affects adipose tissue physiopathology through several mechanisms, thus contributing to increased insulin resistance and enhancing diabetes. However, intimate biological mechanisms linking Cd exposure with obesity and diabetes are still to be adequately investigated. Copyright © 2017 Elsevier B.V. All rights reserved.

Berberine alleviates adipose tissue fibrosis by inducing AMP-activated kinase signaling in high-fat diet-induced obese mice.

PubMed

Wang, Lijun; Ye, Xiao; Hua, Yanyin; Song, Yingxiang

2018-05-28

Adipose tissue fibrosis is a novel mechanism for the development of obesity related insulin resistance. Berberine (BBR) has been shown to relieve several metabolic disorders, including obesity and type 2 diabetes. However, the effects of BBR on obesity related adipose fibrosis remain poorly understood. The objective of this study was to assess the effects of BBR on adipose tissue fibrosis in high fat diet (HFD)-induced obese mice. The results showed that BBR reduced animal body weight and significantly improved glucose tolerance in HFD mice. In addition, BBR treatment markedly attenuated collagen deposition and reversed the up-regulation of fibrosis associated genes in the adipose tissue of HFD mice. Moreover, BBR treatment activated AMP-activated kinase signaling and reduced TGF-β1 and Smad3 phosphorylation. Of note, the inhibitory effects of BBR on adipose tissue fibrosis were significantly blocked by AMPK inhibition with compound C, an AMPK inhibitor. Macrophage infiltration and polarization induced by HFD were also reversed after BBR administration. These findings suggest that BBR displays beneficial effects in the treatment of obesity, in part via improvement of adipose tissue fibrosis. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Epidemiology of Obesity and Diabetes and Their Cardiovascular Complications

PubMed Central

Bhupathiraju, Shilpa N.; Hu, Frank B.

2016-01-01

Obesity and diabetes have reached epidemic proportions in the past few years. In 2011–2012, more than a third of the US population was obese. Although recent trend data indicate that the epidemic has “leveled off”, prevalence of abdominal obesity continues to rise, especially among adults. As seen for obesity, the past few decades have seen a doubling of the diabetes incidence with an increasing number of type 2 diabetes cases being diagnosed in children. Significant racial and ethnic disparities exist in the prevalence and trends of obesity and diabetes. In general, in both adults and children, non-Hispanic blacks and Mexican Americans appear to be at a high risk than their non-Hispanic white counterparts. Secular changes in agricultural policies, diet, food environment, physical activity, and sleep have all contributed to the upward trends in the “diabesity” epidemic. Despite marginal improvements in physical activity and the US diet, the food environment has changed drastically to an “obesogenic” one with increased portion sizes and limited access to healthy food choices especially for disadvantaged populations. Interventions that improve the food environment are critical as both obesity and diabetes raise the risk of cardiovascular disease by nearly two-fold. Among those with type 2 diabetes, significant sex differences occur in the risk of cardiovascular disease such that diabetes completely eliminates or attenuates the advantages of being female. Given the substantial burden of obesity and diabetes, future research efforts should adopt a translational approach to find sustainable and holistic solutions in preventing these costly diseases. PMID:27230638

Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes

PubMed Central

Devedjian, Jean-Christophe; George, Monica; Casellas, Alba; Pujol, Anna; Visa, Joana; Pelegrín, Mireia; Gros, Laurent; Bosch, Fatima

2000-01-01

During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in β cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in β-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease. PMID:10727441

Sodium Butyrate Protects -Against High Fat Diet-Induced Cardiac Dysfunction and Metabolic Disorders in Type II Diabetic Mice.

PubMed

Zhang, Ling; Du, Jianfeng; Yano, Naohiro; Wang, Hao; Zhao, Yu Tina; Dubielecka, Patrycja M; Zhuang, Shougang; Chin, Y Eugene; Qin, Gangjian; Zhao, Ting C

2017-08-01

Histone deacetylases are recently identified to act as key regulators for cardiac pathophysiology and metabolic disorders. However, the function of histone deacetylase (HDAC) in controlling cardiac performance in Type II diabetes and obesity remains unknown. Here, we determine whether HDAC inhibition attenuates high fat diet (HFD)-induced cardiac dysfunction and improves metabolic features. Adult mice were fed with either HFD or standard chow food for 24 weeks. Starting at 12 weeks, mice were divided into four groups randomly, in which sodium butyrate (1%), a potent HDAC inhibitor, was provided to chow and HFD-fed mice in drinking water, respectively. Glucose intolerance, metabolic parameters, cardiac function, and remodeling were assessed. Histological analysis and cellular signaling were examined at 24 weeks following euthanization of mice. HFD-fed mice demonstrated myocardial dysfunction and profound interstitial fibrosis, which were attenuated by HDAC inhibition. HFD-induced metabolic syndrome features insulin resistance, obesity, hyperinsulinemia, hyperglycemia, lipid accumulations, and cardiac hypertrophy, these effects were prevented by HDAC inhibition. Furthermore, HDAC inhibition attenuated myocyte apoptosis, reduced production of reactive oxygen species, and increased angiogenesis in the HFD-fed myocardium. Notably, HFD induced decreases in MKK3, p38, p38 regulated/activated protein kinase (PRAK), and Akt-1, but not p44/42 phosphorylation, which were prevented by HDAC inhibition. These results suggest that HDAC inhibition plays a critical role to preserve cardiac performance and mitigate metabolic disorders in obesity and diabetes, which is associated with MKK3/p38/PRAK pathway. The study holds promise in developing a new therapeutic strategy in the treatment of Type II diabetic-induced heart failure and metabolic disorders. J. Cell. Biochem. 118: 2395-2408, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

[Association of childhood and adolescents obesity with adult diabetes].

PubMed

Hou, Dongqing; Zhao, Xiaoyuan; Liu, Junting; Chen, Fangfang; Yan, Yinkun; Cheng, Hong; Yang, Ping; Shan, Xinying; Mi, Jie

2016-01-01

To investigate the correlation between obesity in children and diabetes in adults from a cohort study, and further more to explore the necessity of preventing diabetes by controlling obesity in children. In 1987, 3 198 children and adolescents aged 6-18 were recruited from 6 elementary schools and 6 high schools located in 3 districts (Chaoyang, Haidian, and Xicheng) of Beijing using stratified cluster sampling design. The physical examination process included physical development test, blood pressure measurement, and questionnaire investigation. All children were invited to participate in the study, except for those who had history of congenital heart disease, chronic kidney disease, and limb disability. A total of 1,225 adults were enrolled in a prospective follow-up study from March 2010 to July 2012, anthropometric measures and blood sample were obtained. The obesity was defined by the following criteria: for children aged 6, the age-and the gender-specific 95th percentile of BMI from the US Centre for Disease Control and Prevention Growth charts 2000 as the baseline; for children age 7-18, recommendation from Working Group on Obesity in China (WGOC) as the standard; for adults, BMI≥28 kg/m(2) as the diagnosis standard. Diabetes was defined based on fasting plasma glucose(FPG) ≥7.0 mmol/L or 2 hours postprandial blood glucose (2 h PG) ≥11.1 mmol/L or glycosylated hemoglobin (HbA1c) ≥6.5% or current using blood glucose-lowering agents or current using insulin. Logistic regression was used to analyze the association obesity in children with diabetes in adults. The prevalence of diabetes diagnosed by FPG and 2 h PG in adults who were obese children (16.2%, 18/111) was higher than those who were non-obese children (5.6%, 62/1,114)(χ(2)=18.76, P<0.001). The prevalence of diabetes diagnosed by HbA1c in adults who were obese children(18.1%,20/111) was higher than those who were non-obese children (6.9%, 77/1,114) (χ(2)=16.66, P<0.001). With multi

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

PubMed Central

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

2016-01-01

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

[D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3, small molecule synthetic peptide leptin mimetics, improve glycemic control in diet-induced obese (DIO) mice.

PubMed

Wang, Anke; Anderson, Brian M; Novakovic, Zachary M; Grasso, Patricia

2018-03-01

We have previously shown that following oral delivery in dodecyl maltoside (DDM), [D-Leu-4]-OB3 and its myristic acid conjugate, MA-[D-Leu-4]-OB3, improved energy balance and glucose homeostasis in genetically obese/diabetic mouse models. More recently, we have provided immunohistochemical evidence indicating that these synthetic peptide leptin mimetics cross the blood-brain barrier and concentrate in the area of the arcuate nucleus of the hypothalamus in normal C57BL/6J and Swiss Webster mice, in genetically obese ob/ob mice, and in diet-induced obese (DIO) mice. In the present study, we describe the effects of oral delivery of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control in diet-induced (DIO) mice, a non-genetic rodent model of obesity and its associated insulin resistance, which more closely recapitulates common obesity and diabetes in humans. Male C57BL/6J and DIO mice, 17, 20, and 28 weeks of age, were maintained on a low-fat or high-fat diet and given vehicle (DDM) alone or [D-Leu-4]-OB3 or MA-[D-Leu-4]-OB3 in DDM by oral gavage for 12 or 14 days. Body weight gain, food and water intake, fasting blood glucose, oral glucose tolerance, and serum insulin levels were measured. Our data indicate that (1) [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 restore glucose tolerance in male DIO mice maintained on a high-fat diet to levels comparable to those of non-obese C57BL/6J wild-type mice of the same age and sex maintained on a low-fat diet; and (2) the influence of [D-Leu-4]-OB3 and MA-[D-Leu-4]-OB3 on glycemic control appears to be independent of their effects on energy balance. These results suggest that [D-Leu-4]-OB3 and/or MA-[D-Leu-4]-OB3 may have application to the management of the majority of cases of common obesity in humans, a state characterized at least in part, by leptin resistance resulting from a defect in leptin transport across the blood-brain barrier. They further suggest that these small molecule synthetic peptide leptin mimetics, through their

Management of obesity in NIDDM (non-insulin-dependent diabetes mellitus).

PubMed

Cheah, J S

1998-08-01

Obesity is common in NIDDM; in a cohort of 314 diabetics in Singapore, 44.3% are overweight. Management of obesity in diabetics differs from that in non-diabetics in that it is more urgent; weight maintenance is more difficult and hypoglycaemic medication may cause weight changes. Like in the non-diabetic, management of obesity in diabetic requires a pragmatic and realistic approach. A team approach is required: the help of the nurse educator, the dietitian, behaviour modification therapist, exercise therapist etc are required. A detailed history, careful physical examination and relevant investigations are required to assess the severity of the diabetic state and to exclude an occasional underlying cause of the obesity in the obese NIDDM. Weight loss is urgent in the obese NIDDM, especially those with android obesity. There must be a reduction in caloric intake. Weight loss leads to improvement in the glucose tolerance, insulin sensitivity, reduction in lipid levels and fall in blood pressure in the hypertensive. Exercise is of limited value except in the younger obese NIDDM. Metformin is the hypoglycaemic drug of choice as it leads to consistent weight reduction. The sulphonylureas may cause weight gain. Insulin should be avoided where possible as it causes further weight gain. Other hypoglycaemic agents include Glucobay (alpha-glucosidase inhibitor) and Troglitazone (insulin sensitizer) which do not alter the weight. Orlistat (lipase inhibitor) is promising as it causes reduction of weight, blood-glucose and lipid levels. Anti-obesity drugs (noradrenergic and serotonergic agents) have modest effects on weight reduction in the obese NIDDM; a widely use preparation, Dexfenfluramine (Adifax) has been withdrawn because of side effects. Surgery such as gastric plication is the last resort in treating the morbidly obese NIDDM. The discovery of leptin in 1994 has led to intense research into energy homeostasis in obesity; hopefully this will lead to better treatment of

Prevalence of overweight and obesity among type 2 diabetic patients attending diabetes clinics in northern Tanzania.

PubMed

Damian, Damian J; Kimaro, Kelvin; Mselle, Godwin; Kaaya, Rose; Lyaruu, Isaac

2017-10-26

To determine the prevalence of overweight and obesity among patients with type 2 diabetes who are attending diabetes clinics in northern Tanzania. In total 227 type 2 diabetic patients attending diabetes clinics were enrolled. Majority of patients 193 (85.0%) were overweight (44.9%) or obese (40.1%). Of them, 65 (33.7%) were overweight/obese after diagnosis of type 2 diabetes. The prevalence of overweight/obesity was significantly higher in female participants than the males [92.2% vs. 69.2%; OR = 5.10; 95% CI 2.22-11.05]. Regarding the region of residence, Kilimanjaro (100.0%) and Arusha (89.8%) regions had significantly highest prevalence of overweight/obesity compared to Tanga region (69.2%) [χ 2  = 32.455, P < 0.001].

Isolation and characterization of Agouti: a diabetes/obesity related gene

DOEpatents

Woychik, Richard P.

1998-01-01

The present invention relates to the cloning and expression of the Agouti gene and analogous genes in transformed, transfected and transgenic mice. The present invention provides an animal model for the study of diabetes, obesity and tumors for the testing of potential therapeutic agents. The present invention provides oligonucleotide probes for the detection of the Agouti gene and mutations in the gene. The present invention also relates to the isolation and recombinant production of the Agouti gene product, production of antibodies to the Agouti gene product and their use as diagnostic and therapeutic agents.

Isolation and characterization of Agouti: a diabetes/obesity related gene

DOEpatents

Woychik, Richard P.

2000-06-27

The present invention relates to the cloning and expression of the Agouti gene and analogous genes in transformed, transfected and transgenic mice. The present invention provides an animal model for the study of diabetes, obesity and tumors for the testing of potential therapeutic agents. The present invention provides oligonucleotide probes for the detection of the Agouti gene and mutations in the gene. The present invention also relates to the isolation and recombinant production of the Agouti gene product, production of antibodies to the Agouti gene product and their use as diagnostic and therapeutic agents.

Anti-obesity effect of intranasal administration of galanin-like peptide (GALP) in obese mice

PubMed Central

Kageyama, Haruaki; Shiba, Kanako; Hirako, Satoshi; Wada, Nobuhiro; Yamanaka, Satoru; Nogi, Yukinori; Takenoya, Fumiko; Nonaka, Naoko; Hirano, Tsutomu; Inoue, Shuji; Shioda, Seiji

2016-01-01

Galanin-like peptide (GALP) has an anti-obesity effect in rats and mice. It has been reported that the uptake of GALP by the brain is higher after intranasal administration than with intravenous injection. This study therefore aimed to clarify the effect of intranasal administration of GALP on the feeding behavior of lean and obese mice. Autoradiography revealed the presence of 125I-GALP in the olfactory bulb and the brain microcirculation. The body weights of ob/ob mice gradually increased during vehicle treatment, but remained unchanged in response to repeated intranasal administration of GALP, with both ob/ob and diet-induced obese mice displaying significantly decreased food intake, water intake and locomotor activity when treated with GALP. These results suggest that intranasal administration is an effective route whereby GALP can exert its effect as an anti-obesity drug. PMID:27323911

Persistent Organic Pollutants as Risk Factors for Obesity and Diabetes.

PubMed

Yang, Chunxue; Kong, Alice Pik Shan; Cai, Zongwei; Chung, Arthur C K

2017-11-02

The rising prevalence of obesity and diabetes cannot be fully explained by known risk factors, such as unhealthy diet, a sedentary lifestyle, and family history. This review summarizes the available studies linking persistent organic pollutants (POPs) to obesity and diabetes and discusses plausible underlying mechanisms. Increasing evidence suggest that POPs may act as obesogens and diabetogens to promote the development of obesity and diabetes and induce metabolic dysfunction. POPs are synthesized chemicals and are used widely in our daily life. These chemicals are resistant to degradation in chemical or biological processes, which enable them to exist in the environment persistently and to be bio-accumulated in animal and human tissue through the food chain. Increasingly, epidemiologic studies suggest a positive association between POPs and risk of developing diabetes. Understanding the relationship of POPs with obesity and diabetes may shed light on preventive strategies for obesity and diabetes.

Canagliflozin, a sodium glucose cotransporter 2 inhibitor, attenuates obesity-induced inflammation in the nodose ganglion, hypothalamus, and skeletal muscle of mice.

PubMed

Naznin, Farhana; Sakoda, Hideyuki; Okada, Tadashi; Tsubouchi, Hironobu; Waise, T M Zaved; Arakawa, Kenji; Nakazato, Masamitsu

2017-01-05

Chronic inflammation in systemic organs, such as adipose tissue, nodose ganglion, hypothalamus, and skeletal muscles, is closely associated with obesity and diabetes mellitus. Because sodium glucose cotransporter 2 (SGLT2) inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of canagliflozin, an SGLT2 inhibitor, on obesity-induced inflammation in neural tissues and skeletal muscles of mice. High-fat diet (HFD)-fed male C57BL/6J mice were treated with canagliflozin for 8 weeks. Canagliflozin attenuated the HFD-mediated increases in body weight, liver weight, and visceral and subcutaneous fat weight. Additionally, canagliflozin decreased blood glucose as well as the fat, triglyceride, and glycogen contents of the liver. Along with these metabolic corrections, canagliflozin attenuated the increases in the mRNA levels of the proinflammatory biomarkers Iba1 and Il6 and the number of macrophages/microglia in the nodose ganglion and hypothalamus. In the skeletal muscle of HFD-fed obese mice, canagliflozin decreased inflammatory cytokine levels, macrophage accumulation, and the mRNA level of the specific atrophic factor atrogin-1. Canagliflozin also increased the mRNA level of insulin-like growth factor 1, protected against muscle mass loss, and restored the contractile force of muscle. These findings suggested that SGLT2 inhibition disrupts the vicious cycle of obesity and inflammation, not only by promoting caloric loss, but also by suppression of obesity-related inflammation in both the nervous system and skeletal muscle. Copyright © 2016 Elsevier B.V. All rights reserved.

Impact of T-cell-specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice

PubMed Central

Kim, Donghee; Lee, Song Mi; Jun, Hee-Sook

2017-01-01

Type 1 diabetes results from autoimmune-mediated pancreatic beta-cell destruction and transforming growth factor-beta (TGF-β) is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T-cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild type (WT) NOD mice. Pathological features such as insulitis, anti-glutamic acid decarboxylase auto-antibody levels and serum IFN-γ levels were significantly increased in Smad4 tKO compared with WT NOD mice. Proportion and number of activated/memory CD4+ T cell were significantly increased in pancreatic lymph nodes of Smad4 tKO compared with WT NOD mice. However, the proportion and function of regulatory T cells was not different. Effector CD4+ T cells from Smad4 tKO were more resistant to suppression by regulatory T cells than effector cells from WT NOD mice. The proliferative potential of effector T cells from Smad4 tKO was significantly elevated compared with WT NOD mice, and activation of sterol regulatory element binding protein-1c (SREBP-1c) in T cells of Smad4 tKO NOD mice was correlated with this proliferative activity. We conclude that Smad4 deletion in T cells of NOD mice accelerated the development of autoimmune diabetes and increased the incidence of the disease by dysregulation of T cell activation at least in part via SREBP-1c activation. PMID:27686408

Impact of T-cell-specific Smad4 deficiency on the development of autoimmune diabetes in NOD mice.

PubMed

Kim, Donghee; Lee, Song Mi; Jun, Hee-Sook

2017-03-01

Type 1 diabetes results from autoimmune-mediated pancreatic beta-cell destruction and transforming growth factor-beta (TGF-β) is known to play a preventive role in type 1 diabetes in non-obese diabetic (NOD) mice. In this study, we investigated the role of Smad4, a key molecule for Smad-dependent TGF-β signaling, in T cells of NOD mice in the pathogenesis of autoimmune diabetes. We generated T-cell-specific Smad4 knockout (Smad4 tKO) NOD mice and assessed the pathological and immunological changes. Smad4 tKO showed earlier onset and increased incidence of diabetes than wild type (WT) NOD mice. Pathological features such as insulitis, anti-glutamic acid decarboxylase auto-antibody levels and serum IFN-γ levels were significantly increased in Smad4 tKO compared with WT NOD mice. Proportion and number of activated/memory CD4 + T cell were significantly increased in pancreatic lymph nodes of Smad4 tKO compared with WT NOD mice. However, the proportion and function of regulatory T cells was not different. Effector CD4 + T cells from Smad4 tKO were more resistant to suppression by regulatory T cells than effector cells from WT NOD mice. The proliferative potential of effector T cells from Smad4 tKO was significantly elevated compared with WT NOD mice, and activation of sterol regulatory element binding protein-1c (SREBP-1c) in T cells of Smad4 tKO NOD mice was correlated with this proliferative activity. We conclude that Smad4 deletion in T cells of NOD mice accelerated the development of autoimmune diabetes and increased the incidence of the disease by dysregulation of T cell activation at least in part via SREBP-1c activation.

Obesity-Induced Diabetes and Lower Urinary Tract Fibrosis Promote Urinary Voiding Dysfunction in a Mouse Model

PubMed Central

Gharaee-Kermani, Mehrnaz; Rodriguez-Nieves, Jose A.; Mehra, Rohit; Vezina, Chad A.; Sarma, Aruna V.; Macoska, Jill A.

2017-01-01

BACKGROUND Progressive aging- and inflammation-associated fibrosis effectively remodels the extracellular matrix (ECM) to increase prostate tissue stiffness and reduce urethral flexibility, resulting in urinary flow obstruction and lower urinary tract symptoms (LUTS). In the current study, we sought to test whether senescence-accelerated mouse prone (SAMP)6 mice, which were reported to develop prostatic fibrosis, would also develop LUTS, and whether these symptoms would be exacerbated by diet-induced obesity and concurrent Type 2 Diabetes Mellitus (T2DM). METHODS To accomplish this, SAMP6 and AKR/J background strain mice were fed regular mouse chow, low fat diet chow, or high fat diet chow for 8 months, then subjected to glucose tolerance tests, assessed for plasma insulin levels, evaluated for urinary voiding function, and assessed for lower urinary tract fibrosis. RESULTS The results of these studies show that SAMP6 mice and AKR/J background strain mice develop diet-induced obesity and T2DM concurrent with urinary voiding dysfunction. Moreover, urinary voiding dysfunction was more severe in SAMP6 than AKR/J mice and was associated with pronounced prostatic and urethral tissue fibrosis. CONCLUSIONS Taken together, these studies suggest that obesity, T2DM, lower urinary tract fibrosis, and urinary voiding dysfunction are inextricably and biologically linked. Prostate. PMID:23532836

Gut microbial markers are associated with diabetes onset, regulatory imbalance, and IFN-γ level in NOD mice.

PubMed

Krych, Ł; Nielsen, D S; Hansen, A K; Hansen, C H F

2015-01-01

Gut microbiota regulated imbalances in the host's immune profile seem to be an important factor in the etiology of type 1 diabetes (T1D), and identifying bacterial markers for T1D may therefore be useful in diagnosis and prevention of T1D. The aim of the present study was to investigate the link between the early gut microbiota and immune parameters of non-obese diabetic (NOD) mice in order to select alleged bacterial markers of T1D. Gut microbial composition in feces was analyzed with 454/FLX Titanium (Roche) pyro-sequencing and correlated with diabetes onset age and immune cell populations measured in diabetic and non-diabetic mice at 30 weeks of age. The early gut microbiota composition was found to be different between NOD mice that later in life were classified as diabetic or non-diabetic. Those differences were further associated with changes in FoxP3(+) regulatory T cells, CD11b(+) dendritic cells, and IFN-γ production. The model proposed in this work suggests that operational taxonomic units classified to S24-7, Prevotella, and an unknown Bacteriodales (all Bacteroidetes) act in favor of diabetes protection whereas members of Lachnospiraceae, Ruminococcus, and Oscillospira (all Firmicutes) promote pathogenesis.

Effect of Hibiscus sabdariffa on obesity in MSG mice.

PubMed

Alarcon-Aguilar, Francisco J; Zamilpa, Alejandro; Perez-Garcia, Ma Dolores; Almanza-Perez, Julio C; Romero-Nuñez, Eunice; Campos-Sepulveda, Efrain A; Vazquez-Carrillo, Laura I; Roman-Ramos, Ruben

2007-10-08

The aim of the present investigation was determine whether a standardized Hibiscus sabdariffa calyces aqueous extract has an effect on body weight in an obese animal model induced by the administration of monosodium glutamate. Hibiscus sabdariffa aqueous extract, containing 33.64 mg of total anthocyanins per each 120 mg of extract, was orally administered (120 mg/kg/day) for 60 days to healthy and obese mice, and body weight gain, food and liquid intake, aspartate aminotransferase (AST), alanine aminotransferase (ALT), cholesterol, and triglycerides levels were measured. Hibiscus sabdariffa administration significantly reduced body weight gain in obese mice and increased liquid intake in healthy and obese mice. ALT levels were significantly increased on the 15th and 45th days in obese mice, but AST levels did not show significant changes. Mortality was not observed in the Hibiscus sabdariffa treated groups. Triglycerides and cholesterol levels showed non-significant reductions in animals treated with Hibiscus sabdariffa. Our data confirm the anti-obesity effect of Hibiscus sabdariffa reported by the Mexican population.

Exercise improves cardiac autonomic function in obesity and diabetes.

PubMed

Voulgari, Christina; Pagoni, Stamatina; Vinik, Aaron; Poirier, Paul

2013-05-01

Physical activity is a key element in the prevention and management of obesity and diabetes. Regular physical activity efficiently supports diet-induced weight loss, improves glycemic control, and can prevent or delay type 2 diabetes diagnosis. Furthermore, physical activity positively affects lipid profile, blood pressure, reduces the rate of cardiovascular events and associated mortality, and restores the quality of life in type 2 diabetes. However, recent studies have documented that a high percentage of the cardiovascular benefits of exercise cannot be attributed solely to enhanced cardiovascular risk factor modulation. Obesity in concert with diabetes is characterized by sympathetic overactivity and the progressive loss of cardiac parasympathetic influx. These are manifested via different pathogenetic mechanisms, including hyperinsulinemia, visceral obesity, subclinical inflammation and increased thrombosis. Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes. The same is true for the role of physical exercise in the restoration of the heart cardioprotective autonomic modulation in these individuals. This review addresses the interplay of cardiac autonomic function in obesity and diabetes, and focuses on the importance of exercise in improving cardiac autonomic dysfunction. Copyright © 2013 Elsevier Inc. All rights reserved.

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.

Physiologic and endocrinologic characterization of male sex-biased diabetes in C57BLKS/J mice congenic for the fat mutation at the carboxypeptidease E locus.

PubMed

Leiter, E H; Kintner, J; Flurkey, K; Beamer, W G; Naggert, J K

1999-02-01

The fat gene in mice represents a recessive mutation at the carboxypeptidase E (Cpe) locus. The mutant allele (Cpe(fat)) encodes a highly unstable enzyme and produces an obesity phenotype characterized by attenuated processing of prohormones such as proinsulin that require this exopeptidase for full maturation. This article presents a preliminary physiologic and endocrinologic characterization of the stock of C57BLKS/LtJ-Cpe(fat)/Cpe(fat) mice at the backcross generation (N10) currently distributed by The Jackson Laboratory. Although previously reported not to be diabetogenic at N5, an additional five backcrosses to the C57BLKS/J background resulted in a male-biased development of both obesity and diabetes. Major differences distinguishing this mutant stock from the phenotypes produced by either the diabetes (Lepr(db)) or obese (Lep(ob)) mutations on the same inbred strain background are lack of hyperphagia and hypercorticism, sensitivity of diabetic males to exogenous insulin, and a milder and male-biased diabetes syndrome that is not associated with widespread beta-cell necrosis and islet atrophy, and that often remits with age.

Withaferin A is a Leptin Sensitizer with Strong Anti-Diabetic Properties in Mice

PubMed Central

Lee, Jaemin; Liu, Junli; Feng, Xudong; Salazar Hernández, Mario Andrés; Mucka, Patrick; Ibi, Dorina; Choi, Jae Won; Ozcan, Umut

2018-01-01

The increasing global prevalence of obesity and its associated disorders point to an urgent need for the development of novel and effective therapeutic strategies that induce healthy weight loss. Obesity is characterized by hyperleptinemia and central leptin resistance. In an attempt to identify compounds that could reverse leptin resistance and thus promote weight loss, we analyzed a library of small molecules with mRNA expression profiles similar to that of celastrol, a naturally-occurring compound we previously identified as a leptin sensitizer. By this process we identified another natural compound, withaferin A, that also acts as a leptin sensitizer. We found that withaferin A treatment of diet-induced obese mice resulted in a 20-25% reduction of body weight, while also decreasing obesity-associated abnormalities including hepatic steatosis. Withaferin A marginally affects the body weight of ob/ob and db/db mice, which are both deficient in leptin signaling. In addition, withaferin A, unlike celastrol, has beneficial effects on glucose metabolism independently from its leptin-sensitizing effect. Our results show that the metabolic abnormalities of diet-induced obesity can be mitigated by sensitizing animals to endogenous leptin, and indicate that withaferin A is a potential leptin sensitizer with additional anti-diabetic actions. PMID:27479085

Therapeutic potential of the original incretin hormone glucose-dependent insulinotropic polypeptide: diabetes, obesity, osteoporosis and Alzheimer's disease?

PubMed

Irwin, Nigel; Gault, Victor; Flatt, Peter R

2010-09-01

Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that potentiates nutrient-induced insulin release. To date, the physiological importance of GIP has received much less attention than its younger sister incretin hormone glucagon-like peptide-1. Thus, it is worthwhile to refocus on this important and somewhat neglected incretin hormone. The potential role of GIP as a treatment option for type 2 diabetes is highlighted. Furthermore, the use of GIP as a new therapeutic option for obesity, osteoporosis and cognitive impairment is also considered. Long-acting GIP receptor agonists offer a potential new class of antidiabetic drugs. Furthermore, recent observations suggest an as yet untapped potential for GIP agonists in the treatment of osteoporosis and cognitive impairment. In addition, GIP is known to play a role in lipid metabolism and fat deposition. Accordingly, both genetic and chemical ablation of GIP signalling in mice with obesity-diabetes can protect against, or reverse, many of the obesity-associated metabolic disturbances. This review focuses on preclinical data generated to date. GIP-based therapeutics have potential for the treatment of type 2 diabetes and obesity, with the possibility of further beneficial actions in osteoporosis and cognitive decline.

Spirulina maxima Extract Reduces Obesity through Suppression of Adipogenesis and Activation of Browning in 3T3-L1 Cells and High-Fat Diet-Induced Obese Mice.

PubMed

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

2018-06-01

Obesity predisposes animals towards the metabolic syndrome and diseases such as type 2 diabetes, atherosclerosis, and cardiovascular disease. Spirulina maxima is a microalga with anti-oxidant, anti-cancer, and neuroprotective activities, but the anti-obesity effect of Spirulina maxima 70% ethanol extract (SM70EE) has not yet been fully established. We investigated the effect of SM70EE on adipogenesis, lipogenesis, and browning using in vitro and in vivo obesity models. SM70EE treatment reduced lipid droplet accumulation by the oil red O staining method and downregulated the adipogenic proteins C/EBPα, PPARγ, and aP2, and the lipogenic proteins SREBP1, ACC, FAS, LPAATβ, Lipin1, and DGAT1 by western blot analysis. In addition, the index components of SM70EE, chlorophyll a, and C-phycocyanin, reduced adipogenesis and lipogenesis protein levels in 3T3-L1 and C3H10T1/2 cells. High-fat diet (HFD)-fed mice administered with SM70EE demonstrated smaller adipose depots and lower blood lipid concentrations than control HFD-fed mice. The lower body mass gain in treated SM70EE-administrated mice was associated with lower protein expression of adipogenesis factors and higher expression of AMPKα-induced adipose browning proteins PRDM16, PGC1α, and UCP1. SM70EE administration ameliorates obesity, likely by reducing adipogenesis and activating the thermogenic program, in 3T3-L1 cells and HFD-induced obese mice.

Combination of exercise training and diet restriction normalizes limited exercise capacity and impaired skeletal muscle function in diet-induced diabetic mice.

PubMed

Suga, Tadashi; Kinugawa, Shintaro; Takada, Shingo; Kadoguchi, Tomoyasu; Fukushima, Arata; Homma, Tsuneaki; Masaki, Yoshihiro; Furihata, Takaaki; Takahashi, Masashige; Sobirin, Mochamad A; Ono, Taisuke; Hirabayashi, Kagami; Yokota, Takashi; Tanaka, Shinya; Okita, Koichi; Tsutsui, Hiroyuki

2014-01-01

Exercise training (EX) and diet restriction (DR) are essential for effective management of obesity and insulin resistance in diabetes mellitus. However, whether these interventions ameliorate the limited exercise capacity and impaired skeletal muscle function in diabetes patients remains unexplored. Therefore, we investigated the effects of EX and/or DR on exercise capacity and skeletal muscle function in diet-induced diabetic mice. Male C57BL/6J mice that were fed a high-fat diet (HFD) for 8 weeks were randomly assigned for an additional 4 weeks to 4 groups: control, EX, DR, and EX+DR. A lean group fed with a normal diet was also studied. Obesity and insulin resistance induced by a HFD were significantly but partially improved by EX or DR and completely reversed by EX+DR. Although exercise capacity decreased significantly with HFD compared with normal diet, it partially improved with EX and DR and completely reversed with EX+DR. In parallel, the impaired mitochondrial function and enhanced oxidative stress in the skeletal muscle caused by the HFD were normalized only by EX+DR. Although obesity and insulin resistance were completely reversed by DR with an insulin-sensitizing drug or a long-term intervention, the exercise capacity and skeletal muscle function could not be normalized. Therefore, improvement in impaired skeletal muscle function, rather than obesity and insulin resistance, may be an important therapeutic target for normalization of the limited exercise capacity in diabetes. In conclusion, a comprehensive lifestyle therapy of exercise and diet normalizes the limited exercise capacity and impaired muscle function in diabetes mellitus.

Prevalence of diabetes and associated obesity in Pennsylvania adults, 1995-2010.

PubMed

Garcia-Dominic, Oralia; Lengerich, Eugene J; Camacho, Fabian; Gallant, Nancy R; Wray, Linda A; Ahern, Frank; Bogdan, Greg; Weinberg, Gene; Ulbrecht, Jan S

2014-07-03

This study examined trends in the prevalence and sociodemographic distributions of diabetes and the associations of diabetes with obesity over time in adult Pennsylvanians from 1995 through 2010. We used Behavioral Risk Factor Surveillance Survey data collected from 1995 through 2010. Diabetes prevalence was assessed by self-report of physician diagnosis. Obesity was assessed by body mass index computed from self-report of height and weight. State-level data for diabetes and associated obesity prevalence from 1995 through 2010 were collected for each year. Data on sociodemographic factors (age, sex, race, income, education) and 1 known disease risk factor (obesity) were also collected. Logistic regression modeling was used to examine associations between diabetes, sociodemographic factors, and obesity. Diabetes prevalence in Pennsylvania, which increased from 5.6% in 1995 to 10.5% in 2010, followed national trends but exceeded the national prevalence each year by approximately 0.6 percentage points for 12 of the 16 years. The increase in prevalence was not equal across all socioeconomic groups. Obesity became a more dominant risk factor for diabetes during these 16 years. The burden of diabetes and obesity in Pennsylvania is substantial and increasing. Program managers and policy makers in Pennsylvania should consider these trends when allocating limited resources and designing programs for reducing diabetes-related illness. Other states may consider similar studies to monitor the prevalence of diabetes and determine whether disparities are changing and whether programs and resources should also shift.

An intravital microscopy model to study early pancreatic inflammation in type 1 diabetes in NOD mice

PubMed Central

Lehmann, Christian; Fisher, Nicholas B.; Tugwell, Barna; Zhou, Juan

2016-01-01

ABSTRACT Intravital microscopy (IVM) of the pancreas has been proven to be an invaluable tool in pancreatitis, transplantation and ischemia/reperfusion research. Also in type 1 diabetes (T1D) pancreatic IVM offers unique advantages for the elucidation of the disease process. Female non-obese diabetic (NOD) mice develop T1D spontaneously by 40 weeks of age. Our goal was to establish an IVM-based method to study early pancreatic inflammation in NOD mice, which can be used to screen novel medications to prevent or delay T1D in future studies. This included evaluation of leukocyte-endothelial interactions as well as disturbances of capillary perfusion in the pancreatic microcirculation. PMID:28243521

Improvement of Type 2 Diabetes Mellitus in Obese and Non-Obese Patients after the Duodenal Switch Operation

PubMed Central

Frenken, M.; Cho, E. Y.; Karcz, W. K.; Grueneberger, J.; Kuesters, S.

2011-01-01

Introduction. Type 2 diabetes mellitus (T2DM) is one of the most important obesity-related comorbidities. This study was undertaken to characterise the effect of the biliopancreatic diversion with duodenal switch (BPD-DS) in morbidly obese and nonmorbidly obese diabetic patients. Methods. Outcome of 74 obese diabetic patients after BPD-DS and 16 non-obese diabetic patients after BPD or gastric bypass surgery was evaluated. Insulin usage, HbA1c-levels, and index of HOMA-IR (homeostasis model assessment of insulin resistence) were measured. Results. A substantial fraction of patients is free of insulin and shows an improved insulin sensitivity early after the operation, another fraction gets free of insulin in a 12-month period after the operation and a small fraction of long-term insulin users will not get free of insulin but nevertheless shows an improved metabolic status (less insulin needed, normal HbA1c-levels). Conclusion. BPD-DS leads to an improvement of T2DM in obese and non-obese patients. Nevertheless, more data is needed to clarify indications and mechanisms of action and to adjust our operation techniques to the needs of non-obese diabetic patients. PMID:21461399

Improvement of type 2 diabetes mellitus in obese and non-obese patients after the duodenal switch operation.

PubMed

Frenken, M; Cho, E Y; Karcz, W K; Grueneberger, J; Kuesters, S

2011-01-01

Introduction. Type 2 diabetes mellitus (T2DM) is one of the most important obesity-related comorbidities. This study was undertaken to characterise the effect of the biliopancreatic diversion with duodenal switch (BPD-DS) in morbidly obese and nonmorbidly obese diabetic patients. Methods. Outcome of 74 obese diabetic patients after BPD-DS and 16 non-obese diabetic patients after BPD or gastric bypass surgery was evaluated. Insulin usage, HbA(1c)-levels, and index of HOMA-IR (homeostasis model assessment of insulin resistence) were measured. Results. A substantial fraction of patients is free of insulin and shows an improved insulin sensitivity early after the operation, another fraction gets free of insulin in a 12-month period after the operation and a small fraction of long-term insulin users will not get free of insulin but nevertheless shows an improved metabolic status (less insulin needed, normal HbA(1c)-levels). Conclusion. BPD-DS leads to an improvement of T2DM in obese and non-obese patients. Nevertheless, more data is needed to clarify indications and mechanisms of action and to adjust our operation techniques to the needs of non-obese diabetic patients.

Daesiho-Tang Is an Effective Herbal Formulation in Attenuation of Obesity in Mice through Alteration of Gene Expression and Modulation of Intestinal Microbiota.

PubMed

Hussain, Ahtesham; Yadav, Mukesh Kumar; Bose, Shambhunath; Wang, Jing-Hua; Lim, Dongwoo; Song, Yun-Kyung; Ko, Seong-Gyu; Kim, Hojun

2016-01-01

Obesity has become a major global health challenge due to its increasing prevalence, and the associated health risk. It is the main cause of various metabolic diseases including diabetes, hypertension, cardiovascular disease, stroke and certain forms of cancer. In the present study we evaluated the anti-obesity property of Daesiho-tang (DSHT), an herbal medicine, using high fat diet (HFD)-induced obese mice as a model. Our results showed that DSHT ameliorated body weight gain, decreased total body fat, regulated expression of leptin and adiponectin genes of adipose tissue and exerted an anti-diabetic effect by attenuating fasting glucose level and serum insulin level in HFD-fed animals. In addition, DSHT-treatment significantly reduced total cholesterol (TC), triglycerides (TG) and increased high density lipoprotein-cholesterol (HDL), glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) levels in serum and reduced deposition of fat droplets in liver. DSHT treatment resulted in significantly increased relative abundance of bacteria including Bacteroidetes, Bacteroidetes/Firmicutes ratio, Akkermansia Bifidobacterium., Lactobacillus, and decreased the level of Firmicutes. Using RT2 profiler PCR array, 39 (46%) genes were found to be differentially expressed in HFD-fed mice compared to normal control. However, normal gene expressions were restored in 36 (92%) genes of HFD-fed mice, when co-exposed to DSHT. The results of this study demonstrated that DSHT is an effective herbal formulation in attenuation of obesity in HFD-fed mice through alteration of gene expressions and modulation of intestinal microbiota.

Stressed hearts in children with obesity and diabetes: a cause for concern?

PubMed

Berry, C; Sattar, N

2011-04-01

Obesity in young people is an emerging public health problem, particularly because of its association with type 2 diabetes. Since obesity and diabetes contribute to the development of cardiovascular disease in adults, the question arises as to whether or not these conditions may be associated with cardiovascular abnormalities in children and adolescents. In this issue of Diabetologia, Shah et al. report the results of a cross-sectional study of heart structure and function in 612 adolescents and young adults (aged 10-24 years) subdivided into three groups: (1) those with obesity and type 2 diabetes; (2) those with type 2 diabetes but without obesity; and (3) lean healthy controls. Their results revealed that left ventricular mass (indexed to body surface area) was greater in the obese individuals than in lean controls. Left ventricular systolic function was more dynamic in obese participants and obese participants with type 2 diabetes compared with lean controls, whereas systolic function was comparable in obese patients with or without type 2 diabetes. Furthermore, compared with the healthy lean control participants, diastolic function was impaired in the obese group and further impaired in the obese individuals with diabetes. These results, and those of a few other similar studies, lend support to the notion that obesity and diabetes in children cause subtle abnormalities in cardiovascular structure and function. The present commentary discusses potential mechanisms and possible clinical ramifications for such findings.

Hepatic delta 6-desaturase activity in lean and genetically obese ob/ob mice.

PubMed Central

Hughes, S; York, D A

1985-01-01

Hepatic delta 6-desaturase activity is primarily located in the mitochondrial fraction in mice. Both delta 6- and delta 5-desaturase activities are increased in the liver of young (6-week-old) obese mice. The increase in hepatic delta 6-desaturase activity in obese mice does not occur until weaning. Neither restriction of food intake nor hyperinsulinaemia normalize hepatic delta 6-desaturase activity of obese mice. Both cold acclimation and tri-iodothyronine (30 micrograms/day per kg) decreased hepatic delta 6-desaturase activity of obese mice to levels observed in lean mice, whereas the increase in activity in obese mice was still maintained after the induction of hypothyroidism. PMID:3977836

B cells promote inflammation in obesity and type 2 diabetes through regulation of T-cell function and an inflammatory cytokine profile

PubMed Central

DeFuria, Jason; Belkina, Anna C.; Jagannathan-Bogdan, Madhumita; Snyder-Cappione, Jennifer; Carr, Jordan David; Nersesova, Yanina R.; Markham, Douglas; Strissel, Katherine J.; Watkins, Amanda A.; Zhu, Min; Allen, Jessica; Bouchard, Jacqueline; Toraldo, Gianluca; Jasuja, Ravi; Obin, Martin S.; McDonnell, Marie E.; Apovian, Caroline; Denis, Gerald V.; Nikolajczyk, Barbara S.

2013-01-01

Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell–null mice have decreased systemic inflammation, inflammatory B- and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell–null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D. PMID:23479618

Chronic rapamycin treatment causes diabetes in male mice

PubMed Central

Schindler, Christine E.; Partap, Uttara; Patchen, Bonnie K.

2014-01-01

Current evidence indicates that the mammalian target of rapamycin inhibitor rapamycin both increases longevity and, seemingly contradictorily, impairs glucose homeostasis. Most studies exploring the dimensions of this paradox have been based on rapamycin treatment in mice for up to 20 wk. We sought to better understand the metabolic effects of oral rapamycin over a substantially longer period of time in HET3 mice. We observed that treatment with rapamycin for 52 wk induced diabetes in male mice, characterized by hyperglycemia, significant urine glucose levels, and severe glucose and pyruvate intolerance. Glucose intolerance occurred in male mice by 4 wk on rapamycin and could be only partially reversed with cessation of rapamycin treatment. Female mice developed moderate glucose intolerance over 1 yr of rapamycin treatment, but not diabetes. The role of sex hormones in the differential development of diabetic symptoms in male and female mice was further explored. HET3 mice treated with rapamycin for 52 wk were gonadectomized and monitored over 10 wk. Castrated male mice remained glucose intolerant, while ovariectomized females developed significant glucose intolerance over the same time period. Subsequent replacement of 17β-estradiol (E2) in ovariectomized females promoted a recovery of glucose tolerance over a 4-wk period, suggesting the protective role of E2 against rapamycin-induced diabetes. These results indicate that 1) oral rapamycin treatment causes diabetes in male mice, 2) the diabetes is partially reversible with cessation of treatment, and 3) E2 plays a protective role against the development of rapamycin-induced diabetes. PMID:24965794

Cellular Plasticity in the Diabetic Myocardium

DTIC Science & Technology

2017-09-01

demonstrated that obese diabetic db/db mice in a C57Bl6J background exhibit cardiac remodeling, associated with modest ventricular dilation...HFpEF, the cellular basis for fibrotic remodeling of the ventricle is poorly understood. Metabolic diseases (such as obesity and diabetes) are

Anti-diabetic effects of rice hull smoke extract in alloxan-induced diabetic mice

USDA-ARS?s Scientific Manuscript database

We investigated the protective effect of a liquid rice hull smoke extract (RHSE) against diabetes in alloxan-induced diabetic mice. Anti-diabetic effects of RHSE were evaluated in both the rat insulinoma-1 cell line (INS-1) and diabetic ICR mice induced by inraperitoneal (ip) injection of alloxan. ...

Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

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

Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro

2011-07-08

Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan,more » an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation

Diet-Induced Obesity Alters Vincristine Pharmacokinetics in Blood and Tissues of Mice

PubMed Central

Behan, James W.; Avramis, Vassilios I.; Yun, Jason P.; Louie, Stan G.; Mittelman, Steven D.

2010-01-01

Obesity is associated with poorer outcome from many cancers, including leukemia. One possible contributor to this could be suboptimal chemotherapy dosing in obese patients. We have previously found that vincristine (VCR) is less effective in obese compared to non-obese mice with leukemia, despite weight-based dosing. In the present study, we administered 3H-VCR to obese and control mice to determine whether obesity would cause suboptimal VCR exposure. Blood VCR concentrations were fitted with a 3-compartment model using pharmacokinetic analysis (two-stage PK) in 3 subsets of VCR concentrations vs. time method. Tissue and blood VCR concentrations were also analyzed using non-compartmental modeling. Blood VCR concentrations showed a triexponential decay and tended to be slightly higher in the obese mice at all time-points. However, the t½β and t½γ were shorter in the obese mice (9.7 vs. 44.5 minutes and 60.3 vs. 85.6 hours, respectively), resulting in a lower AUC0→∞ (13,099 vs. 15,384 ng/ml*hr). Had the dose of VCR been “capped”, as is done in clinical practice, the AUC0→∞ would have been 36% lower in the obese mice than the controls. Tissue disposition of VCR revealed a biexponential decay from spleen, liver, and adipose. Interestingly, VCR slowly accumulated in the bone marrow of control mice, but had a slow decay from the marrow in the obese mice. Thus, obesity alters VCR PK, causing a lower overall exposure in circulation and bone marrow. Given the high prevalence of obesity, additional PK studies should be performed in obese subjects to optimize chemotherapy dosing regimens. PMID:20083201

AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice.

PubMed

Mallol, Cristina; Casana, Estefania; Jimenez, Veronica; Casellas, Alba; Haurigot, Virginia; Jambrina, Claudia; Sacristan, Victor; Morró, Meritxell; Agudo, Judith; Vilà, Laia; Bosch, Fatima

2017-07-01

Type 1 diabetes is characterized by autoimmune destruction of β-cells leading to severe insulin deficiency. Although many improvements have been made in recent years, exogenous insulin therapy is still imperfect; new therapeutic approaches, focusing on preserving/expanding β-cell mass and/or blocking the autoimmune process that destroys islets, should be developed. The main objective of this work was to test in non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, the effects of local expression of Insulin-like growth factor 1 (IGF1), a potent mitogenic and pro-survival factor for β-cells with immunomodulatory properties. Transgenic NOD mice overexpressing IGF1 specifically in β-cells (NOD-IGF1) were generated and phenotyped. In addition, miRT-containing, IGF1-encoding adeno-associated viruses (AAV) of serotype 8 (AAV8-IGF1-dmiRT) were produced and administered to 4- or 11-week-old non-transgenic NOD females through intraductal delivery. Several histological, immunological, and metabolic parameters were measured to monitor disease over a period of 28-30 weeks. In transgenic mice, local IGF1 expression led to long-term suppression of diabetes onset and robust protection of β-cell mass from the autoimmune insult. AAV-mediated pancreatic-specific overexpression of IGF1 in adult animals also dramatically reduced diabetes incidence, both when vectors were delivered before pathology onset or once insulitis was established. Transgenic NOD-IGF1 and AAV8-IGF1-dmiRT-treated NOD animals had much less islet infiltration than controls, preserved β-cell mass, and normal insulinemia. Transgenic and AAV-treated islets showed less expression of antigen-presenting molecules, inflammatory cytokines, and chemokines important for tissue-specific homing of effector T cells, suggesting IGF1 modulated islet autoimmunity in NOD mice. Local expression of Igf1 by AAV-mediated gene transfer counteracts progression to diabetes in NOD mice. This study suggests a

May diabetes patients have trouble sleeping despite not having obesity?

PubMed

Rizzi, Maurizio; Razionale, Giancarlo; Bamberga, Michele; Barrella, Massimo; Kotzalidis, Georgios D; Certan, Diana; Bevilacqua, Maurizio

2014-06-01

Obstructive sleep apnea (OSA) and periodic limb movements during sleep (PLMs) are sleep-related disorders with a high prevalence in type 2 diabetes. Commonly OSA is considered as a consequence of obesity, but several previous studies have shown the presence of OSA in non-obese diabetic patients. A previous study showed higher PLMs prevalence in patients with type 2 diabetes, compared to age-matched controls. We speculated that both OSA and PLMs may reflect the presence of diabetic autonomic neuropathy. To test this hypothesis, we compared a group of 112 non-obese patients with type 2 diabetes with 66 age-, sex-, and body mass index- matched nondiabetic patients. Both groups have been investigated through a set of tests including the Epworth Sleepiness Scale, polysomnography, and the Orthostatic Grading Scale (OGS), a questionnaire to assess the degree of autonomic dysfunction. Diabetic patients with OSA and PLMs scored higher on the OGS than controls. Our results confirm that both OSA and PLMs are related to dysautonomy and may be unrelated to obesity in type 2 diabetes patients.

Delivery of RNAi reagents in murine models of obesity and diabetes.

PubMed

Wilcox, Denise M; Yang, Ruojing; Morgan, Sherry J; Nguyen, Phong T; Voorbach, Martin J; Jung, Paul M; Haasch, Deanna L; Lin, Emily; Bush, Eugene N; Opgenorth, Terry J; Jacobson, Peer B; Collins, Christine A; Rondinone, Cristina M; Surowy, Terry; Landschulz, Katherine T

2006-11-29

RNA interference (RNAi) is an exciting new tool to effect acute in vivo knockdown of genes for pharmacological target validation. Testing the application of this technology to metabolic disease targets, three RNAi delivery methods were compared in two frequently utilized preclinical models of obesity and diabetes, the diet-induced obese (DIO) and B6.V-Lep/J (ob/ob) mouse. Intraperitoneal (i.p.) and high pressure hydrodynamic intravenous (i.v.) administration of naked siRNA, and low pressure i.v. administration of shRNA-expressing adenovirus were assessed for both safety and gene knockdown efficacy using constructs targeting cJun N-terminal kinase 1 (JNK1). Hydrodynamic delivery of siRNA lowered liver JNK1 protein levels 40% in DIO mice, but was accompanied by iatrogenic liver damage. The ob/ob model proved even more intolerant of this technique, with hydrodynamic delivery resulting in severe liver damage and death of most animals. While well-tolerated, i.p. injections of siRNA in DIO mice did not result in any knockdown or phenotypic changes in the mice. On the other hand, i.v. injected adenovirus expressing shRNA potently reduced expression of JNK1 in vivo by 95% without liver toxicity. In conclusion, i.p. and hydrodynamic injections of siRNA were ineffective and/or inappropriate for in vivo gene targeting in DIO and ob/ob mice, while adenovirus-mediated delivery of shRNA provided a relatively benign and effective method for exploring liver target silencing.

MAP4K4 and IL-6+ Th17 cells play important roles in non-obese type 2 diabetes.

PubMed

Chuang, Huai-Chia; Tan, Tse-Hua

2017-01-07

Obesity is a causal factor of type 2 diabetes (T2D); however, people without obesity (including lean, normal weight, or overweight) may still develop T2D. Non-obese T2D is prevalent in Asia and also frequently occurs in Europe. Recently, multiple evidences oppose the notion that either obesity or central obesity (visceral fat accumulation) promotes non-obese T2D. Several factors such as inflammation and environmental factors contribute to non-obese T2D. According to the data derived from gene knockout mice and T2D clinical samples in Asia and Europe, the pathogenesis of non-obese T2D has been unveiled recently. MAP4K4 downregulation in T cells results in enhancement of the IL-6 + Th17 cell population, leading to insulin resistance and T2D in both human and mice. Moreover, MAP4K4 single nucleotide polymorphisms and epigenetic changes are associated with T2D patients. Interactions between MAP4K4 gene variants and environmental factors may contribute to MAP4K4 attenuation in T cells, leading to non-obese T2D. Future investigations of the pathogenesis of non-obese T2D shall lead to development of precision medicine for non-obese T2D.

Exercise decreases CLK2 in the liver of obese mice and prevents hepatic fat accumulation.

PubMed

Muñoz, Vitor R; Gaspar, Rafael C; Kuga, Gabriel K; Nakandakari, Susana C B R; Baptista, Igor L; Mekary, Rania A; da Silva, Adelino S R; de Moura, Leandro P; Ropelle, Eduardo R; Cintra, Dennys E; Pauli, José R

2018-03-25

The accumulation of fatty acids in the liver associated with obesity condition is also known as nonalcoholic fatty liver disease (NAFLD). The impaired fat oxidation in obesity condition leads to increased hepatic fat accumulation and increased metabolic syndrome risk. On the other hand, physical exercise has been demonstrated as a potent strategy in the prevention of NAFLD. Also, these beneficial effects of exercise occur through different mechanisms. Recently, the Cdc2-like kinase (CLK2) protein was associated with the suppression of fatty acid oxidation and hepatic ketogenesis. Thus, obese animals demonstrated elevated levels of hepatic CLK2 and decreased fat acid oxidation. Here, we explored the effects of chronic physical exercise in the hepatic metabolism of obese mice. Swiss mice were distributed in Lean, Obese (fed with high-fat diet during 16 weeks) and Trained Obese group (fed with high-fat diet during 16 weeks and exercised (at 60% exhaustion velocity during 1 h/5 days/week) during 8 weeks. In our results, the obese animals showed insulin resistance, increased hepatic CLK2 content and increased hepatic fat accumulation compared to the Lean group. Otherwise, the chronic physical exercise improved insulin resistance state, prevented the increased CLK2 in the liver and attenuated hepatic fat accumulation. In summary, these data reveal a new protein involved in the prevention of hepatic fat accumulation after chronic physical exercise. More studies can evidence the negative role of CLK2 in the control of liver metabolism, contributing to the improvement of insulin resistance, obesity, and type 2 diabetes. © 2018 Wiley Periodicals, Inc.

Effects of Selenium Supplementation on the Diabetic Condition Depend on the Baseline Selenium Status in KKAy Mice.

PubMed

Febiyanto, Novian; Yamazaki, Chiho; Kameo, Satomi; Sari, Dian K; Puspitasari, Irma M; Sunjaya, Deni K; Herawati, Dewi M D; Nugraha, Gaga I; Fukuda, Toshio; Koyama, Hiroshi

2018-01-01

Oxidative stress in obesity leads to insulin resistance in type 2 diabetes. Some selenoproteins possess antioxidant properties, suggesting that selenium (Se) may protect against type 2 diabetes; however, evidence from epidemiological studies is contradictory. We hypothesized that Se status before supplementation (baseline) contributes to the supplementation outcome. This study aimed to clarify the influence of baseline Se status on the effect of Se supplementation on the diabetic condition. Six-week-old KKAy mice were fed a diet without supplemental Se or with 0.1 ppm Se in the form of L-selenomethionine (SeM) for 2 weeks to create low-Se and sufficient-Se baseline statuses, respectively. For the next 4 weeks, low-Se mice were given a SeM (0.5 ppm Se)-supplemented diet, and sufficient-Se mice were given either a SeM (0.5 ppm Se)- or sodium selenite (0.5 ppm Se)-supplemented diet; control groups continued on baseline diets. Serum Se concentrations, glutathione peroxidase (GPx) activities, adiponectin levels, glucose tolerance, and insulin sensitivity were analyzed. All mice became diabetic during the 2-week baseline induction period. At the end of the supplementation period, Se-receiving groups demonstrated significantly higher Se concentrations and GPx activities than their respective controls. Sufficient-Se mice receiving SeM had lower blood glucose levels and better insulin sensitivity than control and sodium selenite-receiving mice, whereas low-Se mice receiving SeM showed no such improvements compared with their controls. Our results suggest that Se supplementation in the form of SeM may help prevent type 2 diabetes aggravation in people taking the 55 μg/day Se recommended dietary allowance.

Anti-diabetic properties of Momordica charantia L. polysaccharide in alloxan-induced diabetic mice.

PubMed

Xu, Xin; Shan, Bin; Liao, Cai-Hu; Xie, Jian-Hua; Wen, Ping-Wei; Shi, Jia-Yi

2015-11-01

A water-soluble polysaccharide (MCP) was isolated from the fruits of Momordica charantia L., and the hypoglycemic effects of MCP were investigated in both normal healthy and alloxan-induced diabetic mice. MCP was orally administered once a day after 3 days of alloxan-induction at 100, 200 and 300mg/kg body weight for 28 day. Results showed that fasting blood glucose level (BGL) was significantly decreased, whereas the glucose tolerance was marked improvement in alloxan-induced diabetic mice, and loss in body weight was also prevented in diabetic mice compared to the diabetic control group. The dosage of 300mg/kg body weight exhibited the best effects. In addition, MCP did not exhibit any toxic symptoms in the limited toxicity evaluation in mice. The results suggest that MCP possess significantly dose-dependent anti-diabetic activity on alloxan-induced diabetic mice. Hence, MCP can be incorporated as a supplement in health-care food, drugs and/or combined with other hypoglycemic drugs. Copyright © 2015 Elsevier B.V. All rights reserved.

The induction of autoimmune hepatitis in the human leucocyte antigen‐DR4 non‐obese diabetic mice autoimmune hepatitis mouse model

PubMed Central

Yuksel, M.; Xiao, X.; Tai, N.; Vijay, G. M.; Gülden, E.; Beland, K.; Lapierre, P.; Alvarez, F.; Hu, Z.; Colle, I.; Ma, Y.

2016-01-01

Summary Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti‐smooth muscle actin and/or anti‐nuclear, anti‐liver kidney microsomal type 1 (anti‐LKM1) and anti‐liver cytosol type 1 (anti‐LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)‐DR3, ‐DR7 and ‐DR13. HLA‐DR4 has the second strongest association with adult AIH, after HLA‐DR3. We investigated the role of HLA‐DR4 in the development of AIH by immunization of HLA‐DR4 (DR4) transgenic non‐obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti‐LKM1/anti‐LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (Tregs), which had decreased programmed death (PD)‐1 expression. Splenic Tregs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8+ T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild‐type (WT) NOD mice. Our results demonstrate that HLA‐DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of Tregs and reduced PD‐1 expression may result in spontaneous activation of key immune cell subsets, such as antigen‐presenting cells and CD8+ T effectors, facilitating the induction of AIH and persistent liver damage. PMID:27414259

The induction of autoimmune hepatitis in the human leucocyte antigen-DR4 non-obese diabetic mice autoimmune hepatitis mouse model.

PubMed

Yuksel, M; Xiao, X; Tai, N; Vijay, G M; Gülden, E; Beland, K; Lapierre, P; Alvarez, F; Hu, Z; Colle, I; Ma, Y; Wen, L

2016-11-01

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by progressive inflammation, female preponderance and seropositivity for autoantibodies such as anti-smooth muscle actin and/or anti-nuclear, anti-liver kidney microsomal type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) in more than 80% of cases. AIH is linked strongly to several major histocompatibility complex (MHC) alleles, including human leucocyte antigen (HLA)-DR3, -DR7 and -DR13. HLA-DR4 has the second strongest association with adult AIH, after HLA-DR3. We investigated the role of HLA-DR4 in the development of AIH by immunization of HLA-DR4 (DR4) transgenic non-obese diabetic (NOD) mice with DNA coding for human CYP2D6/FTCD fusion autoantigen. Immunization of DR4 mice leads to sustained mild liver injury, as assessed biochemically by elevated alanine aminotransferase, histologically by interface hepatitis, plasma cell infiltration and mild fibrosis and immunologically by the development of anti-LKM1/anti-LC1 antibodies. In addition, livers from DR4 mice had fewer regulatory T cells (T regs ), which had decreased programmed death (PD)-1 expression. Splenic T regs from these mice also showed impaired inhibitory capacity. Furthermore, DR4 expression enhanced the activation status of CD8 + T cells, macrophages and dendritic cells in naive DR4 mice compared to naive wild-type (WT) NOD mice. Our results demonstrate that HLA-DR4 is a susceptibility factor for the development of AIH. Impaired suppressive function of T regs and reduced PD-1 expression may result in spontaneous activation of key immune cell subsets, such as antigen-presenting cells and CD8 + T effectors, facilitating the induction of AIH and persistent liver damage. © 2016 British Society for Immunology.

Do obese children with diabetic ketoacidosis have type 1 or type 2 diabetes?

PubMed

Low, Joey C; Felner, Eric I; Muir, Andrew B; Brown, Milton; Dorcelet, Margalie; Peng, Limin; Umpierrez, Guillermo E

2012-04-01

Many obese children with unprovoked diabetic ketoacidosis (DKA) display clinical features of type 2 diabetes during follow up. We describe the clinical presentation, autoimmune markers and the long-term course of obese and lean children with DKA. We reviewed the medical records on the initial acute hospitalization and outpatient follow-up care of 21 newly diagnosed obese and 20 lean children with unprovoked DKA at Emory University affiliated children's hospitals between 1/2003 and 12/2006. Obese children with DKA were older and predominantly male, had acanthosis nigricans, and had lower prevalence of autoantibodies to islet cells and glutamic acid decarboxylase than lean children. Half of the obese, but none of the lean children with DKA achieve near-normoglycemia remission and discontinued insulin therapy during follow-up. Time to achieve remission was 2.2±2.3 months. There were no differences on clinical presentation between obese children who achieved near-normoglycemia remission versus those who did not. The addition of metformin to insulin therapy shortly after resolution of DKA resulted in lower hemoglobin A1c (HbA1c) levels, higher rates of near-normoglycemia remission, and lower frequency of DKA recurrence. Near-normoglycemia remission, however, was of short duration and the majority of obese patients required reinstitution of insulin treatment within 15 months of follow-up. In contrast to lean children with DKA, many obese children with unprovoked DKA display clinical and immunologic features of type 2 diabetes during follow-up. The addition of metformin to insulin therapy shortly after resolution of DKA improves glycemic control, facilitates achieving near-normoglycemia remission and prevents DKA recurrence in obese children with DKA. Copyright © 2011 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Diet-induced obesity alters vincristine pharmacokinetics in blood and tissues of mice.

PubMed

Behan, James W; Avramis, Vassilios I; Yun, Jason P; Louie, Stan G; Mittelman, Steven D

2010-05-01

Obesity is associated with poorer outcome from many cancers, including leukemia. One possible contributor to this could be suboptimal chemotherapy dosing in obese patients. We have previously found that vincristine (VCR) is less effective in obese compared to non-obese mice with leukemia, despite weight-based dosing. In the present study, we administered (3)H-VCR to obese and control mice to determine whether obesity would cause suboptimal VCR exposure. Blood VCR concentrations were fitted with a three-compartment model using pharmacokinetic analysis (two-stage PK) in three subsets of VCR concentrations vs. time method. Tissue and blood VCR concentrations were also analyzed using non-compartmental modeling. Blood VCR concentrations showed a triexponential decay and tended to be slightly higher in the obese mice at all time-points. However, the t(1/2,beta) and t(1/2,gamma) were shorter in the obese mice (9.7 min vs. 44.5 min and 60.3h vs. 85.6h, respectively), resulting in a lower AUC(0-infinity) (13,099 ng/m Lh vs. 15,384 ng/mL h). Had the dose of VCR been "capped", as is done in clinical practice, the AUC(0-infinity) would have been 36% lower in the obese mice than the controls. Tissue disposition of VCR revealed a biexponential decay from spleen, liver, and adipose. Interestingly, VCR slowly accumulated in the bone marrow of control mice, but had a slow decay from the marrow in the obese mice. Thus, obesity alters VCR PK, causing a lower overall exposure in circulation and bone marrow. Given the high prevalence of obesity, additional PK studies should be performed in obese subjects to optimize chemotherapy dosing regimens. (c) 2010 Elsevier Ltd. All rights reserved.

Racial/Ethnic Residential Segregation, Obesity, and Diabetes Mellitus.

PubMed

Kershaw, Kiarri N; Pender, Ashley E

2016-11-01

Persistent racial/ethnic disparities in obesity and type 2 diabetes mellitus seen in the US are likely due to a combination of social, biological, and environmental factors. A growing number of studies have examined the role of racial/ethnic residential segregation with respect to these outcomes because this macro-level process is believed to be a fundamental cause of many of the factors that contribute to these disparities. This review provides an overview of findings from studies of racial/ethnic residential segregation with obesity and diabetes published between 2013 and 2015. Findings for obesity varied by geographic scale of the segregation measure, gender, ethnicity, and racial identity (among Hispanics/Latinos). Recent studies found no association between racial/ethnic residential segregation and diabetes prevalence, but higher segregation of Blacks was related to higher diabetes mortality. Implications of these recent studies are discussed as well as promising areas of future research.

Polyinosine-polycytidylic acid promotes excessive iodine intake induced thyroiditis in non-obese diabetic mice via Toll-like receptor 3 mediated inflammation.

PubMed

Shi, Ya-nan; Liu, Feng-hua; Yu, Xiu-jie; Liu, Ze-bing; Li, Qing-xin; Yuan, Ji-hong; Zang, Xiao-yi; Li, Lan-ying

2013-02-01

Excessive iodine intake and viral infection are recognized as both critical factors associated with autoimmune thyroid diseases. Toll-like receptors (TLRs) have been reported to play an important role in autoimmune and inflammatory disorders. In this study, we aimed to clarify the possible mechanism of TLR3 involved in polyinosine-polycytidylic acid (poly(I:C)) promoting excessive iodine intake induced thyroiditis in non-obese diabetic (NOD) mice. Both NOD and BALB/c mice were randomly assigned to four groups: control group (n = 5), high iodine intake (HI) group (n = 7), poly(I:C) group (n = 7) and combination of excessive iodine and poly(I:C) injection (HIP) group (n = 7). After 8 weeks, mice were weighed and blood samples were collected. All the mice were sacrificed before dissection of spleen and thyroid gland. Then, thyroid histology, thyroid secreted hormone, expression of CD3(+) cells and TLR3 as well as inflammatory mRNA level were evaluated. Both NOD and BALB/c mice from HI and HIP group represented goiter and increasing thyroid relative weight. Thyroid histology evidence indicated that only HIP group of NOD mice showed severe thyroiditis with lymphocytes infiltration in majority of thyroid tissue, severe damage of follicles and general fibrosis. Immunofluorescence staining results displayed a large number of CD3(+) cells in HIP NOD mice. Real-time polymerase chain reaction (PCR) results suggested interferon (IFN)-α increased over 30 folds and IFN-γ expression was doubled compared with control group, but interleukin (IL)-4 remained unchanged in HIP group of NOD mice thyroid. Meanwhile, over one third decrease of blood total thyroxine (TT4) and increased thyroid-stimulating hormone (TSH) was observed in HIP group of NOD mice. Only HIP group of NOD mice represented significantly elevation of TLR3 expression. Poly(I:C) enhanced excessive dietary iodine induced thyroiditis in NOD mice through increasing TLR3 mediated inflammation.

Effect of acute ozone exposure on the lung metabolomes of obese and lean mice.

PubMed

Mathews, Joel Andrew; Kasahara, David Itiro; Cho, Youngji; Bell, Lauren Nicole; Gunst, Philip Ross; Karoly, Edward D; Shore, Stephanie Ann

2017-01-01

Pulmonary responses to the air pollutant, ozone, are increased in obesity. Both obesity and ozone cause changes in systemic metabolism. Consequently, we examined the impact of ozone on the lung metabolomes of obese and lean mice. Lean wildtype and obese db/db mice were exposed to acute ozone (2 ppm for 3 h) or air. 24 hours later, the lungs were excised, flushed with PBS to remove blood and analyzed via liquid-chromatography or gas-chromatography coupled to mass spectrometry for metabolites. Both obesity and ozone caused changes in the lung metabolome. Of 321 compounds identified, 101 were significantly impacted by obesity in air-exposed mice. These included biochemicals related to carbohydrate and lipid metabolism, which were each increased in lungs of obese versus lean mice. These metabolite changes may be of functional importance given the signaling capacity of these moieties. Ozone differentially affected the lung metabolome in obese versus lean mice. For example, almost all phosphocholine-containing lysolipids were significantly reduced in lean mice, but this effect was attenuated in obese mice. Glutathione metabolism was also differentially affected by ozone in obese and lean mice. Finally, the lung metabolome indicated a role for the microbiome in the effects of both obesity and ozone: all measured bacterial/mammalian co-metabolites were significantly affected by obesity and/or ozone. Thus, metabolic derangements in obesity appear to impact the response to ozone.

Role of Omentin, Vaspin, Cardiotrophin-1, TWEAK and NOV/CCN3 in Obesity and Diabetes Development

PubMed Central

Escoté, Xavier; Gómez-Zorita, Saioa; López-Yoldi, Miguel; Fernández-Quintela, Alfredo; Moreno-Aliaga, María J.; Portillo, María P.

2017-01-01

Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects of omentin, vaspin, cardiotrophin-1, Tumor necrosis factor-like Weak Inducer of Apoptosis (TWEAK) and nephroblastoma overexpressed (NOV/CCN3) on obesity and diabetes. Omentin is produced by the stromal-vascular fraction of visceral adipose tissue. Obesity reduces omentin serum concentrations and adipose tissue secretion in adults and adolescents. This adipokine regulates insulin sensitivity, but its clinical relevance has to be confirmed. Vaspin is produced by visceral and subcutaneous adipose tissues. Vaspin levels are higher in obese subjects, as well as in subjects showing insulin resistance or type 2 diabetes. Cardiotrophin-1 is an adipokine with a similar structure as cytokines from interleukin-6 family. There is some controversy regarding the regulation of cardiotrophin-1 levels in obese -subjects, but gene expression levels of cardiotrophin-1 are down-regulated in white adipose tissue from diet-induced obese mice. It also shows anti-obesity and hypoglycemic properties. TWEAK is a potential regulator of the low-grade chronic inflammation characteristic of obesity. TWEAK levels seem not to be directly related to adiposity, and metabolic factors play a critical role in its regulation. Finally, a strong correlation has been found between plasma NOV/CCN3 concentration and fat mass. This adipokine improves insulin actions. PMID:28809783

Transgenic neuronal expression of proopiomelanocortin attenuates hyperphagic response to fasting and reverses metabolic impairments in leptin-deficient obese mice.

PubMed

Mizuno, Tooru M; Kelley, Kevin A; Pasinetti, Giulio M; Roberts, James L; Mobbs, Charles V

2003-11-01

Hypothalamic proopiomelanocortin (POMC) gene expression is reduced in many forms of obesity and diabetes, particularly in those attributable to deficiencies in leptin or its receptor. To assess the functional significance of POMC in mediating metabolic phenotypes associated with leptin deficiency, leptin-deficient mice bearing a transgene expressing the POMC gene under control of the neuron-specific enolase promoter were produced. The POMC transgene attenuated fasting-induced hyperphagia in wild-type mice. Furthermore, the POMC transgene partially reversed obesity, hyperphagia, and hypothermia and effectively normalized hyperglycemia, glucosuria, glucose intolerance, and insulin resistance in leptin-deficient mice. Effects of the POMC transgene on glucose homeostasis were independent of the partial correction of hyperphagia and obesity. Furthermore, the POMC transgene normalized the profile of hepatic and adipose gene expression associated with gluconeogenesis, glucose output, and insulin sensitivity. These results indicate that central POMC is a key modulator of glucose homeostasis and that agonists of POMC products may provide effective therapy in treating impairments in glucose homeostasis when hypothalamic POMC expression is reduced, as occurs with leptin deficiency, hypothalamic damage, and aging.

Prevalence of Diabetes and Associated Obesity in Pennsylvania Adults, 1995–2010

PubMed Central

Lengerich, Eugene J.; Camacho, Fabian; Gallant, Nancy R.; Wray, Linda A.; Ahern, Frank; Bogdan, Greg; Weinberg, Gene; Ulbrecht, Jan S.

2014-01-01

Introduction This study examined trends in the prevalence and sociodemographic distributions of diabetes and the associations of diabetes with obesity over time in adult Pennsylvanians from 1995 through 2010. Methods We used Behavioral Risk Factor Surveillance Survey data collected from 1995 through 2010. Diabetes prevalence was assessed by self-report of physician diagnosis. Obesity was assessed by body mass index computed from self-report of height and weight. State-level data for diabetes and associated obesity prevalence from 1995 through 2010 were collected for each year. Data on sociodemographic factors (age, sex, race, income, education) and 1 known disease risk factor (obesity) were also collected. Logistic regression modeling was used to examine associations between diabetes, sociodemographic factors, and obesity. Results Diabetes prevalence in Pennsylvania, which increased from 5.6% in 1995 to 10.5% in 2010, followed national trends but exceeded the national prevalence each year by approximately 0.6 percentage points for 12 of the 16 years. The increase in prevalence was not equal across all socioeconomic groups. Obesity became a more dominant risk factor for diabetes during these 16 years. Conclusion The burden of diabetes and obesity in Pennsylvania is substantial and increasing. Program managers and policy makers in Pennsylvania should consider these trends when allocating limited resources and designing programs for reducing diabetes-related illness. Other states may consider similar studies to monitor the prevalence of diabetes and determine whether disparities are changing and whether programs and resources should also shift. PMID:24995653

Anti-obesity and pro-diabetic effects of hemochromatosis.

PubMed

Abbas, Mousa Al; Abraham, Deveraprabu; Kushner, James P; McClain, Donald A

2014-10-01

Levels of tissue iron contribute to determining diabetes risk, but little is known about the effects of higher iron levels on weight, and on the interaction of weight and iron overload on diabetes risk. Therefore, the effect of iron on body mass index and diabetes in individuals with iron overload from hereditary hemochromatosis (HH), compared to non-HH siblings and historical controls was examined. Chart reviews were performed on a cohort of adults (age ≥40, N = 101) with the common C282Y/C282Y HFE genotype, compared to wild type siblings (N = 32) and comparable NHANES cohorts, with respect to body mass index and diabetes status. Males with HH have lower body mass index (BMI) than control siblings. Females had a trend toward decreased BMI that was not significant, possibly related to decreased degrees of iron overload. In both males and females, increased rates of diabetes were seen, especially in the overweight or obese. High tissue iron levels may be both pro- and anti-diabetic. The prevalence of obesity and diabetes in HH is likely dependent upon the degree of iron overload, caloric intake, and other genetic and environmental factors, contributing to the observed heterogeneity in the frequency of disease-related morbidities in HH. Copyright © 2014 The Obesity Society.

Gastric bypass surgery reveals independency of obesity and diabetes melitus type 2.

PubMed

Fenger, Mogens; Hansen, Dorte Lindqvist; Worm, Dorte; Hvolris, Lisbeth; Kristiansen, Viggo B; Carlsson, Elin Rebecka; Madsbad, Sten

2016-11-09

Roux-en-Y gastric bypass surgery is widely applied to ameliorate morbid obesity, including diabetes in people with type 2 diabetes. The latter vanish a few days after surgery for many, but not in all patients before any weight reduction has occurred. The explanation for this change in metabolic status is poorly understood, but the observation may suggest that the fate obesity and diabetes is only partly linked after surgery. The trajectories of weight reduction measured as reduced body mass index (BMI) in 741obese subjects with and without diabetes were evaluated. Evaluation was performed on three groups: 1) subjects that were non-diabetic before and after surgery; 2) subjects that were diabetics before surgery but non-diabetics after surgery; and 3) subjects that were diabetics before surgery and remained diabetics after surgery. The diabetic state was established at HbA1c above 48 mmol/mol. The trajectories differ significantly between groups and any sub-populations of groups, the latter identified by the distance between individual trajectories using a k-means procedure. The results suggest that different domains in the enormous genetic network governing basic metabolism are perturbed in obesity and diabetes, and in fact some of the patients are affected by two distinct diseases: obesity and diabetes mellitus type 2. Although RYGB "normalized" many glycaemic parameters in some of the diabetic subjects apparently converting to a non-diabetics state, other diabetic subjects stay diabetic in the context of the new gut anatomy after surgery. Thus, the obesity part of the glycaemic derangement may have been ameliorated, but some defects of the diabetic state had not.

α-Motoneurons maintain biophysical heterogeneity in obesity and diabetes in Zucker rats.

PubMed

MacDonell, Christopher W; Chopek, Jeremy W; Gardiner, Kalan R; Gardiner, Phillip F

2017-10-01

Small-diameter sensory dysfunction resulting from diabetes has received much attention in the literature, whereas the impact of diabetes on α-motoneurons (MN) has not. In addition, the chance of developing insulin resistance and diabetes is increased in obesity. No study has examined the impact of obesity or diabetes on the biophysical properties of MN. Lean Zucker rats and Zucker diabetic fatty (ZDF) rats were separated into lean, obese (ZDF fed standard chow), and diabetic (ZDF fed high-fat diet that led to diabetes) groups. Glass micropipettes recorded hindlimb MN properties from identified flexor and extensor MN. MN were separated within their groups on the basis of input conductance, which created high- and low-input conductance subpopulations for each. A significant shorter (20%) afterhyperpolarization half-decay (AHP 1/2 ) was found in low-conductance MN for the diabetic group only, whereas AHP½ tended to be shorter in the obese group (19%). Significant positive correlations were found among rheobase and input conductance for both lean and obese animals. No differences were found between the groups for afterhyperpolarization amplitude (AHP amp ), input conductance, rheobase, or any of the rhythmic firing properties (frequency-current slope and spike-frequency adaptation index). MN properties continue to be heterogeneous in obese and diabetic animals. Obesity does not seem to influence lumbar MN. Despite the resistance of MN to the impact of diabetes, the reduced AHP 1/2 decay and the tendency for a reduction in AHP amp may be the first sign of change to MN function. NEW & NOTEWORTHY Knowledge about the impact of obesity and diabetes on the biophysical properties of motoneurons is lacking. We found that diabetes reduces the duration of the afterhyperpolarization and that motoneuron function is unchanged by obesity. A reduced afterhyperpolarization may impact discharge characteristics and may be the first sign of change to motoneuron function. Copyright �

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

PubMed Central

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

2014-01-01

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

The JAK/STAT pathway in obesity and diabetes.

PubMed

Gurzov, Esteban N; Stanley, William J; Pappas, Evan G; Thomas, Helen E; Gough, Daniel J

2016-08-01

Diabetes mellitus are complex, multi-organ metabolic pathologies characterized by hyperglycemia. Emerging evidence shows that the highly conserved and potent JAK/STAT signaling pathway is required for normal homeostasis, and, when dysregulated, contributes to the development of obesity and diabetes. In this review, we analyze the role of JAK/STAT activation in the brain, liver, muscle, fat and pancreas, and how this affects the course of the disease. We also consider the therapeutic implications of targeting the JAK/STAT pathway in treatment of obesity and diabetes. © 2016 Federation of European Biochemical Societies.

Delayed Intervention With Pyridoxamine Improves Metabolic Function and Prevents Adipose Tissue Inflammation and Insulin Resistance in High-Fat Diet-Induced Obese Mice.

PubMed

Maessen, Dionne E; Brouwers, Olaf; Gaens, Katrien H; Wouters, Kristiaan; Cleutjens, Jack P; Janssen, Ben J; Miyata, Toshio; Stehouwer, Coen D; Schalkwijk, Casper G

2016-04-01

Obesity is associated with an increased risk for the development of type 2 diabetes and vascular complications. Advanced glycation end products are increased in adipose tissue and have been associated with insulin resistance, vascular dysfunction, and inflammation of adipose tissue. Here, we report that delayed intervention with pyridoxamine (PM), a vitamin B6 analog that has been identified as an antiglycating agent, protected against high-fat diet (HFD)-induced body weight gain, hyperglycemia, and hypercholesterolemia, compared with mice that were not treated. In both HFD-induced and db/db obese mice, impaired glucose metabolism and insulin resistance were prevented by PM supplementation. PM inhibited the expansion of adipose tissue and adipocyte hypertrophy in mice. In addition, adipogenesis of murine 3T3-L1 and human Simpson-Golabi-Behmel Syndrome preadipocytes was dose- and time-dependently reduced by PM, as demonstrated by Oil Red O staining and reduced expression of adipogenic differentiation genes. No ectopic fat deposition was found in the liver of HFD mice. The high expression of proinflammatory genes in visceral adipose tissue of the HFD group was significantly attenuated by PM. Treatment with PM partially prevented HFD-induced mild vascular dysfunction. Altogether, these findings highlight the potential of PM to serve as an intervention strategy in obesity. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Consumption of Acidic Water Alters the Gut Microbiome and Decreases the Risk of Diabetes in NOD Mice

PubMed Central

Wolf, Kyle J.; Daft, Joseph G.; Tanner, Scott M.; Hartmann, Riley; Khafipour, Ehsan

2014-01-01

Infant formula and breastfeeding are environmental factors that influence the incidence of Type 1 Diabetes (T1D) as well as the acidity of newborn diets. To determine if altering the intestinal microbiome is one mechanism through which an acidic liquid plays a role in T1D, we placed non-obese diabetic (NOD)/ShiLtJt mice on neutral (N) or acidified H2O and monitored the impact on microbial composition and diabetes incidence. NOD-N mice showed an increased development of diabetes, while exhibiting a decrease in Firmicutes and an increase in Bacteroidetes, Actinobacteria, and Proteobacteria from as early as 2 weeks of age. NOD-N mice had a decrease in the levels of Foxp3 expression in CD4+Foxp3+ cells, as well as decreased CD4+IL17+ cells, and a lower ratio of IL17/IFNγ CD4+ T-cells. Our data clearly indicates that a change in the acidity of liquids consumed dramatically alters the intestinal microbiome, the presence of protective Th17 and Treg cells, and the incidence of diabetes. This data suggests that early dietary manipulation of intestinal microbiota may be a novel mechanism to delay T1D onset in genetically pre-disposed individuals. PMID:24453191

Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice.

PubMed

Wolf, Kyle J; Daft, Joseph G; Tanner, Scott M; Hartmann, Riley; Khafipour, Ehsan; Lorenz, Robin G

2014-04-01

Infant formula and breastfeeding are environmental factors that influence the incidence of Type 1 Diabetes (T1D) as well as the acidity of newborn diets. To determine if altering the intestinal microbiome is one mechanism through which an acidic liquid plays a role in T1D, we placed non-obese diabetic (NOD)/ShiLtJt mice on neutral (N) or acidified H2O and monitored the impact on microbial composition and diabetes incidence. NOD-N mice showed an increased development of diabetes, while exhibiting a decrease in Firmicutes and an increase in Bacteroidetes, Actinobacteria, and Proteobacteria from as early as 2 weeks of age. NOD-N mice had a decrease in the levels of Foxp3 expression in CD4(+)Foxp3(+) cells, as well as decreased CD4(+)IL17(+) cells, and a lower ratio of IL17/IFNγ CD4+ T-cells. Our data clearly indicates that a change in the acidity of liquids consumed dramatically alters the intestinal microbiome, the presence of protective Th17 and Treg cells, and the incidence of diabetes. This data suggests that early dietary manipulation of intestinal microbiota may be a novel mechanism to delay T1D onset in genetically pre-disposed individuals.

Incident Type 2 Diabetes Risk is Influenced by Obesity and Diabetes in Social Contacts: a Social Network Analysis.

PubMed

Raghavan, Sridharan; Pachucki, Mark C; Chang, Yuchiao; Porneala, Bianca; Fox, Caroline S; Dupuis, Josée; Meigs, James B

2016-10-01

Obesity and diabetes family history are the two strongest risk factors for type 2 diabetes (T2D). Prior work shows that an individual's obesity risk is associated with obesity in social contacts, but whether T2D risk follows similar patterns is unknown. We aimed to estimate the relationship between obesity or diabetes in an individual's social contacts and his/her T2D risk. We hypothesized that obesity and diabetes in social contacts would increase an individual's T2D risk. This was a retrospective analysis of the community-based Framingham Offspring Study (FOS). FOS participants with T2D status, height and weight, and at least one social contact were eligible for this study (n = 4797 at Exam 1). Participants' interpersonal ties, cardiometabolic and demographic variables were available at eight exams from 1971 to 2008, and a T2D additive polygenic risk score was measured at the fifth exam. Primary exposures were T2D (fasting glucose ≥ 7 mmol/L or taking diabetes medications) and obesity status (BMI ≥ 30 kg/m(2)) of social contacts at a prior exam. Primary outcome was incident T2D in participants. Incident T2D was associated with having a social contact with diabetes (OR 1.32, p = 0.004) or with obesity (OR 1.21, p = 0.004). In stratified analyses, incident T2D was associated with diabetes in siblings (OR 1.64, p = 0.001) and obesity in spouses (OR 1.54, p = 0.0004). The associations between diabetes and obesity in social contacts and an individual's incident diabetes risk were stronger in individuals with a high diabetes genetic risk score. T2D and obesity in social contacts, particularly siblings and spouses, were associated with an individual's risk of incident diabetes even after accounting for parental T2D history. Assessing risk factors in an individual's siblings and spouses can inform T2D risk; furthermore, social network based lifestyle interventions involving spouses and siblings might be a novel T2D prevention approach.

Long-term human immune system reconstitution in non-obese diabetic (NOD)-Rag (-)-γ chain (-) (NRG) mice is similar but not identical to the original stem cell donor.

PubMed

Harris, D T; Badowski, M; Balamurugan, A; Yang, O O

2013-12-01

The murine immune system is not necessarily identical to it human counterpart, which has led to the construction of humanized mice. The current study analysed whether or not a human immune system contained within the non-obese diabetic (NOD)-Rag1(null) -γ chain(null) (NRG) mouse model was an accurate representation of the original stem cell donor and if multiple mice constructed from the same donor were similar to one another. To that end, lightly irradiated NRG mice were injected intrahepatically on day 1 of life with purified cord blood-derived CD34(+) stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analysed quarterly for changes in the immune system, and followed for periods up to 12 months post-transplant. Mice from the same donor were compared directly with each other as well as with the original donor. Analyses were performed for immune reconstitution, including flow cytometry, T cell receptor (TCR) and B cell receptor (BCR) spectratyping. It was observed that NRG mice could be 'humanized' long-term using cord blood stem cells, and that animals constructed from the same cord blood donor were nearly identical to one another, but quite different from the original stem cell donor immune system. © 2013 British Society for Immunology.

[Carbohydrate metabolism disorders among obese children and adolescents. Diabetes mellitus type 2].

PubMed

Sergeyev, E; Wagner, I; Neef, M; Adler, M; Körner, A; Kiess, W

2013-04-01

As obesity has become more prevalent, the incidence of type 2 diabetes mellitus in children and adolescents has also increased. Obesity during adolescence leads to an increased risk for disease and premature death during adulthood, independent of obesity during adulthood. Obesity is the major risk factor impacting insulin sensitivity. Subjects with insulin resistance are at risk for progression to diabetes. Type 2 diabetes mellitus in obese children and adolescents is frequently asymptomatic. It is essential to identify children at high risk who need aggressive lifestyle modification focused on weight reduction and increased physical activity. Early detection and therapy of obese children and adolescents with type 2 diabetes may reduce the risk of cardiometabolic consequences and other long-term complications in adulthood.

The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice

PubMed Central

Wang, Dong; Luo, Yuhuan; Wang, Xiaoxin; Orlicky, David J.; Myakala, Komuraiah; Yang, Pengyuan; Levi, Moshe

2018-01-01

Obesity and obesity related kidney and liver disease have become more prevalent over the past few decades, especially in the western world. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with promising effects on cardiovascular and renal function. Given SGLT2 inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of the highly selective renal SGLT2 inhibitor dapagliflozin in mice with Western diet (WD) induced obesity. Low fat (LF) diet or WD-fed male C57BL/6J mice were treated with dapagliflozin for 26 weeks. Dapagliflozin attenuated the WD-mediated increases in body weight, plasma glucose and plasma triglycerides. Treatment with dapagliflozin prevented podocyte injury, glomerular pathology and renal fibrosis determined by second harmonic generation (SHG), nephrin, synaptopodin, collagen IV, and fibronectin immunofluorescence microscopy. Oil Red O staining showed dapagliflozin also decreased renal lipid accumulation associated with decreased SREBP-1c mRNA abundance. Moreover, renal inflammation and oxidative stress were lower in the dapagliflozin-treated WD-fed mice than in the untreated WD-fed mice. In addition, dapagliflozin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic lipid accumulation as determined by H&E and Oil Red O staining, and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, and hepatic fibrosis as determined by picrosirius red (PSR) staining and TPE-SHG microscopy in WD-fed mice. Thus, our study demonstrated that the co-administration of the SGLT2 inhibitor dapagliflozin attenuates renal and liver disease during WD feeding of mice. PMID:29301371

The Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin Prevents Renal and Liver Disease in Western Diet Induced Obesity Mice.

PubMed

Wang, Dong; Luo, Yuhuan; Wang, Xiaoxin; Orlicky, David J; Myakala, Komuraiah; Yang, Pengyuan; Levi, Moshe

2018-01-03

Obesity and obesity related kidney and liver disease have become more prevalent over the past few decades, especially in the western world. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of antidiabetic agents with promising effects on cardiovascular and renal function. Given SGLT2 inhibitors exert both anti-diabetic and anti-obesity effects by promoting urinary excretion of glucose and subsequent caloric loss, we investigated the effect of the highly selective renal SGLT2 inhibitor dapagliflozin in mice with Western diet (WD) induced obesity. Low fat (LF) diet or WD-fed male C57BL/6J mice were treated with dapagliflozin for 26 weeks. Dapagliflozin attenuated the WD-mediated increases in body weight, plasma glucose and plasma triglycerides. Treatment with dapagliflozin prevented podocyte injury, glomerular pathology and renal fibrosis determined by second harmonic generation (SHG), nephrin, synaptopodin, collagen IV, and fibronectin immunofluorescence microscopy. Oil Red O staining showed dapagliflozin also decreased renal lipid accumulation associated with decreased SREBP-1c mRNA abundance. Moreover, renal inflammation and oxidative stress were lower in the dapagliflozin-treated WD-fed mice than in the untreated WD-fed mice. In addition, dapagliflozin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), hepatic lipid accumulation as determined by H&E and Oil Red O staining, and Coherent Anti-Stokes Raman Scattering (CARS) microscopy, and hepatic fibrosis as determined by picrosirius red (PSR) staining and TPE-SHG microscopy in WD-fed mice. Thus, our study demonstrated that the co-administration of the SGLT2 inhibitor dapagliflozin attenuates renal and liver disease during WD feeding of mice.

Diabetes among non-obese Filipino Americans: Findings from a large population-based study.

PubMed

Fuller-Thomson, Esme; Roy, Adity; Chan, Keith Tsz-Kit; Kobayashi, Karen M

2017-04-20

Filipino Americans form the second-largest Asian American and Pacific Islanders subgroup. Growing evidence suggests that Filipino Americans have higher rates of diabetes than non-Hispanic whites. The key objectives of this study are 1) to determine the prevalence of diabetes in non-obese Filipino Americans compared to non-obese non-Hispanic whites, and 2) to identify risk factors for diabetes in non-obese Filipino men and women. Secondary analysis of population-based data from combined waves (2007, 2009 and 2011) of the adult California Health Interview Survey (CHIS). The study sample was restricted to non-obese Filipino Americans (n = 1629) and non-Hispanic whites (n = 72 072). Non-obese Filipino Americans had more than twice the odds of diabetes compared to non-Hispanic whites, even after correcting for several known risk factors (OR = 2.80, p < 0.001). For non-obese Filipino men, older age, poverty, cigarette smoking, and being overweight are associated with increased odds for diabetes, while older age was the only factor associated with diabetes among Filipina women. Diabetes prevention approaches need to be targeted towards non-obese Filipino Americans, due to their high risk of diabetes.

Trends in diabetes and obesity in Samoa over 35 years, 1978-2013.

PubMed

Lin, S; Naseri, T; Linhart, C; Morrell, S; Taylor, R; McGarvey, S T; Magliano, D J; Zimmet, P

2017-05-01

Population surveys of Type 2 diabetes mellitus and obesity conducted in Samoa over three decades have used varying methodologies and definitions. This study standardizes measures, and trends of Type 2 diabetes mellitus and obesity for 1978-2013 are projected to 2020 for adults aged 25-64 years. Unit records from eight surveys (n = 12 516) were adjusted to the previous census for Division of residence, sex and age to improve national representativeness. Type 2 diabetes mellitus is defined as a fasting plasma glucose ≥ 7.0 mmol/l and/or on medication. Obesity is defined as BMI ≥ 30 kg/m 2 . Random effects meta-regression was employed to assess time trends following logit transformation. Poisson regression from strata was used to assess the effects of mean BMI changes on Type 2 diabetes mellitus period trends. Over 1978-2013, Type 2 diabetes mellitus prevalence increased from 1.2% to 19.6% in men (2.3% per 5 years), and from 2.2% to 19.5% in women (2.2% per 5 years). Obesity prevalence increased from 27.7% to 53.1% in men (3.6% per 5 years) and from 44.4% to 76.7% (4.5% per 5 years) in women. Type 2 diabetes mellitus and obesity prevalences increased in all age groups. From period trends, Type 2 diabetes mellitus prevalence in 2020 is projected to be 26% in men and women. Projected obesity prevalence is projected to be 59% in men and 81% in women. Type 2 diabetes mellitus period trends attributable to BMI increase are estimated as 31% (men) and 16% (women), after adjusting for age. This is the first study to produce trends of Type 2 diabetes mellitus and obesity in Samoa based on standardized data from population surveys. Type 2 diabetes mellitus is equally prevalent in both sexes, and obesity is widespread. Type 2 diabetes mellitus prevalence in Samoa is likely to continue to increase in the near future. © 2016 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

[Epigenetics of childhood obesity and diabetes].

PubMed

Valladares-Salgado, Adán; Suárez-Sánchez, Fernando; Burguete-García, Ana I; Cruz, Miguel

2014-01-01

Obesity and type 2 diabetes mellitus (T2DM) result from sedentary lifestyle, high-carbohydrate diets and genetic predisposition. Epigenetics is a form of genetic regulation in specialized cells that does not involve changes in the deoxyribonucleic acid (DNA) sequence, but it can be inherited to one or more generations through mitosis or meiosis. Children whose mothers develop gestational diabetes are more likely to become obese and diabetic in adult life. DNA methylation is a major mechanism in the regulation of transcription and gene expression of several genes. High levels of glucose and insulin during pregnancy modify the risk of developing T2DM, suggesting that the expression pattern is modified due to cell memory in a specific tissue. If T2DM is linked to adaptation in utero, the obvious primary prevention is to protect the fetal development. Future epidemiological studies need to employ more accurate indicators or markers of development to show the relationship between a specific disease and the exposure to environmental factors. The mechanisms by which malnutrition, and intrauterine growth retardation produce changes in the metabolism of glucose and insuline are worth to explore in order to control obesity and T2DM.

[Overweight, obesity and lipids abnormalities in adolescents with type 1 diabetes].

PubMed

Wysocka-Mincewicz, Marta; Kołodziejczyk, Honorata; Wierzbicka, Elżbieta; Szalecki, Mieczysław

2016-02-18

Overweight children are growing problem as in the pediatric, as well in the diabetic population. The aim of the study was to research the percentage of overweight and obesity in a group of adolescents with type 1 diabetes, and to analyzethe lipid parameters, as well risk factors of these abnormalities. The study group consist of 60 type 1 diabetic adolescents (including 32 girls, 53.3%), aged above 12 years (mean age for girls 14.6+/-0,3years, boys 15.6+/-0.4 years) with diabetes duration (girls 5.7+-0.6 years, boys 4.4+/-0.8 years). Statistical analysis was performed using Statistica v 9.0 and SPSS v20. The study revealed that boys with type 1 diabetes are significantly higher than healthy population, with weight, waist circumference and BMI comparable to the healthy counterparts. However, diabetic girls are more likely to be overweight and have bigger waist circumference, and higher BMI than the healthy population. Overweight were 12 adolescents (20%) using BMI ≥1SD criterion, and 10 (16%) using waist circumference as obesity parameter. Logistic regression revealed that the most important factors for obesity and abdominal obesity are female gender (OR=2.43 and OR=4.56for obesity and abdominal, respectively), diabetes duration above 5 years (respectively OR=1.96 and OR=3.27) and poor metabolic control (respectively OR=1.74 and OR=2.89). The most important risk factor for obesity in adolescents with type 1 diabetes is female gender. Lipids profile is closely dependent on metabolic control and mass excess. Diabetes duration, metabolic control and lipids profile are significant risk factors for overweight and abdominal obesity. © Polish Society for Pediatric Endocrinology and Diabetology.

Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography

PubMed Central

Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R.; Marin, C.; Van der Schueren, B.; Carmeliet, G.; Luyten, F. P.; Geris, L.; Vandamme, K.

2016-01-01

High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 μm scale, no change was observed in the intracortical structure. At 1 μm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging. PMID:27759061

Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography

NASA Astrophysics Data System (ADS)

Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R.; Marin, C.; van der Schueren, B.; Carmeliet, G.; Luyten, F. P.; Geris, L.; Vandamme, K.

2016-10-01

High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 μm scale, no change was observed in the intracortical structure. At 1 μm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging.

Prevention of obesity and diabetes in childbearing women.

PubMed

Trout, Kimberly K; Ellis, Kathryn K; Bratschie, Alexandra

2013-01-01

Obesity and diabetes have become pandemic in the United States, with more than one-third of the US population obese and 8.3% of the population affected by diabetes. Efforts to prevent type 2 diabetes focus primarily on healthy eating and physical activity. In particular, women from at-risk racial and ethnic groups and those who have experienced gestational diabetes are at high risk for developing type 2 diabetes. Achieving a healthy weight prior to conception, staying within weight gain guidelines during pregnancy, and losing accumulated pregnancy weight postpartum are key prevention factors. Maintaining a healthy weight in the long-term is a challenge. Behavioral psychology and coaching techniques are presented in this article that can be useful in sustaining behaviors that promote a healthy weight. © 2013 by the American College of Nurse-Midwives.

Regulation of hepatic fatty acid elongase and desaturase expression in diabetes and obesity

PubMed Central

Wang, Yun; Botolin, Daniela; Xu, Jinghua; Christian, Barbara; Mitchell, Ernestine; Jayaprakasam, Bolleddula; Nair, Muraleedharan; Peters, Jeffery M.; Busik, Julia; Olson, L. Karl; Jump, Donald B.

2009-01-01

Fatty acid elongases and desaturases play an important role in hepatic and whole body lipid composition. We examined the role that key transcription factors played in the control of hepatic elongase and desaturase expression. Studies with peroxisome proliferator-activated receptor α (PPARα)-deficient mice establish that PPARα was required for WY14643-mediated induction of fatty acid elongase-5 (Elovl-5), Elovl-6, and all three desaturases [Δ5 desaturase (Δ5D), Δ6D, and Δ9D]. Increased nuclear sterol-regulatory element binding protein-1 (SREBP-1) correlated with enhanced expression of Elovl-6, Δ5D, Δ6D, and Δ9D. Only Δ9D was also regulated independently by liver X receptor (LXR) agonist. Glucose induction of L-type pyruvate kinase, Δ9D, and Elovl-6 expression required the carbohydrate-regulatory element binding protein/MAX-like factor X (ChREBP/MLX) heterodimer. Suppression of Elovl-6 and Δ9D expression in livers of streptozotocin-induced diabetic rats and high fat-fed glucose-intolerant mice correlated with low levels of nuclear SREBP-1. In leptin-deficient obese mice (Lepob/ob), increased SREBP-1 and MLX nuclear content correlated with the induction of Elovl-5, Elovl-6, and Δ9D expression and the massive accumulation of monoun-saturated fatty acids (18:1,n-7 and 18:1,n-9) in neutral lipids. Diabetes- and obesity-induced changes in hepatic lipid composition correlated with changes in elongase and desaturase expression. In conclusion, these studies establish a role for PPARα, LXR, SREBP-1, ChREBP, and MLX in the control of hepatic fatty acid elongase and desaturase expression and lipid composition. PMID:16790840

Curcumin rescues high fat diet-induced obesity and insulin sensitivity in mice through regulating SREBP pathway

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

Ding, Lili; Li, Jinmei

Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gainmore » and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance. - Highlights: • Curcumin decreases biosynthesis of cholesterol and fatty acid in vitro. • Curcumin as a SREBP inhibitor ameliorates HFD-induced obesity. • Curcumin as a SREBP inhibitor improves insulin resistance.« less

Effects of obesity surgery on non-insulin-dependent diabetes mellitus.

PubMed

Greenway, Scott E; Greenway, Frank L; Klein, Stanley

2002-10-01

Most individuals who have non-insulin-dependent diabetes mellitus are obese. The obese population has proved a frustrating entity regarding weight loss and diabetes control. Results of medical weight loss programs, medications, and behavior therapy have proved disappointing. Bariatric surgery is the most effective method of diabetes management and cure in the morbidly obese population. Surgical procedures to cause malabsorption provide a more dramatic effect on diabetes owing to the imparted bypass of the hormonally active foregut. Pertinent journal articles spanning the last 40 years, as well as textbooks. Bariatric surgical procedures have proven a much more successful method of weight loss and diabetes control in the obese population than conservative methods. These surgical procedures have proven safe with reported mortality rates of 0% to 1.5%. Bariatric operations may be divided based on the method of weight loss and effect on diabetes. The first category is restrictive and includes vertical banded gastroplasty and adjustable silicone gastric banding. These operations improve diabetes by decreasing food intake and body weight with a slowing of gastric emptying. The second category not only contains restrictive components but also elements of malabsorption. This category includes the Roux-en-Y gastric bypass and biliary-pancreatic diversion, which bypass the foregut. Although all of the surgical procedures for obesity offer improved weight loss and diabetes control compared with conservative methods, the Roux-en-Y gastric bypass and biliary-pancreatic diversion offer superior weight loss and resolution of diabetes. The more dramatic effect seen in the surgical procedures to cause malabsorption is likely secondary to the bypass of the foregut resulting in increased weight loss and elevation of the enteroglucagon level.

A High Level of Intestinal Alkaline Phosphatase Is Protective Against Type 2 Diabetes Mellitus Irrespective of Obesity.

PubMed

Malo, Madhu S

2015-12-01

Mice deficient in intestinal alkaline phosphatase (IAP) develop type 2 diabetes mellitus (T2DM). We hypothesized that a high level of IAP might be protective against T2DM in humans. We determined IAP levels in the stools of 202 diabetic patients and 445 healthy non-diabetic control people. We found that compared to controls, T2DM patients have approx. 50% less IAP (mean +/- SEM: 67.4 +/- 3.2 vs 35.3 +/- 2.5 U/g stool, respectively; p < 0.000001) indicating a protective role of IAP against T2DM. Multiple logistic regression analyses showed an independent association between the IAP level and diabetes status. With each 25 U/g decrease in stool IAP, there is a 35% increased risk of diabetes. The study revealed that obese people with high IAP (approx. 65 U/g stool) do not develop T2DM. Approx. 65% of the healthy population have < 65.0 U/g stool IAP, and predictably, these people might have 'the incipient metabolic syndrome', including 'incipient diabetes', and might develop T2DM and other metabolic disorders in the near future. In conclusion, high IAP levels appear to be protective against diabetes irrespective of obesity, and a 'temporal IAP profile' might be a valuable tool for predicting 'the incipient metabolic syndrome', including 'incipient diabetes'.

Chronic Trypanosoma cruzi infection potentiates adipose tissue macrophage polarization toward an anti-inflammatory M2 phenotype and contributes to diabetes progression in a diet-induced obesity model.

PubMed

Cabalén, María E; Cabral, María F; Sanmarco, Liliana M; Andrada, Marta C; Onofrio, Luisina I; Ponce, Nicolás E; Aoki, María P; Gea, Susana; Cano, Roxana C

2016-03-22

Chronic obesity and Chagas disease (caused by the protozoan Trypanosoma cruzi) represent serious public health concerns. The interrelation between parasite infection, adipose tissue, immune system and metabolism in an obesogenic context, has not been entirely explored. A novel diet-induced obesity model (DIO) was developed in C57BL/6 wild type mice to examine the effect of chronic infection (DIO+I) on metabolic parameters and on obesity-related disorders. Dyslipidemia, hyperleptinemia, and cardiac/hepatic steatosis were strongly developed in DIO mice. Strikingly, although these metabolic alterations were collectively improved by infection, plasmatic apoB100 levels remain significantly increased in DIO+I, suggesting the presence of pro-atherogenic small and dense LDL particles. Moreover, acute insulin resistance followed by chronic hyperglycemia with hypoinsulinemia was found, evidencing an infection-related-diabetes progression. These lipid and glucose metabolic changes seemed to be highly dependent on TLR4 expression since TLR4-/- mice were protected from obesity and its complications. Notably, chronic infection promoted a strong increase in MCP-1 producing macrophages with a M2 (F4/80+CD11c-CD206+) phenotype associated to oxidative stress in visceral adipose tissue of DIO+I mice. Importantly, infection reduced lipid content but intensified inflammatory infiltrates in target tissues. Thus, parasite persistence in an obesogenic environment and the resulting host immunometabolic dysregulation may contribute to diabetes/atherosclerosis progression.

Type 2 diabetes, but not obesity, prevalence is positively associated with ambient temperature.

PubMed

Speakman, John R; Heidari-Bakavoli, Sahar

2016-08-01

Cold exposure stimulates energy expenditure and glucose disposal. If these factors play a significant role in whole body energy balance, and glucose homeostasis, it is predicted that both obesity and type 2 diabetes prevalence would be lower where it is colder. Previous studies have noted connections between ambient temperature and obesity, but the direction of the effect is confused. No previous studies have explored the link of type 2 diabetes to ambient temperature. We used county level data for obesity and diabetes prevalence across the mainland USA and matched this to county level ambient temperature data. Average ambient temperature explained 5.7% of the spatial variation in obesity and 29.6% of the spatial variation in type 2 diabetes prevalence. Correcting the type 2 diabetes data for the effect of obesity reduced the explained variation to 26.8%. Even when correcting for obesity, poverty and race, ambient temperature explained 12.4% of the variation in the prevalence of type 2 diabetes, and this significant effect remained when latitude was entered into the model as a predictor. When obesity prevalence was corrected for poverty and race the significant effect of temperature disappeared. Enhancing energy expenditure by cold exposure will likely not impact obesity significantly, but may be useful to combat type 2 diabetes.

Genetic induction of phosphate toxicity significantly reduces the survival of hypercholesterolemic obese mice

PubMed Central

Ohnishi, Mutsuko; Kato, Shigeko; Razzaque, M. Shawkat

2013-01-01

Objective The adverse effects of metabolic disorders in obesity have been extensively studied; however, the pathologic effects of hyperphosphatemia or phosphate toxicity in obesity have not been studied in similar depth and detail, chiefly because such an association is thought to be uncommon. Studies have established that the incidence of obesity-associated nephropathy is increasing. Because hyperphosphatemia is a major consequence of renal impairment, this study determines the in vivo effects of hyperphosphatemia in obesity. Methods and results We genetically induced hyperphosphatemia in leptin-deficient obese (ob/ob) mice by generating ob/ob and klotho double knockout [ob/ob-klotho−/−] mice. As a control, we made ob/ob mice with hypophosphatemia by generating ob/ob and 1-alpha hydroxylase double knockout [ob/ob-1α(OH)ase−/−] mice. Compared to the wild-type mice, all three obese background mice, namely ob/ob, ob/ob-klotho−/−, and ob/ob-1α(OH)ase−/− mice developed hypercholesterolemia. In addition, the hyperphosphatemic, ob/ob-klotho−/− genetic background induced generalized tissue atrophy and widespread soft-tissue and vascular calcifications, which led to a shorter lifespan; no such changes were observed in the hypophosphatemic, ob/ob-1α(OH)ase−/− mice. Significantly, in contrast to the reduced survival of the ob/ob-klotho−/− mice, lowering serum phosphate levels in ob/ob-1α(OH)ase−/− mice showed no such compromised survival, despite both mice being hypercholesterolemic. Conclusion These genetic manipulation studies suggest phosphate toxicity is an important risk factor in obesity that can adversely affect survival. PMID:22037453

Genetic induction of phosphate toxicity significantly reduces the survival of hypercholesterolemic obese mice.

PubMed

Ohnishi, Mutsuko; Kato, Shigeko; Razzaque, M Shawkat

2011-11-25

The adverse effects of metabolic disorders in obesity have been extensively studied; however, the pathologic effects of hyperphosphatemia or phosphate toxicity in obesity have not been studied in similar depth and detail, chiefly because such an association is thought to be uncommon. Studies have established that the incidence of obesity-associated nephropathy is increasing. Because hyperphosphatemia is a major consequence of renal impairment, this study determines the in vivo effects of hyperphosphatemia in obesity. We genetically induced hyperphosphatemia in leptin-deficient obese (ob/ob) mice by generating ob/ob and klotho double knockout [ob/ob-klotho(-/-)] mice. As a control, we made ob/ob mice with hypophosphatemia by generating ob/ob and 1-alpha hydroxylase double knockout [ob/ob-1α(OH)ase(-/-)] mice. Compared to the wild-type mice, all three obese background mice, namely ob/ob, ob/ob-klotho(-/-), and ob/ob-1α(OH)ase(-/-) mice developed hypercholesterolemia. In addition, the hyperphosphatemic, ob/ob-klotho(-/-) genetic background induced generalized tissue atrophy and widespread soft-tissue and vascular calcifications, which led to a shorter lifespan; no such changes were observed in the hypophosphatemic, ob/ob-1α(OH)ase(-/-) mice. Significantly, in contrast to the reduced survival of the ob/ob-klotho(-/-) mice, lowering serum phosphate levels in ob/ob-1α(OH)ase(-/-) mice showed no such compromised survival, despite both mice being hypercholesterolemic. These genetic manipulation studies suggest phosphate toxicity is an important risk factor in obesity that can adversely affect survival. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluating the evidence for macrophage presence in skeletal muscle and its relation to insulin resistance in obese mice and humans: a systematic review protocol.

PubMed

Bhatt, Meha; Rudrapatna, Srikesh; Banfield, Laura; Bierbrier, Rachel; Wang, Pei-Wen; Wang, Kuan-Wen; Thabane, Lehana; Samaan, M Constantine

2017-08-08

The current global rates of obesity and type 2 diabetes are staggering. In order to implement effective management strategies, it is imperative to understand the mechanisms of obesity-induced insulin resistance and diabetes. Macrophage infiltration and inflammation of the adipose tissue in obesity is a well-established paradigm, yet the role of macrophages in muscle inflammation, insulin resistance and diabetes is not adequately studied. In this systematic review, we will examine the evidence for the presence of macrophages in skeletal muscle of obese humans and mice, and will assess the association between muscle macrophages and insulin resistance. We will identify published studies that address muscle macrophage content and phenotype, and its association with insulin resistance. We will search MEDLINE/PubMed, EMBASE, and Web of Science for eligible studies. Grey literature will be searched in ProQuest. Quality assessment will be conducted using the Systematic Review Centre for Laboratory Animal Experimentation risk of bias Tool for animal studies. The findings of this systematic review will shed light on immune-metabolic crosstalk in obesity, and allow the consideration of targeted therapies to modulate muscle macrophages in the treatment and prevention of diabetes. The review will be published in a peer-reviewed journal and presented at conferences.

Accelerated recovery from acute hypoxia in obese mice is due to obesity-associated up-regulation of interleukin-1 receptor antagonist.

PubMed

Sherry, Christina L; Kim, Stephanie S; Freund, Gregory G

2009-06-01

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 +/- 77 pg/mg protein in HFD mice as compared with 15 +/- 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA.

Accelerated Recovery from Acute Hypoxia in Obese Mice Is Due to Obesity-Associated Up-Regulation of Interleukin-1 Receptor Antagonist

PubMed Central

Sherry, Christina L.; Kim, Stephanie S.; Freund, Gregory G.

2009-01-01

The proinflammatory consequences of obesity are thought to be due, in part, to macrophage infiltration into adipose tissue. There are, however, potential antiinflammatory consequences of obesity that include obesity-associated up-regulation of IL-1 receptor antagonist (IL-1RA). Here we show that obesity-associated up-regulation of IL-1RA speeds recovery from hypoxia. We found that high-fat diet-fed (HFD) mice recovered from acute hypoxia 5 times faster than normal-diet-fed (ND) mice. HFD mice had a 10-fold increase in serum IL-1RA when compared with ND mice. White adipose tissue (WAT) was a significant source of IL-RA, generating 330 ± 77 pg/mg protein in HFD mice as compared with 15 ± 5 pg/mg protein in ND mice. Peritoneal macrophages isolated from HFD mice showed little difference in IL-1RA production when compared with ND mice, but WAT macrophages from HFD mice generated 11-fold more IL-1RA than those from ND mice. When ND mice were given an ip transfer of the stromal vascular fraction portion of WAT from HFD mice, serum IL-1RA increased 836% and recovery from acute hypoxia was faster than in mice that did not receive a stromal vascular fraction transfer. To determine whether IL-1RA was important to this accelerated recovery, ND mice were administered exogenous IL-1RA prior to hypoxia, and their recovery matched that of HFD mice. Inversely, when IL-1RA was immunoabsorbed in HFD mice with IL-1RA antiserum, recovery from acute hypoxia was attenuated. Taken together these data demonstrate that HFD-induced obesity speeds recovery from hypoxia due to obesity-associated up-regulation of IL-1RA. PMID:19213834

Tumour necrosis factor-α inhibition with lenalidomide alleviates tissue oxidative injury and apoptosis in ob/ob obese mice.

PubMed

Zhu, Xiaoling; Jiang, Shasha; Hu, Nan; Luo, Fuling; Dong, Hailong; Kang, Yu-Ming; Jones, Kyla R; Zou, Yunzeng; Xiong, Lize; Ren, Jun

2014-07-01

Lenalidomide (Revlimid; Selleck Chemicals, Houston, TX, USA), an analogue of thalidomide, possesses potent cytokine modulatory capacity through inhibition of cytokines such as tumour necrosis factor (TNF)-α, a cytokine pivotal for the onset and development of complications in obesity and diabetes mellitus. The present study was designed to evaluate the effect of lenalidomide on oxidative stress, protein and DNA damage in multiple organs in an ob/ob murine model of obesity. To this end, C57BL/6 lean and ob/ob obese mice were administered lenalidomide (50 mg/kg per day, p.o.) for 5 days. Oxidative stress, protein and DNA damage were assessed using the conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG), carbonyl formation and Comet assay, respectively. Apoptosis was evaluated using caspase 3 activity, and levels of Bax, Bcl-2, Bip, caspase 8, caspase 9 and TNF-α were assessed using western blot analysis. Lenalidomide treatment did not affect glucose clearance in lean or ob/ob mice. Obese mice exhibited a reduced GSH/GSSG ratio in the liver, gastrocnemius skeletal muscle and small intestine, as well as enhanced protein carbonyl formation, DNA damage and caspase 3 activity in the liver, kidney, skeletal muscle and intestine; these effects were alleviated by lenalidomide, with the exception of obesity-associated DNA damage in the liver and kidney. Western blot analysis revealed elevated TNF-α, Bax, Bcl-2, Bip, caspase 8 and caspase 9 in ob/ob mice with various degrees of reversal by lenalidomide treatment. Together, these data indicate that lenalidomide protects against obesity-induced tissue injury and protein damage, possibly in association with antagonism of cytokine production and cytokine-induced apoptosis and oxidative stress. © 2014 Wiley Publishing Asia Pty Ltd.

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse.

PubMed

Peterson, Richard G; Jackson, Charles Van; Zimmerman, Karen M; Alsina-Fernandez, Jorge; Michael, M Dodson; Emmerson, Paul J; Coskun, Tamer

2017-01-01

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents.

Glucose dysregulation and response to common anti-diabetic agents in the FATZO/Pco mouse

PubMed Central

Jackson, Charles Van; Zimmerman, Karen M.; Alsina-Fernandez, Jorge; Michael, M. Dodson; Emmerson, Paul J.; Coskun, Tamer

2017-01-01

The FATZO/Pco mouse is the result of a cross of the C57BL/6J and AKR/J strains. The crossing of these two strains and the selective inbreeding for obesity, insulin resistance and hyperglycemia has resulted in an inbred strain exhibiting obesity in the presumed presence of an intact leptin pathway. Routinely used rodent models for obesity and diabetes research have a monogenic defect in leptin signaling that initiates obesity. Given that obesity and its sequelae in humans are polygenic in nature and not associated with leptin signaling defects, the FATZO mouse may represent a more translatable rodent model for study of obesity and its associated metabolic disturbances. The FATZO mouse develops obesity spontaneously when fed a normal chow diet. Glucose intolerance with increased insulin levels are apparent in FATZO mice as young as 6 weeks of age. These progress to hyperglycemia/pre-diabetes and frank diabetes with decreasing insulin levels as they age. The disease in these mice is multi-faceted, similar to the metabolic syndrome apparent in obese individuals, and thus provides a long pre-diabetic state for determining the preventive value of new interventions. We have assessed the utility of this new model for the pre-clinical screening of agents to stop or slow progression of the metabolic syndrome to severe diabetes. Our assessment included: 1) characterization of the spontaneous development of disease, 2) comparison of metabolic disturbances of FATZO mice to control mice and 3) validation of the model with regard to the effectiveness of current and emerging anti-diabetic agents; rosiglitazone, metformin and semaglutide. Conclusion: Male FATZO mice spontaneously develop significant metabolic disease when compared to normal controls while maintaining hyperglycemia in the presence of high leptin levels and hyperinsulinemia. The disease condition responds to commonly used antidiabetic agents. PMID:28640857

Exogenous estrogen protects mice from the consequences of obesity and alcohol.

PubMed

Holcomb, Valerie B; Hong, Jina; Núñez, Nomelí P

2012-06-01

Breast cancer is the second leading cause of cancer death among American women. Risk factors for breast cancer include obesity, alcohol consumption, and estrogen therapy. In the present studies, we determine the simultaneous effects of these three risk factors on wingless int (Wnt)-1 mammary tumor growth. Ovariectomized female mice were fed diets to induce different body weights (calorie restricted, low fat, high fat), provided water or 20% alcohol, implanted with placebo or estrogen pellets and injected with Wnt-1 mouse mammary cancer cells. Our results show that obesity promoted the growth of Wnt-1 tumors and induced fatty liver. Tumors tended to be larger in alcohol-consuming mice and alcohol exacerbated fatty liver in obese mice. Estrogen treatment promoted weight loss in obese mice, which was associated with the suppression of tumor growth and fatty liver. In summary, we show that estrogen protects against obesity, which is associated with the inhibition of fatty liver and tumor growth.

FREQUENCY OF ABDOMINAL OBESITY AND ITS ASSOCIATION WITH DIABETES MELLITUS AMONG PEOPLE OF PESHAWAR.

PubMed

Khan, Attaullah; Faheem, Muhammad; Shah, Syed Tahir; Hadi, Abdul; Rafiullah; Ahmad, Salman; Gul, Adnan Mahmood; Shah, Sayyad Farhat Abbas; Jan, Hikmatullah; Hafizullah, Mohammad

2015-01-01

Increased body weight is a major risk factor for the metabolic syndrome which is a cluster of coronary heart disease risk factors, like: hypertension, diabetes mellitus and dyslipidaemia. This study was conducted to determine the frequency of abdominal obesity and diabetes mellitus in the population of Peshawar and association between them. This was a cross sectional study, performed by the Cardiology Department, Lady Reading Hospital Peshawar, in the population of Peshawar. All participants were interviewed in detail regarding known risk factors for coronary artery disease. Waist circumference (≥102 cm in male and ≥88 cm in females) was used as the surrogate marker for abdominal obesity in already diagnosed patients of type-2 diabetes mellitus. A total of 2548 individuals were included, 71.1% were male. Mean age was 37.94±12.59 years. Mean waist circumference was 90.25±13.45cm in males and 90.52±12.52cm in females. Diabetes was present in 4.4% of the participants and abdominal obesity in 56.6% Among the male, abdominal obesity was present in 39.4% and diabetes in 2.9%. Out of 39.4% males with abdominal obesity, 2% were diabetic. Out of 38.6% males with no abdominal obesity, 0.9% was diabetic. Amongst the total 559 (21.1%) female subjects, 17.2% were having abdominal obesity and 1.4% was diabetics. Among 123 (4.8%) females with no abdominal obesity, 0.1% was diabetic. A positive association was established between abdominal obesity and diabetes mellitus with a significant p-valve (<0.05). Abdominal obesity is more common in the local population of Peshawar and associated with type-2 diabetes mellitus.

Development of diabetic nephropathy in nude mice.

PubMed

Lin, S; Xu, P C; Huang, Q E; Jia, J Y; Jia, Z H; Wei, L; Zheng, Z F; Shang, W Y

2013-12-01

Immune dysfunction is very common in diabetes mellitus (DM). However, there is no evidence whether such immune dysfunction can influence the development of DM, especially the development of diabetic nephropathy (DN). To investigate the influence of absence of T cells on DN. Balb/c nude mice and Balb/c wild-type nude (WT) mice were injected with streptozotocin (STZ). Serum tumor necrosis factor α (TNF-α), blood glucose, body weight, urine albumin/creatinine ratio and rate of kidney weight to body weight (KW/BW) were measured. After modeling, there was no difference of blood glucose level between nude mice and WT mice except at week 2 (28.3 ± 4.9 mmol/l vs 23.1 ± 3.9 mmol/l, p<0.01). At week 4, the serum TNF- α level of nude mice got to 175.08 ± 46.03 pg/ml (p<0.05, compared with baseline level 80.19 ± 8.46 pg/ml), whereas the TNF- α levels of WT mice was stable. At week 4, the body weight of nude mice was lower than that of WT mice (14.7 ± 3.15 g vs 17.97 ± 2.85 g, p<0.05); the urine albumin/creatinine ratio (Alb/Cr) of nude mice was higher than that of WT mice (50.96 ± 5.57 mg/mmol vs 41.09 ± 5.79 mg/mmol, p<0.05); the kidney weight to body weight of nude mice was higher than that of WT mice (0.01352 ± 0.00163 vs 0.01173 ± 0.00131, p<0.05). Correlation analysis showed urine Alb/Cr positively correlated with serum TNF-α level at week 4 (r = 0.588, p<0.01). At week 4, the increase of type IV collagen in the glomeruli was more prominent in diabetic nude mice than in diabetic WT mice (p<0.05). Absence of T cells in DM might influence the development of DN.

Pharmacotherapy for obesity in individuals with type 2 diabetes.

PubMed

Chukir, Tariq; Shukla, Alpana P; Saunders, Katherine H; Aronne, Louis J

2018-02-01

Type 2 diabetes (T2DM) is associated with significant morbidity and mortality. Obesity is one of the main risk factors for T2DM and its management requires a multidisciplinary approach, which may include pharmacotherapy. Areas covered: In this paper, data on efficacy, tolerability and safety of FDA-approved pharmacotherapies for obesity (orlistat, phentermine/topiramate extended-release, lorcaserin, bupropion sustained release/naltrexone sustained release and liraglutide) are reviewed, focusing on individuals with type 2 diabetes. Expert opinion: Obesity is the major pathophysiologic driver of T2DM; conversely 5-10% weight loss leads to significant improvement in glycemic control, lipids and blood pressure. Weight loss maintenance is difficult with lifestyle interventions alone and may require adjunctive therapies. There is good evidence for the efficacy and tolerability of approved anti-obesity pharmacotherapies in individuals with T2DM, with current cardiovascular safety data being most favorable for liraglutide, orlistat and lorcaserin. Given the link between obesity and T2DM, a weight-centric therapeutic approach including use of weight reducing anti-diabetic therapies, and anti-obesity pharmacotherapies is both intuitive and rational to improve glycemic and other metabolic outcomes in patients with T2DM.

Emodin improves lipid and glucose metabolism in high fat diet-induced obese mice through regulating SREBP pathway.

PubMed

Li, Jinmei; Ding, Lili; Song, Baoliang; Xiao, Xu; Qi, Meng; Yang, Qiaoling; Yang, Qiming; Tang, Xiaowen; Wang, Zhengtao; Yang, Li

2016-01-05

Currently, obesity has become a worldwide epidemic associated with Type 2 diabetes, dyslipidemia, cardiovascular disease and chronic metabolic diseases. Emodin is one of the active anthraquinone derivatives from Rheum palmatum and some other Chinese herbs with anti-inflammatory, anticancer and hepatoprotective properties. In the present study, we investigated the anti-obesity effects of emodin in obese mice and explore its potential pharmacological mechanisms. Male C57BL/6 mice were fed with high-fat diet for 12 weeks to induce obesity. Then the obese mice were divided into four groups randomly, HFD or emodin (40mg/kg/day and 80mg/kg/day) or lovastatin (30mg/kg/ day) for another 6 weeks. Body weight and food intake were recorded every week. At the end of the treatment, the fasting blood glucose, glucose and insulin tolerance test, serum and hepatic lipid levels were assayed. The gene expressions of liver and adipose tissues were analyzed with a quantitative PCR assay. Here, we found that emodin inhibited sterol regulatory element-binding proteins (SREBPs) transactivity in huh7 cell line. Furthermore, emodin (80mg/kg/day) treatment blocked body weight gain, decreased blood lipids, hepatic cholesterol and triglyceride content, ameliorated insulin sensitivity, and reduced the size of white and brown adipocytes. Consistently, SREBP-1 and SREBP-2 mRNA levels were significantly reduced in the liver and adipose tissue after emodin treatment. These data demonstrated that emodin could improve high-fat diet-induced obesity and associated metabolic disturbances. The underlying mechanism is probably associated with regulating SREBP pathway. Copyright © 2015 Elsevier B.V. All rights reserved.

Childhood obesity and type 2 diabetes in India.

PubMed

Praveen, Pradeep A; Tandon, Nikhil

2016-04-01

India is witnessing an increase in the burden of childhood obesity, especially among the upper socioeconomic strata and in urban areas. Emerging literature suggests a link between childhood obesity and the diabetes epidemic in India. Asian-Indian children and adolescents are increasingly susceptible to a high percentage of body fat and abdominal adiposity. Further, they are exposed to an obesogenic environment, created by rapid urbanization and nutrition transition in India. Obese children have a higher risk of developing abnormalities that are recognized as precursors to diabetes, such as subclinical inflammation, insulin resistance and metabolic syndrome, which often track to adulthood. A review of the literature suggests the need for more longitudinal studies to improve understanding of the long-term consequences of childhood obesity in India. A life-course approach with a combination of population- and risk-based strategies is warranted, to prevent childhood obesity and curtail its consequences in adulthood.

Anti-Diabetic Activity and Metabolic Changes Induced by Andrographis paniculata Plant Extract in Obese Diabetic Rats.

PubMed

Akhtar, Muhammad Tayyab; Bin Mohd Sarib, Mohamad Syakir; Ismail, Intan Safinar; Abas, Faridah; Ismail, Amin; Lajis, Nordin Hj; Shaari, Khozirah

2016-08-09

Andrographis paniculata is an annual herb and widely cultivated in Southeast Asian countries for its medicinal use. In recent investigations, A. paniculata was found to be effective against Type 1 diabetes mellitus (Type 1 DM). Here, we used a non-genetic out-bred Sprague-Dawley rat model to test the antidiabetic activity of A. paniculata against Type 2 diabetes mellitus (Type 2 DM). Proton Nuclear Magnetic Resonance (¹H-NMR) spectroscopy in combination with multivariate data analyses was used to evaluate the A. paniculata and metformin induced metabolic effects on the obese and obese-diabetic (obdb) rat models. Compared to the normal rats, high levels of creatinine, lactate, and allantoin were found in the urine of obese rats, whereas, obese-diabetic rats were marked by high glucose, choline and taurine levels, and low lactate, formate, creatinine, citrate, 2-oxoglutarate, succinate, dimethylamine, acetoacetate, acetate, allantoin and hippurate levels. Treatment of A. paniculata leaf water extract was found to be quite effective in restoring the disturbed metabolic profile of obdb rats back towards normal conditions. Thisstudy shows the anti-diabetic potential of A. paniculata plant extract and strengthens the idea of using this plant against the diabetes. Further classical genetic methods and state of the art molecular techniques could provide insights into the molecular mechanisms involved in the pathogenesis of diabetes mellitus and anti-diabetic effects of A. paniculata water extract.

Hepatic overexpression of steroid sulfatase ameliorates mouse models of obesity and type 2 diabetes through sex-specific mechanisms.

PubMed

Jiang, Mengxi; He, Jinhan; Kucera, Heidi; Gaikwad, Nilesh W; Zhang, Bin; Xu, Meishu; O'Doherty, Robert M; Selcer, Kyle W; Xie, Wen

2014-03-21

The steroid sulfatase (STS)-mediated desulfation is a critical metabolic mechanism that regulates the chemical and functional homeostasis of endogenous and exogenous molecules. In this report, we first showed that the liver expression of Sts was induced in both the high fat diet (HFD) and ob/ob models of obesity and type 2 diabetes and during the fed to fasting transition. In defining the functional relevance of STS induction in metabolic disease, we showed that overexpression of STS in the liver of transgenic mice alleviated HFD and ob/ob models of obesity and type 2 diabetes, including reduced body weight, improved insulin sensitivity, and decreased hepatic steatosis and inflammation. Interestingly, STS exerted its metabolic benefit through sex-specific mechanisms. In female mice, STS may have increased hepatic estrogen activity by converting biologically inactive estrogen sulfates to active estrogens and consequently improved the metabolic functions, whereas ovariectomy abolished this protective effect. In contrast, the metabolic benefit of STS in males may have been accounted for by the male-specific decrease of inflammation in white adipose tissue and skeletal muscle as well as a pattern of skeletal muscle gene expression that favors energy expenditure. The metabolic benefit in male STS transgenic mice was retained after castration. Treatment with the STS substrate estrone sulfate also improved metabolic functions in both the HFD and ob/ob models. Our results have uncovered a novel function of STS in energy metabolism and type 2 diabetes. Liver-specific STS induction or estrogen/estrogen sulfate delivery may represent a novel approach to manage metabolic syndrome.

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.

Catalase deletion promotes prediabetic phenotype in mice.

PubMed

Heit, Claire; Marshall, Stephanie; Singh, Surrendra; Yu, Xiaoqing; Charkoftaki, Georgia; Zhao, Hongyu; Orlicky, David J; Fritz, Kristofer S; Thompson, David C; Vasiliou, Vasilis

2017-02-01

Hydrogen peroxide is produced endogenously and can be toxic to living organisms by inducing oxidative stress and cell damage. However, it has also been identified as a signal transduction molecule. By metabolizing hydrogen peroxide, catalase protects cells and tissues against oxidative damage and may also influence signal transduction mechanisms. Studies suggest that acatalasemic individuals (i.e., those with very low catalase activity) have a higher risk for the development of diabetes. We now report catalase knockout (Cat -/- ) mice, when fed a normal (6.5% lipid) chow, exhibit an obese phenotype that manifests as an increase in body weight that becomes more pronounced with age. The mice demonstrate altered hepatic and muscle lipid deposition, as well as increases in serum and hepatic triglycerides (TGs), and increased hepatic transcription and protein expression of PPARγ. Liver morphology revealed steatosis with inflammation. Cat -/- mice also exhibited pancreatic morphological changes that correlated with impaired glucose tolerance and increased fasting serum insulin levels, conditions consistent with pre-diabetic status. RNA-seq analyses revealed a differential expression of pathways and genes in Cat -/- mice, many of which are related to metabolic syndrome, diabetes, and obesity, such as Pparg and Cidec. In conclusion, the results of the present study show mice devoid of catalase develop an obese, pre-diabetic phenotype and provide compelling evidence for catalase (or its products) being integral in metabolic regulation. Copyright © 2016. Published by Elsevier Inc.

Obesity and Diabetes: The Increased Risk of Cancer and Cancer-Related Mortality

PubMed Central

LeRoith, Derek

2015-01-01

Obesity and type 2 diabetes are becoming increasingly prevalent worldwide, and both are associated with an increased incidence and mortality from many cancers. The metabolic abnormalities associated with type 2 diabetes develop many years before the onset of diabetes and, therefore, may be contributing to cancer risk before individuals are aware that they are at risk. Multiple factors potentially contribute to the progression of cancer in obesity and type 2 diabetes, including hyperinsulinemia and insulin-like growth factor I, hyperglycemia, dyslipidemia, adipokines and cytokines, and the gut microbiome. These metabolic changes may contribute directly or indirectly to cancer progression. Intentional weight loss may protect against cancer development, and therapies for diabetes may prove to be effective adjuvant agents in reducing cancer progression. In this review we discuss the current epidemiology, basic science, and clinical data that link obesity, diabetes, and cancer and how treating obesity and type 2 diabetes could also reduce cancer risk and improve outcomes. PMID:26084689

Obesity and metabolic surgery in type 1 diabetes mellitus.

PubMed

Raab, Heike; Weiner, R A; Frenken, M; Rett, K; Weiner, S

2013-03-01

Obesity surgery is an effective method for treating obesity and diabetes mellitus type 2. This type of diabetes can be completely resolved in 78.1% of diabetic patients and can be improved or resolved in 86.6% of diabetic patients. But little is known about bariatric surgery in type 1 diabetes mellitus. We report of 6 female obese patients with diabetes mellitus type 1 who had bariatric surgery. Two of them underwent Roux-en Y gastric bypass (RNYGB), one of them had sleeve gastrectomy and the remaining three had biliopancreatic diversion with duodenal-switch (BPD-DS). Our results showed a remarkable weight reduction as well as an improvement in their blood glucose control and the insulin requirement in the followup years after surgery. Pre-surgery the BMI of our 6 patients ranged between 37.3-46.0 kg/m2 and improved to 25.8-29.0 kg/m2 one year after surgery. HbA1c decreased from 6.7-9.8% pre-surgery to 5.7-8.5% after one year post-surgery. The total amount of daily insulin requirement was reduced from 62-150 IU/day pre-surgery to 15- 54 IU/day after one year. The results are impressive and show an improvement in insulin sensitivity following obesity surgery. However, an optimal blood glucose control still remains very important in the therapy of diabetes mellitus type 1 to avoid long-term-complications. Copyright © AULA MEDICA EDICIONES 2013. Published by AULA MEDICA. All rights reserved.

Glucocorticoid deprivation alters in vivo glucose uptake by muscle and adipose tissues of GTG-obese mice.

PubMed

Blair, S C; Caterson, I D; Cooney, G J

1995-11-01

The effect of 1 wk of glucocorticoid deprivation by surgical adrenalectomy (ADX) on tissue 2-deoxy(-)[U-14C]glucose (2-DG) uptake and hepatic glucose production (HGP) was assessed in conscious, catheterized mice 5 wk after the induction of obesity with gold thioglucose (GTG). Despite the prevailing hyperglycemia and hyperinsulinemia, glucose uptake by heart, quadriceps muscle, and interscapular brown adipose tissue (BAT) of GTG-obese mice was unchanged compared with controls, suggesting that the hyperglycemia of GTG-obese mice is able to compensate for the insulin resistance of these tissues. In contrast, epididymal white adipose tissue (WAT) of GTG-obese mice showed increased glucose uptake with hyperglycemia and hyperinsulinemia. ADX decreased the hyperglycemia and lowered the elevated glycogen content of the liver of GTG-obese mice. ADX reduced glucose uptake by heart and WAT of control and GTG-obese mice, consistent with the concomitant decrease in insulinemia. Glucose uptake by muscle of control and GTG-obese mice was not significantly decreased after ADX despite the decrease in insulin, and ADX increased glucose uptake by BAT of GTG-obese mice, suggesting increased sympathetically mediated thermogenesis in this tissue. HGP was increased in GTG-obese mice compared with controls, and ADX significantly reduced HGP in both GTG-obese and control mice. These results suggest that the improved glucose tolerance of ADX GTG-obese mice and ADX control mice is due to a decrease in HGP rather than an increase in peripheral glucose uptake.

Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice[S

PubMed Central

Tripathy, Sasmita; Lytle, Kelli A.; Stevens, Robert D.; Bain, James R.; Newgard, Christopher B.; Greenberg, Andrew S.; Huang, Li-Shin; Jump, Donald B.

2014-01-01

Nonalcoholic fatty liver disease is a major public health concern in the obese and type 2 diabetic populations. The high-fat lard diet induces obesity and fatty liver in C57BL/6J mice and suppresses expression of the PPAR-target gene, FA elongase 5 (Elovl5). Elovl5 plays a key role in MUFA and PUFA synthesis. Increasing hepatic Elovl5 activity in obese mice lowered hepatic TGs and endoplasmic reticulum stress markers (X-box binding protein 1 and cAMP-dependent transcription factor 6α) and increased TG catabolism and fatty acyl carnitines. Increased hepatic Elovl5 activity did not increase hepatic capacity for β-oxidation. Elovl5 effects on hepatic TG catabolism were linked to increased protein levels of adipocyte TG lipase (ATGL) and comparative gene identification 58 (CGI58). Elevated hepatic Elovl5 activity also induced the expression of some (pyruvate dehydrogenase kinase 4 and fibroblast growth factor 21), but not other cytochrome P450 4A10 (CYP4A10), PPAR-target genes. FA products of Elovl5 activity increased ATGL, but not CGI58, mRNA through PPARβ-dependent mechanisms in human HepG2 cells. Treatment of mouse AML12 hepatocytes with the PPARβ agonist (GW0742) decreased 14C-18:2,n-6 in TGs but did not affect β-oxidation. These studies establish that Elovl5 activity regulates hepatic levels of FAs controlling PPARβ activity, ATGL expression, and TG catabolism, but not FA oxidation. PMID:24814977

Obesity Paradox: Comparison of Heart Failure Patients With and Without Comorbid Diabetes.

PubMed

Lee, Kyoung Suk; Moser, Debra K; Lennie, Terry A; Pelter, Michele M; Nesbitt, Thomas; Southard, Jeffrey A; Dracup, Kathleen

2017-03-01

Diabetes is a common comorbid condition in patients with heart failure and is strongly associated with poor outcomes. Patients with heart failure who have diabetes are more likely to be obese than are those without diabetes. Obesity is positively associated with survival in patients with heart failure, but how comorbid diabetes influences the relationship between obesity and favorable prognosis is unclear. To explore whether the relationship between body mass index and survival differs between patients with heart failure who do or do not have diabetes. The sample consisted of 560 ambulatory patients with heart failure (mean age, 66 years; mean body mass index, 32; diabetes, 41%). The association between body mass index and all-cause mortality was examined by using multivariate Cox proportional hazards regression after adjustments for covariates. In patients without diabetes, higher body mass index was associated with a lower risk for all-cause mortality after adjustments for covariates (hazard ratio, 0.952; 95% CI, 0.909-0.998). In patients with diabetes, body mass index was not predictive of all-cause death after adjustments for covariates. Obesity was a survival benefit in heart failure patients without comorbid diabetes but not in those with comorbid diabetes. The mechanisms underlying the difference in the relationship between obesity and survival due to the presence of diabetes in patients with heart failure need to be elucidated. ©2017 American Association of Critical-Care Nurses.

Extreme obesity reduces bone mineral density: complementary evidence from mice and women.

PubMed

Núñez, Nomelí P; Carpenter, Catherine L; Perkins, Susan N; Berrigan, David; Jaque, S Victoria; Ingles, Sue Ann; Bernstein, Leslie; Forman, Michele R; Barrett, J Carl; Hursting, Stephen D

2007-08-01

To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women. We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study. In mice, higher levels of body adiposity (>40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women. The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m2) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis.

Treating Diet-Induced Diabetes and Obesity with Human Embryonic Stem Cell-Derived Pancreatic Progenitor Cells and Antidiabetic Drugs

PubMed Central

Bruin, Jennifer E.; Saber, Nelly; Braun, Natalie; Fox, Jessica K.; Mojibian, Majid; Asadi, Ali; Drohan, Campbell; O’Dwyer, Shannon; Rosman-Balzer, Diana S.; Swiss, Victoria A.; Rezania, Alireza; Kieffer, Timothy J.

2015-01-01

Summary Human embryonic stem cell (hESC)-derived pancreatic progenitor cells effectively reverse hyperglycemia in rodent models of type 1 diabetes, but their capacity to treat type 2 diabetes has not been reported. An immunodeficient model of type 2 diabetes was generated by high-fat diet (HFD) feeding in SCID-beige mice. Exposure to HFDs did not impact the maturation of macroencapsulated pancreatic progenitor cells into glucose-responsive insulin-secreting cells following transplantation, and the cell therapy improved glucose tolerance in HFD-fed transplant recipients after 24 weeks. However, since diet-induced hyperglycemia and obesity were not fully ameliorated by transplantation alone, a second cohort of HFD-fed mice was treated with pancreatic progenitor cells combined with one of three antidiabetic drugs. All combination therapies rapidly improved body weight and co-treatment with either sitagliptin or metformin improved hyperglycemia after only 12 weeks. Therefore, a stem cell-based therapy may be effective for treating type 2 diabetes, particularly in combination with antidiabetic drugs. PMID:25801507

Adrenoceptor Polymorphisms in Hypertension and Diabetes with obesity-update in 2014.

PubMed

Masuo, K

2014-08-12

Hypertension, diabetes mellitus (especially type 2 diabetes mellitus) and metabolic syndrome associated with obesity are rapidly growing public health problems. Sympathetic nerve activation is well documented in hypertension, diabetes mellitus, and obesity, hypertension and diabetes are determined by genetic background and environmental factors. Reduced energy expenditure and resting metabolic rate are predictive of weight gain, and the sympathetic nervous system participates in regulating energy balance through thermogenesis. The thermogenic effects of sympathetic nervous system in obesity have been mainly mediated via the β2 and β3-adrenergic receptors in humans. Further, β2-adrenoceptors importantly influence vascular reactivity and may regulate blood pressure. Genetic polymorphisms of the -adrenoceptor gene have been shown to alter the function of several adrenoceptor subtype and thus to modify the response to catecholamine. Among β2-adrenoceptor polymorphisms, Arg16Gly, Gln27Glu, and Thr164Ile are considered the most functionally important. β2-adrenoceptor genes have been studied in relation to hypertension. Genetic variations in the β3-adrenoceptor, such as the Try64Arg variant, are also associated with both obesity and hypertension. This review is an update of several versions published of the relationships between adrenoceptor polymorphisms and hypertension, diabetes and obesiy based on the my own review on the relationship with obesity in 2011 in "Journal of Obesity" [1], and another of my own reviews on the relationships with hypertension in 2010 in "International journal of Hypertension" [2], with 37 articles provided by the "PubMed" with the keywords of "adrenoceptor polymorphisms, obesity, hypertension and diabetes" searched on December 2013. However, the relationships of the polymorphisms of β2- and β3-adrenoceptor genes with sympathetic nervous system activity, hypertension and metabolic syndrome have been still discordant, it might be

Transmaternal bisphenol A exposure accelerates diabetes type 1 development in NOD mice.

PubMed

Bodin, Johanna; Bølling, Anette Kocbach; Becher, Rune; Kuper, Frieke; Løvik, Martinus; Nygaard, Unni Cecilie

2014-02-01

Diabetes mellitus type 1 is an autoimmune disease with a genetic predisposition that is triggered by environmental factors during early life. Epidemiological studies show that bisphenol A (BPA), an endocrine disruptor, has been detected in about 90% of all analyzed human urine samples. In this study, BPA was found to increase the severity of insulitis and the incidence of diabetes in female non obese diabetic (NOD) mice offspring after transmaternal exposure through the dams' drinking water (0, 0.1, 1, and 10mg/l). Both the severity of insulitis in the pancreatic islets at 11 weeks of age and the diabetes prevalence at 20 weeks were significantly increased for female offspring in the highest exposure group compared to the control group. Increased numbers of apoptotic cells, a reduction in tissue resident macrophages and an increase in regulatory T cells were observed in islets prior to insulitis development in transmaternally exposed offspring. The detectable apoptotic cells were identified as mostly glucagon producing alpha-cells but also tissue resident macrophages and beta-cells. In the local (pancreatic) lymph node neither regulatory T cell nor NKT cell populations were affected by maternal BPA exposure. Maternal BPA exposure may have induced systemic immune changes in offspring, as evidenced by alterations in LPS- and ConA-induced cytokine secretion in splenocytes. In conclusion, transmaternal BPA exposure, in utero and through lactation, accelerated the spontaneous diabetes development in NOD mice. This acceleration appeared to be related to early life modulatory effects on the immune system, resulting in adverse effects later in life.

A proteomic approach to obesity and type 2 diabetes

PubMed Central

López-Villar, Elena; Martos-Moreno, Gabriel Á; Chowen, Julie A; Okada, Shigeru; Kopchick, John J; Argente, Jesús

2015-01-01

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area. PMID:25960181

Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice.

PubMed

Baumeier, Christian; Kaiser, Daniel; Heeren, Jörg; Scheja, Ludger; John, Clara; Weise, Christoph; Eravci, Murat; Lagerpusch, Merit; Schulze, Gunnar; Joost, Hans-Georg; Schwenk, Robert Wolfgang; Schürmann, Annette

2015-05-01

Caloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species. Copyright © 2015. Published by Elsevier B.V.

Trends in obesity and diabetes prevalence in a Chilean urban population: 1993-2001.

PubMed

Cuevas, Ada; Molina, Alfredo; Rigotti, Attilio; Miquel, Juan Francisco; Marshall, Guillermo; Reyes, Soledad; Nervi, Flavio

2008-09-01

In recent years, the Chilean population has suffered significant lifestyle changes associated with the rapid socioeconomic development of the country. These changes can induce a significant increase in the prevalence of some chronic diseases, such as obesity, dyslipidemia, and diabetes mellitus. We aimed to assess diabetes mellitus, obesity, and hypercholesterolemia trends in a Chilean urban population followed between 1993 and 2001. A total of 1584 adults, living in Santiago, the capital of Chile, were randomly enrolled in a cross-sectional epidemiologic study in 1993. The same population was re-evaluated in 2001, recruiting 964 individuals from the original sample. Prevalences of diabetes mellitus, obesity, and hypercholesterolemia were determined according to standard criteria. We tested the significance of the differences between the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia in the 964 subjects evaluated in 2001 compared with the expected prevalence according to population aging based in data from 1993. In 1993, 3.8% of the sample population had diabetes mellitus, 21.8% had obesity, and 37.3 % exhibited hypercholesterolemia. In 2001, the observed prevalence of diabetes mellitus, obesity, and hypercholesterolemia was 10.1%, 32%, and 58%, respectively. The latter percentages were significantly higher than the expected prevalence according to the aging of the population (6.5% for diabetes mellitus, 27.7% for obesity, and 47.7 for hypercholesteromia). Our findings indicate that Chilean population has suffered an accelerated increase in the prevalence of diabetes mellitus, obesity, and hypercholesterolemia, due to the ongoing epidemiological transition that will lead to an enormous public health burden in the near future.

JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage.

PubMed

Becattini, Barbara; Zani, Fabio; Breasson, Ludovic; Sardi, Claudia; D'Agostino, Vito Giuseppe; Choo, Min-Kyung; Provenzani, Alessandro; Park, Jin Mo; Solinas, Giovanni

2016-09-01

Obesity and insulin resistance are associated with oxidative stress, which may be implicated in the progression of obesity-related diseases. The kinase JNK1 has emerged as a promising drug target for the treatment of obesity and type 2 diabetes. JNK1 is also a key mediator of the oxidative stress response, which can promote cell death or survival, depending on the magnitude and context of its activation. In this article, we describe a study in which the long-term effects of JNK1 inactivation on glucose homeostasis and oxidative stress in obese mice were investigated for the first time. Mice lacking JNK1 (JNK1(-/-)) were fed an obesogenic high-fat diet (HFD) for a long period. JNK1(-/-) mice fed an HFD for the long term had reduced expression of antioxidant genes in their skin, more skin oxidative damage, and increased epidermal thickness and inflammation compared with the effects in control wild-type mice. However, we also observed that the protection from obesity, adipose tissue inflammation, steatosis, and insulin resistance, conferred by JNK1 ablation, was sustained over a long period and was paralleled by decreased oxidative damage in fat and liver. We conclude that compounds targeting JNK1 activity in brain and adipose tissue, which do not accumulate in the skin, may be safer and most effective.-Becattini, B., Zani, F., Breasson, L., Sardi, C., D'Agostino, V. G., Choo, M.-K., Provenzani, A., Park, J. M., Solinas, G. JNK1 ablation in mice confers long-term metabolic protection from diet-induced obesity at the cost of moderate skin oxidative damage. © FASEB.

Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.

PubMed

Ornellas, Fernanda; Souza-Mello, Vanessa; Mandarim-de-Lacerda, Carlos Alberto; Aguila, Marcia Barbosa

2016-01-01

We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.

GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice.

PubMed

Schwenk, Robert W; Baumeier, Christian; Finan, Brian; Kluth, Oliver; Brauer, Christine; Joost, Hans-Georg; DiMarchi, Richard D; Tschöp, Matthias H; Schürmann, Annette

2015-03-01

Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)-oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1-oestrogen during beta cell failure under glucolipotoxic conditions. Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1-oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1-oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed. In contrast to GLP-1, GLP-1-oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1-oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1-oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells. GLP-1-oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone.

Exacerbation of Diabetic Renal Alterations in Mice Lacking Vasohibin-1

PubMed Central

Hinamoto, Norikazu; Maeshima, Yohei; Yamasaki, Hiroko; Nasu, Tatsuyo; Saito, Daisuke; Watatani, Hiroyuki; Ujike, Haruyo; Tanabe, Katsuyuki; Masuda, Kana; Arata, Yuka; Sugiyama, Hitoshi; Sato, Yasufumi; Makino, Hirofumi

2014-01-01

Vasohibin-1 (VASH1) is a unique endogenous inhibitor of angiogenesis that is induced in endothelial cells by pro-angiogenic factors. We previously reported renoprotective effect of adenoviral delivery of VASH1 in diabetic nephropathy model, and herein investigated the potential protective role of endogenous VASH1 by using VASH1-deficient mice. Streptozotocin-induced type 1 diabetic VASH1 heterozygous knockout mice (VASH1+/−) or wild-type diabetic mice were sacrificed 16 weeks after inducing diabetes. In the diabetic VASH1+/− mice, albuminuria were significantly exacerbated compared with the diabetic wild-type littermates, in association with the dysregulated distribution of glomerular slit diaphragm related proteins, nephrin and ZO-1, glomerular basement membrane thickning and reduction of slit diaphragm density. Glomerular monocyte/macrophage infiltration and glomerular nuclear translocation of phosphorylated NF-κB p65 were significantly exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates, accompanied by the augmentation of VEGF-A, M1 macrophage-derived MCP-1 and phosphorylation of IκBα, and the decrease of angiopoietin-1/2 ratio and M2 macrophage-derived Arginase-1. The glomerular CD31+ endothelial area was also increased in the diabetic VASH1+/− mice compared with the diabetic-wild type littermates. Furthermore, the renal and glomerular hypertrophy, glomerular accumulation of mesangial matrix and type IV collagen and activation of renal TGF-β1/Smad3 signaling, a key mediator of renal fibrosis, were exacerbated in the diabetic VASH1+/− mice compared with the diabetic wild-type littermates. In conditionally immortalized mouse podocytes cultured under high glucose condition, transfection of VASH1 small interfering RNA (siRNA) resulted in the reduction of nephrin, angiopoietin-1 and ZO-1, and the augmentation of VEGF-A compared with control siRNA. These results suggest that endogenous VASH1 may regulate the

Obesity and neuroinflammatory phenotype in mice lacking endothelial megalin.

PubMed

Bartolome, Fernando; Antequera, Desiree; Tavares, Eva; Pascual, Consuelo; Maldonado, Rosario; Camins, Antoni; Carro, Eva

2017-01-31

The multiligand receptor megalin controls the brain uptake of a number of ligands, including insulin and leptin. Despite the role of megalin in the transport of these metabolically relevant hormones, the role of megalin at the blood-brain-barrier (BBB) has not yet been explored in the context of metabolic regulation. Here we investigate the role of brain endothelial megalin in energy metabolism and leptin signaling using an endothelial cell-specific megalin deficient (EMD) mouse model. We found megalin is important to protect mice from developing obesity and metabolic syndrome when mice are fed a normal chow diet. EMD mice developed neuroinflammation, by triggering several pro-inflammatory cytokines, displayed reduced neurogenesis and mitochondrial deregulation. These results implicate brain endothelial megalin expression in obesity-related metabolic changes through the leptin signaling pathway proposing a potential link between obesity and neurodegeneration.

Models and mechanisms for hippocampal dysfunction in obesity and diabetes

PubMed Central

Stranahan, Alexis M.

2015-01-01

Clinical studies suggest that obesity and type 2 (insulin resistant) diabetes impair the structural integrity of medial temporal lobe regions involved in memory and confer greater vulnerability to neurological insults. While eliminating obesity and its endocrine comorbidities would be the most straightforward way to minimize cognitive risk, structural barriers to physical activity and the widespread availability of calorically dense, highly palatable foods will likely necessitate additional strategies to maintain brain health over the lifespan. Research in rodents has identified numerous correlates of hippocampal functional impairment in obesity and diabetes, with several studies demonstrating causality in subsequent mechanistic studies. This review highlights recent work on pathways and cell-cell interactions underlying the synaptic consequences of obesity, diabetes, or in models with both pathological conditions. Although the mechanisms vary across different animal models, immune activation has emerged as a shared feature of obesity and diabetes, with synergistic exacerbation of neuroinflammation in model systems with both conditions. This Review discusses these findings with reference to the benefits of incorporating existing models from the fields of obesity and metabolic disease. Many transgenic lines with basal metabolic alterations or differential susceptibility to diet-induced obesity have yet to be characterized with respect to their cognitive and synaptic phenotype. Adopting these models, and building on the extensive knowledge base used to generate them, is a promising avenue for understanding interactions between peripheral disease states and neurodegenerative disorders. PMID:25934036

Effects of Fortunella margarita fruit extract on metabolic disorders in high-fat diet-induced obese C57BL/6 mice.

PubMed

Tan, Si; Li, Mingxia; Ding, Xiaobo; Fan, Shengjie; Guo, Lu; Gu, Ming; Zhang, Yu; Feng, Li; Jiang, Dong; Li, Yiming; Xi, Wanpeng; Huang, Cheng; Zhou, Zhiqin

2014-01-01

Obesity is a nutritional disorder associated with many health problems such as dyslipidemia, type 2 diabetes and cardiovascular diseases. In the present study, we investigated the anti-metabolic disorder effects of kumquat (Fortunella margarita Swingle) fruit extract (FME) on high-fat diet-induced C57BL/6 obese mice. The kumquat fruit was extracted with ethanol and the main flavonoids of this extract were analyzed by HPLC. For the preventive experiment, female C57BL/6 mice were fed with a normal diet (Chow), high-fat diet (HF), and high-fat diet with 1% (w/w) extract of kumquat (HF+FME) for 8 weeks. For the therapeutic experiment, female C57BL/6 mice were fed with high-fat diet for 3 months to induce obesity. Then the obese mice were divided into two groups randomly, and fed with HF or HF+FME for another 2 weeks. Body weight and daily food intake amounts were recorded. Fasting blood glucose, glucose tolerance test, insulin tolerance test, serum and liver lipid levels were assayed and the white adipose tissues were imaged. The gene expression in mice liver and brown adipose tissues were analyzed with a quantitative PCR assay. In the preventive treatment, FME controlled the body weight gain and the size of white adipocytes, lowered the fasting blood glucose, serum total cholesterol (TC), serum low density lipoprotein cholesterol (LDL-c) levels as well as liver lipid contents in high-fat diet-fed C57BL/6 mice. In the therapeutic treatment, FME decreased the serum triglyceride (TG), serum TC, serum LDL-c, fasting blood glucose levels and liver lipid contents, improved glucose tolerance and insulin tolerance. Compared with the HF group, FME significantly increased the mRNA expression of PPARα and its target genes. Our study suggests that FME may be a potential dietary supplement for preventing and ameliorating the obesity and obesity-related metabolic disturbances.

Role of gut microbiota in obesity, type 2 diabetes and Alzheimer's disease.

PubMed

Naseer, Muhammad I; Bibi, Fehmida; Alqahtani, Mohammed H; Chaudhary, Adeel G; Azhar, Esam I; Kamal, Mohammad A; Yasir, Muhammad

2014-03-01

In recent years, there is a growing interest in research to investigate the importance of gut microbiome in health and diseases. This opens a new area of research for the role of microbial flora of the human gut in inflammation, energy homeostasis, pathogenesis of obesity and other associated disorders. Recent studies propose association of the gut microbiome with development of obesity and metabolic syndromes, such as type 2 diabetes mellitus (T2DM). The T2DM is a metabolic disease that is mainly caused by obesity-linked insulin resistance. The vascular effects of obesity appears to play a role in the development of Alzheimer's disease (AD) that is one of the rapidly growing diseases of a late stage of life all over the world. Studies from both humans and mice models have been demonstrated the engagement of gut microbial flora in the pathogenesis of obesity and host metabolism. The aim of this review is to discuss the current findings that may explain the cascade of gut microbial flora participation in the development of obesity, T2DM and further initiation of AD. In addition, the available data regarding the mechanisms that have been proposed to elucidate the role of gut microbiota in weight gain and possible cause of T2DM and AD have been examined.

Increased hypothalamic 5-HT2A receptor gene expression and effects of pharmacologic 5-HT2A receptor inactivation in obese A{sup y} mice

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

Nonogaki, Katsunori; Nozue, Kana; Oka, Yoshitomo

2006-12-29

Serotonin (5-hydroxytryptamine; 5-HT) 2A receptors contribute to the effects of 5-HT on platelet aggregation and vascular smooth muscle cell proliferation, and are reportedly involved in decreases in plasma levels of adiponectin, an adipokine, in diabetic subjects. Here, we report that systemic administration of sarpogrelate, a 5-HT2A receptor antagonist, suppressed appetite and increased hypothalamic pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript, corticotropin releasing hormone, 5-HT2C, and 5-HT1B receptor gene expression. A{sup y} mice, which have ectopic expression of the agouti protein, significantly increased hypothalamic 5-HT2A receptor gene expression in association with obesity compared with wild-type mice matched for age. Systemic administration ofmore » sarpogrelate suppressed overfeeding, body weight gain, and hyperglycemia in obese A{sup y} mice, whereas it did not increase plasma adiponectin levels. These results suggest that obesity increases hypothalamic 5-HT2A receptor gene expression, and pharmacologic inactivation of 5-HT2A receptors inhibits overfeeding and obesity in A{sup y} mice, but did not increase plasma adiponectin levels.« less

Epidemiological bases and molecular mechanisms linking obesity, diabetes, and cancer.

PubMed

Gutiérrez-Salmerón, María; Chocarro-Calvo, Ana; García-Martínez, José Manuel; de la Vieja, Antonio; García-Jiménez, Custodia

2017-02-01

The association between diabetes and cancer was hypothesized almost one century ago. Today, a vast number of epidemiological studies support that obese and diabetic populations are more likely to experience tissue-specific cancers, but the underlying molecular mechanisms remain unknown. Obesity, diabetes, and cancer share many hormonal, immune, and metabolic changes that may account for the relationship between diabetes and cancer. In addition, antidiabetic treatments may have an impact on the occurrence and course of some cancers. Moreover, some anticancer treatments may induce diabetes. These observations aroused a great controversy because of the ethical implications and the associated commercial interests. We report an epidemiological update from a mechanistic perspective that suggests the existence of many common and differential individual mechanisms linking obesity and type 1 and 2 diabetes mellitus to certain cancers. The challenge today is to identify the molecular links responsible for this association. Classification of cancers by their molecular signatures may facilitate future mechanistic and epidemiological studies. Copyright © 2016 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

Some pharmacological effects of cinnamon and ginger herbs in obese diabetic rats

PubMed Central

Shalaby, Mostafa Abbas; Saifan, Hamed Yahya

2014-01-01

Aims: The present study was designed to assess some pharmacological effects of cinnamon (CAE) and ginger (GAE) aqueous extracts in obese diabetic rats, and to elucidate the potential mechanisms. Materials and Methods: Forty-two Sprague-Dawley rats were randomized into 6 equal groups. Group 1 was a negative control and the other groups were rendered obese by feeding rats on high-fat diet for 4 weeks. The obese rats were subcutaneously injected with alloxan for 5*days to induce diabetes. Group 2 was a positive control, and Groups 3, 4, 5 and 6 were orally given CAE in doses 200 and 400 mg/kg and GAE in the same doses, respectively for 6 weeks. Blood samples were collected for serum biochemical analyses. Kidneys were dissected out to assay activity of tissue antioxidant enzymes: Superoxide dismutase, glutathione peroxidase and catalase. Results: CAE and GAE significantly reduced body weight and body fat mass; normalized serum levels of liver enzymes; improved lipid profile; decreased blood glucose and leptin and increased insulin serum levels in obese diabetic rats. Both extracts also increased activity of kidney antioxidant enzymes. Conclusion: CAE and GAE exhibit anti-obesity, hepatoprotective, hypolipidemic, antidiabetic and anti-oxidant effects in obese diabetic rats. These results confirm the previous reports on both extracts. The potential mechanisms underlying these effects are fully discussed and clarified. Our results affirm the traditional use of cinnamon and ginger for treating patients suffering from obesity and diabetes. The obese diabetic rat model used in this study is a novel animal model used in pharmacology researches. PMID:26401364

Exposure to bisphenol A, but not phthalates, increases spontaneous diabetes type 1 development in NOD mice.

PubMed

Bodin, Johanna; Kocbach Bølling, Anette; Wendt, Anna; Eliasson, Lena; Becher, Rune; Kuper, Frieke; Løvik, Martinus; Nygaard, Unni Cecilie

2015-01-01

Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of insulin producing pancreatic beta-cells due to a genetic predisposition and can be triggered by environmental factors. We have previously shown that bisphenol A (BPA) accelerates the spontaneous development of diabetes in non-obese diabetic (NOD) mice. Here, we hypothesized that oral exposure to a mixture of the endocrine disruptors BPA and phthalates, relevant for human exposure, would accelerate diabetes development compared to BPA alone. NOD mice were exposed to BPA (1 mg/l), a mixture of phthalates (DEHP 1 mg/l, DBP 0.2 mg/l, BBP 10 mg/l and DiBP 20 mg/l) or a combination of BPA and the phthalate mixture through drinking water from conception and throughout life. Previous observations that BPA exposure increased the prevalence of diabetes and insulitis and decreased the number of tissue resident macrophages in pancreas were confirmed, and extended by demonstrating that BPA exposure also impaired the phagocytic activity of peritoneal macrophages. None of these effects were observed after phthalate exposure alone. The phthalate exposure in combination with BPA seemed to dampen the BPA effects on macrophage number and function as well as diabetes development, but not insulitis development. Exposure to BPA alone or in combination with phthalates decreased cytokine release (TNFα, IL-6, IL-10, IFNγ, IL-4) from in vitro stimulated splenocytes and lymph node cells, indicating systemic changes in immune function. In conclusion, exposure to BPA, but not to phthalates or mixed exposure to BPA and phthalates, accelerated diabetes development in NOD mice, apparently in part via systemic immune alterations including decreased macrophage function.

Trends of obesity prevalence among Spanish adults with diabetes, 1987-2012.

PubMed

Basterra-Gortari, Francisco Javier; Bes-Rastrollo, Maira; Ruiz-Canela, Miguel; Gea, Alfredo; Sayón-Orea, Carmen; Martínez-González, Miguel Ángel

2018-04-24

Our aim was to examine the secular trends in obesity prevalence among Spanish adults with diabetes. Data were collected from 8 waves (from 1987 to 2012) of the National Health Surveys (NHS). NHS are cross-sectional studies conducted in representative samples of the Spanish adult population. Data of 7378 adults (≥16 years) who reported having been diagnosed of diabetes were analyzed. Previously validated self-reported weight and height were used to estimate body mass index (BMI). Obesity was defined as a BMI of 30kg/m 2 or greater. Age-adjusted obesity prevalence for each wave was calculated by the direct standardization method. From 1987 to 2012 age-adjusted prevalence of obesity among persons with diabetes increased from 18.2% (95% confidence interval [CI]: 14.2-22.2%) to 39.8% (95% CI: 36.8-42.8%). Age-adjusted prevalence of obesity in males with diabetes increased from 13.2% (95% CI: 7.3-19.1%) to 38.0% (95% CI: 33.8-42.1%) and in females from 23.0% (95% CI: 17.6-28.4%) to 42.3% (95% CI: 38.0-46.6%). Between 1987 and 2012 the prevalence of obesity markedly increased in Spain among adults with diabetes. Copyright © 2018 Elsevier España, S.L.U. All rights reserved.

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.

Beyond gut microbiota: understanding obesity and type 2 diabetes.

PubMed

Lau, Eva; Carvalho, Davide; Pina-Vaz, Cidália; Barbosa, José-Adelino; Freitas, Paula

2015-01-01

Obesity and type 2 diabetes are metabolic diseases that have reached epidemic proportions worldwide. Although their etiology is complex, both result from interplay between behaviour, environment and genetic factors. Within ambient determinants, human overall gut bacteria have been identified as a crucial mediator of obesity and its consequences. Gut microbiota plays a crucial role in gastro-intestinal mucosa permeability and regulates the fermentation and absorption of dietary polyssacharides, which may explain its importance in the regulation of fat accumulation and the resultant development of obesity-related diseases. The main objective of this review is to address the pathogenic association between gut microbiota and obesity and to explore related innovative therapeutic targets. New insights into the role of the small bowel and gut microbiota in diabetes and obesity may make possible the development of integrated strategies to prevent and treat these metabolic disorders.

Noninvasive Imaging of Retinal Morphology and Microvasculature in Obese Mice Using Optical Coherence Tomography and Optical Microangiography

PubMed Central

Zhi, Zhongwei; Chao, Jennifer R.; Wietecha, Tomasz; Hudkins, Kelly L.; Alpers, Charles E.; Wang, Ruikang K.

2014-01-01

Purpose. To evaluate early diabetes-induced changes in retinal thickness and microvasculature in a type 2 diabetic mouse model by using optical coherence tomography (OCT)/optical microangiography (OMAG). Methods. Twenty-two-week-old obese (OB) BTBR mice (n = 10) and wild-type (WT) control mice (n = 10) were imaged. Three-dimensional (3D) data volumes were captured with spectral domain OCT using an ultrahigh-sensitive OMAG scanning protocol for 3D volumetric angiography of the retina and dense A-scan protocol for measurement of the total retinal blood flow (RBF) rate. The thicknesses of the nerve fiber layer (NFL) and that of the NFL to the inner plexiform layer (IPL) were measured and compared between OB and WT mice. The linear capillary densities within intermediate and deep capillary layers were determined by the number of capillaries crossing a 500-μm line. The RBF rate was evaluated using an en face Doppler approach. These quantitative measurements were compared between OB and WT mice. Results. The retinal thickness of the NFL to IPL was significantly reduced in OB mice (P < 0.01) compared to that in WT mice, whereas the NFL thickness between the two was unchanged. 3D depth-resolved OMAG angiography revealed the first in vivo 3D model of mouse retinal microcirculation. Although no obvious differences in capillary vessel densities of the intermediate and deep capillary layers were detected between normal and OB mice, the total RBF rate was significantly lower (P < 0.05) in OB mice than in WT mice. Conclusions. We conclude that OB BTBR mice have significantly reduced NFL–IPL thicknesses and total RBF rates compared with those of WT mice, as imaged by OCT/OMAG. OMAG provides an unprecedented capability for high-resolution depth-resolved imaging of mouse retinal vessels and blood flow that may play a pivotal role in providing a noninvasive method for detecting early microvascular changes in patients with diabetic retinopathy. PMID:24458155

CD44 gene vaccination for insulin-dependent diabetes mellitus in non-obese diabetic mice.

PubMed

Weiss, Lola; Botero-Anug, Ana Maria; Hand, Carla; Slavin, Shimon; Naor, David

2008-01-01

Standard CD44 and its alternatively spliced variants were found to be associated with the metastatic potential of tumor cells and with cell migration of autoimmune inflammatory cells, including cells involved in experimental insulin-dependent diabetes mellitus. To investigate whether induction of anti-CD44 immune reactivity, through cDNA vaccination, could attenuate IDDM in a transfer model of NOD mice. Our vaccination technique involved the insertion of CD44s or CD44v cDNA into a silicone tube filled with a 2.5 cm long segment of hydroxylated-polyvinyl acetate wound dressing sponge (forming a virtual lymph node) which was implanted under the skin of male NOD recipients reconstituted with diabetogenic spleen cells of female NOD donors. The VLN were implanted 20 days before and 3 days after cell transfer. In contrast to control groups of recipient mice, recipients vaccinated with VLN loaded with CD44v or CD44s cDNAs developed resistance to IDDM almost to the same extent. Our results suggest that the gene vaccination effect was mediated by anti-CD44 antibody rather than by cellular immunity. Histopathological examinations revealed a significant protection of pancreatic islets in the DNA-vaccinated recipients, whereas the islets of control recipients of diabetogenic cells were almost totally destroyed. These findings may open new opportunities for IDDM therapy in the future.

Prevalence of disability in Australian elderly: Impact of trends in obesity and diabetes.

PubMed

Wong, Evelyn; Woodward, Mark; Stevenson, Christopher; Backholer, Kathryn; Sarink, Danja; Peeters, Anna

2016-01-01

We aimed to estimate the impact of past and future changes in obesity and diabetes prevalence in mid-life on disability prevalence for adult Australians. We analysed data from the Australian Diabetes, Obesity and Lifestyle study (AusDiab) including participants aged 45-64years, disability-free at baseline (1999/2000) with disability information at follow-up (2011/12) (n=2107). We used coefficients from multinomial logistic regression to predict 10-year probabilities of disability and death from baseline predictors (age, sex, obesity, smoking, diabetes and hypertension). We estimated the prevalence of disability attributable to past (1980) and expected future (2025) changes in obesity and diabetes prevalence using the life table approach. We estimated that the prevalence of disability for those aged between 55 and 74years would have been 1697 cases per 100,000 persons less in 2010 (10.3% less) if the rates of obesity and diabetes observed in 2000 had been as low as the levels observed in 1980. However, if instead the prevalence of obesity and diabetes had been as high as the levels expected in 2025, then the prevalence of disability would have been an additional 2173 per 100,000 persons (an additional 13.2%). We demonstrate, for the first time, a substantial potential impact of obesity and diabetes trends on disability amongst those aged 55-74years. In Australian adults by 2025 we estimate that around 26% of disability cases would have been avoidable if there had been no change in obesity and diabetes prevalence since 1980. A similar impact is likely around the world in developed countries. Copyright © 2015 Elsevier Inc. All rights reserved.

Neotomodon alstoni mice present sex differences between lean and obese in daily hypothalamic leptin signaling.

PubMed

Pérez-Mendoza, Moisés; Luna-Moreno, Dalia; Carmona-Castro, Agustín; Rodríguez-Guadarrama, Hugo A; Montoya-Gómez, Luis M; Díaz-Muñoz, Mauricio; Miranda-Anaya, Manuel

2017-01-01

This article compared the effects of spontaneous obesity on the daily profile in the relative amount of the leptin receptor (LepRb), and its output. That is the precursor Pro-opiomelanocortin (POMC) over a 24-hour period and compared with differences in locomotion and food intake in periods of artificial light. Differences between lean and obese mice were examined, as were sex differences. Body weight, food intake and locomotor activity were monitored in freely moving lean and obese mice. Hypothalamic tissue was collected at 5 h, 10 h, 15 h, 19 h and 24 h. Samples were analyzed by western blotting to determine the relative presence of protein for LepRb, STAT3 phosphorylation (by pSTAT3/STAT3 ratio) and POMC. Obese mice were 60% less active in locomotion than lean mice during the night. While both locomotor activity and food intake were noticeably greater during the day in obese mice than in lean mice, the hypothalamus in obese mice showed a lower relative abundance of POMC and reduced pSTAT3/STAT3 ratio and leptin receptors. Behavioral and biochemical differences were more evident in obese females than in obese males. These results indicate that obesity in N. alstoni affects hypothalamic leptin signaling according to sex.

Maternal overweight and obesity and risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes.

PubMed

Persson, Martina; Cnattingius, Sven; Wikström, Anna-Karin; Johansson, Stefan

2016-10-01

Women with type 1 or type 2 diabetes are at increased risk of pre-eclampsia. Overweight and obesity are associated with an increased risk of pre-eclampsia in women without diabetes. The aim of the study was to investigate the impact of maternal overweight and obesity on the risk of pre-eclampsia in women with type 1 diabetes or type 2 diabetes. In a population-based cohort study including singleton births in Sweden, we estimated the risk of pre-eclampsia among women with type 1 diabetes (n = 7062) and type 2 diabetes (n = 886), and investigated whether maternal overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI ≥30.0 kg/m(2)) modified the risk. Logistic regression analyses were used to estimate crude and adjusted ORs with 95% CIs, using women without diabetes as the reference group (n = 1,509,525). Compared with women without diabetes, the adjusted ORs for pre-eclampsia in women with type 1 and type 2 diabetes were 5.74 (95% CI 5.31, 6.20) and 2.11 (95% CI 1.65, 2.70), respectively. The corresponding risks of pre-eclampsia combined with preterm birth were even higher. Risks of pre-eclampsia increased with maternal overweight (BMI 25-29.9 kg/m(2)) and obesity (BMI ≥30.0 kg/m(2)), foremost in women without diabetes, to a lesser extent in women with type 1 diabetes but not in women with type 2 diabetes. Maternal overweight and obesity increased risks of pre-eclampsia in women with type 1 diabetes but not in women with type 2 diabetes. Even so, considering associations between maternal BMI and overall maternal and offspring risk, all women (with and without diabetes) should aim for a normal weight before pregnancy.

Monocyte Chemoattractant Protein 1 (MCP-1) in Obesity and Diabetes

PubMed Central

Panee, Jun

2012-01-01

Monocyte chemoattractant protein-1 (MCP-1) is the first discovered and most extensively studied CC chemokine, and the amount of studies on its role in the etiologies of obesity- and diabetes-related diseases have increased exponentially during the past 2 decades. This review attempted to provide a panoramic perspective of the history, regulatory mechanisms, functions, and therapeutic strategies of this chemokine. The highlights of this review include the roles of MCP-1 in the development of obesity, diabetes, cardiovascular diseases, insulitis, diabetic nephropathy, and diabetic retinopathy. Therapies that specifically or non-specifically inhibit MCP-1 overproduction have been summarized. PMID:22766373

The TRPC1 Ca2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes.

PubMed

Krout, Danielle; Schaar, Anne; Sun, Yuyang; Sukumaran, Pramod; Roemmich, James N; Singh, Brij B; Claycombe-Larson, Kate J

2017-12-15

The transient receptor potential canonical channel-1 (TRPC1) is a Ca 2+ -permeable channel found in key metabolic organs and tissues, including the hypothalamus, adipose tissue, and skeletal muscle. Loss of TRPC1 may alter the regulation of cellular energy metabolism resulting in insulin resistance thereby leading to diabetes. Exercise reduces insulin resistance, but it is not known whether TRPC1 is involved in exercise-induced insulin sensitivity. The role of TRPC1 in adiposity and obesity-associated metabolic diseases has not yet been determined. Our results show that TRPC1 functions as a major Ca 2+ entry channel in adipocytes. We have also shown that fat mass and fasting glucose concentrations were lower in TRPC1 KO mice that were fed a high-fat (HF) (45% fat) diet and exercised as compared with WT mice fed a HF diet and exercised. Adipocyte numbers were decreased in both subcutaneous and visceral adipose tissue of TRPC1 KO mice fed a HF diet and exercised. Finally, autophagy markers were decreased and apoptosis markers increased in TRPC1 KO mice fed a HF diet and exercised. Overall, these findings suggest that TRPC1 plays an important role in the regulation of adiposity via autophagy and apoptosis and that TRPC1 inhibits the positive effect of exercise on type II diabetes risk under a HF diet-induced obesity environment.

Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice

PubMed Central

Weisberg, S; Leibel, R; Tortoriello, D V

2016-01-01

Background: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). Results: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. Conclusions: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance. PMID:27110686

Empowerment in the Treatment of Diabetes and Obesity.

PubMed

Łuczyński, Włodzimierz; Głowińska-Olszewska, Barbara; Bossowski, Artur

2016-01-01

As the available therapies for diabetes and obesity are not effective enough, diabetologists and educators search for new methods to collaborate with patients in order to support their health behaviors. The aim of this review is to discuss perspectives for the development of new empowerment-type therapies in the treatment of diabetes/obesity. Empowerment is a process whereby patients gain the necessary knowledge to influence their own behavior to improve the quality of their lives. It is carried out in five stages: (1) identify the problem, (2) explain the feelings and meanings, (3) build a plan, (4) act, and (5) experience and assess the execution. Although many years have passed since the advent and popularization of the concept of empowerment, the area remains controversial, mainly with regard to the methodology of therapy. Some previous studies have confirmed the positive effect of empowerment on body weight, metabolic control, and quality of life of patients with type 2 diabetes; however, few studies have been conducted in patients with type 1 diabetes. There is still a need to confirm the effectiveness of empowerment in accordance with Evidence Based Medicine by performing long-term observational studies in a large group of patients. In future, empowerment may become part of the standard of care for patients with diabetes and/or obesity.

Empowerment in the Treatment of Diabetes and Obesity

PubMed Central

2016-01-01

As the available therapies for diabetes and obesity are not effective enough, diabetologists and educators search for new methods to collaborate with patients in order to support their health behaviors. The aim of this review is to discuss perspectives for the development of new empowerment-type therapies in the treatment of diabetes/obesity. Empowerment is a process whereby patients gain the necessary knowledge to influence their own behavior to improve the quality of their lives. It is carried out in five stages: (1) identify the problem, (2) explain the feelings and meanings, (3) build a plan, (4) act, and (5) experience and assess the execution. Although many years have passed since the advent and popularization of the concept of empowerment, the area remains controversial, mainly with regard to the methodology of therapy. Some previous studies have confirmed the positive effect of empowerment on body weight, metabolic control, and quality of life of patients with type 2 diabetes; however, few studies have been conducted in patients with type 1 diabetes. There is still a need to confirm the effectiveness of empowerment in accordance with Evidence Based Medicine by performing long-term observational studies in a large group of patients. In future, empowerment may become part of the standard of care for patients with diabetes and/or obesity. PMID:28090541

Fetal growth restriction promotes physical inactivity and obesity in female mice.

PubMed

Baker, M S; Li, G; Kohorst, J J; Waterland, R A

2015-01-01

Environmental exposures during critical periods of prenatal and early postnatal life affect the development of mammalian body weight regulatory mechanisms, influencing lifelong risk of obesity. The specific biological processes that mediate the persistence of such effects, however, remain poorly understood. The objectives of this study were to determine the developmental timing and physiological basis of the obesity-promoting effect previously reported in offspring of obese agouti viable yellow (A(vy)/a) mothers. Newborn offspring of obese A(vy)/a and lean (a/a) mothers were cross-fostered shortly after birth to study separately the effects of in utero or suckling period exposure to A(vy)/a dams. Body composition, food intake, physical activity and energy expenditure were measured in offspring shortly after weaning and in adulthood. Offspring of obese A(vy)/a dams paradoxically experienced fetal growth restriction, which was followed by adult-onset obesity specifically in females. Our main analyses focused on wild-type (a/a) offspring, because a subset of adult A(vy)/a offspring contracted a kidney disease resembling diabetic nephropathy. Detailed physiological characterization demonstrated that, both shortly after weaning and in adulthood, female wild-type mice born to A(vy)/a mothers are not hyperphagic but have reduced physical activity and energy expenditure. No such coordinated changes were detected in male offspring. Mediational regression analysis of our longitudinal data supported a causal pathway in which fetal growth restriction persistently reduces physical activity, leading to adult obesity. Our data are consistent with several recent human epidemiological studies showing female-specific effects of perinatal nutritional restriction on later obesity, and provide the novel mechanistic insight that this may occur via permanent and sex-specific changes in one's inherent propensity for physical activity.

How Effective Are Antioxidant Supplements in Obesity and Diabetes?

PubMed Central

Abdali, Daniyal; Samson, Sue E.; Grover, Ashok Kumar

2015-01-01

Obesity is a central health issue due to its epidemic prevalence and its association with type 2 diabetes and other comorbidities. Obesity is not just being overweight. It is a metabolic disorder due to the accumulation of excess dietary calories into visceral fat and the release of high concentrations of free fatty acids into various organs. It represents a state of chronic oxidative stress and low-grade inflammation whose intermediary molecules may include leptin, adiponectin and cytokines. It may progress to hyperglycemia, leading to type 2 diabetes. Whether or not dietary antioxidant supplements are useful in the management of obesity and type 2 diabetes is discussed in this review. Only the benefits for obesity and diabetes are examined here. Other health benefits of antioxidants are not considered. There are difficulties in comparing studies in this field because they differ in the time frame, participants' ethnicity, administration of antioxidant supplements, and even in how obesity was measured. However, the literature presents reasonable evidence for marginal benefits of supplementation with zinc, lipoic acid, carnitine, cinnamon, green tea, and possibly vitamin C plus E, although the evidence is much weaker for omega-3 polyunsaturated fatty acids, coenzyme Q10, green coffee, resveratrol, or lycopene. Overall, antioxidant supplements are not a panacea to compensate for a fast-food and video-game way of living, but antioxidant-rich foods are recommended as part of the lifestyle. Such antioxidant foods are commonly available. PMID:25791371

Abdominal obesity validates the association between elevated alanine aminotransferase and newly diagnosed diabetes mellitus.

PubMed

Yueh, Chen-Yu; Yang, Yao-Hsu; Sung, Yi-Ting; Lee, Li-Wen

2014-01-01

To examine how elevated alanine aminotransferase (ALT) could be associated with newly diagnosed diabetes mellitus. We conducted a cross-sectional analysis on a mass health examination. The odds ratios (ORs) for diabetes mellitus and newly diagnosed diabetes mellitus were compared between people with and without abdominal obesity, together with and without elevated ALT levels. 5499 people were included in this study. Two hundred fifty two (4.6%) fulfilled the diagnosis of diabetes mellitus with 178 (3.2%) undiagnosed before. Metabolic syndrome was vigorously associated with diabetes mellitus and newly diagnosed diabetes mellitus (12.4% vs. 1.4% and 9.0% vs. 0.9%), but elevated ALT alone was not. However, coexisting with obesity, elevated ALTs were robustly associated with diabetes mellitus and newly diagnosed diabetes mellitus. For the incidence of newly diagnosed diabetes mellitus, in comparison to non-obese people with normal ALT (1.7%, OR = 1), obese people especially with elevated ALT levels had significantly higher ORs (obese with ALT ≤ 40 U/L: 4.7%, OR 1.73, 95% CI 1.08-2.77, P 0.023; ALT 41-80 U/L: 6.8%, OR 2.06, 95% CI 1.20-3.55, P 0.009; ALT 81-120 U/L: 8.8%, OR 3.07, 95% CI 1.38-6.84, P 0.006; ALT > 120 U/L: 18.2%, OR 7.44, 95% CI 3.04-18.18, P < 0.001). Abdominal obesity validates the association between elevated alanine aminotransferase and diabetes mellitus and newly diagnosed diabetes mellitus. People with abdominal obesity, especially with coexisting elevated ALT levels should be screened for undiagnosed diabetes mellitus.

Effects of canagliflozin on weight loss in high-fat diet-induced obese mice.

PubMed

Ji, Wenjun; Zhao, Mei; Wang, Meng; Yan, Wenhui; Liu, Yuan; Ren, Shuting; Lu, Jun; Wang, Bing; Chen, Lina

2017-01-01

Canagliflozin, an inhibitor of sodium glucose co-transporter (SGLT) 2, has been shown to reduce body weight during the treatment of type 2 diabetes mellitus (T2DM). In this study, we sought to determine the role of canagliflozin in body weight loss and liver injury in obesity. C57BL/6J mice were fed a high-fat diet to simulate diet-induced obesity (DIO). Canagliflozin (15 and 60 mg/kg) was administered to DIO mice for 4 weeks. Orlistat (10 mg/kg) was used as a positive control. The body weight, liver weight, liver morphology, total cholesterol (TC) and triglyceride (TG) levels were examined. Signaling molecules, including diacylgycero1 acyltransferase-2 (DGAT2), peroxisome proliferation receptor alpha-1 (PPARα1), PPARγ1, PPARγ2 mRNA levels and the protein expression of SGLT2 were evaluated. Canagliflozin reduced body weight, especially the high-dose canagliflozin, and resulted in increased body weight loss compared with orlistat. Moreover, canagliflozin reduced the liver weight and the ratio of liver weight to body weight, lowered the serum levels of TC and TG, and ameliorated liver steatosis. During the canagliflozin treatment, SGLT2, DGAT2, PPARγ1 and PPARγ2 were inhibited, and PPARα1 was elevated in the liver tissues. This finding may explain why body weight was reduced and secondary liver injury was ameliorated in response to canagliflozin. Together, the results suggest that canagliflozin may be a potential anti-obesity strategy.

Bardoxolone methyl analogs RTA 405 and dh404 are well tolerated and exhibit efficacy in rodent models of Type 2 diabetes and obesity.

PubMed

Chin, Melanie; Lee, Chun-Yue Ivy; Chuang, Jen-Chieh; Bumeister, Ron; Wigley, W Christian; Sonis, Stephen T; Ward, Keith W; Meyer, Colin

2013-06-15

Bardoxolone methyl and related triterpenoids are well tolerated and efficacious in numerous animal models potentially relevant to patients with Type 2 diabetes and chronic kidney disease. These agents enhance glucose control and regulate lipid accumulation in rodent models of diabetes and obesity, and improve renal function, reduce inflammation, and prevent structural injury in models of renal disease. However, a recent study in Zucker diabetic fatty (ZDF) rats noted poor tolerability with the bardoxolone methyl analog RTA 405 within 1 mo after treatment initiation, although this study was confounded in part by the use of an impure RTA 405 batch. To investigate these discordant observations, the present studies were conducted to further characterize triterpenoids in rodent models of diabetes and obesity. A follow-up study was conducted in ZDF rats with two related triterpenoids (RTA 405 and dh404) for 1.5 mo. Consistent with previous rodent experience, and in contrast to the more recent ZDF report, ZDF rats administered RTA 405 or dh404 exhibited no adverse clinical signs, had laboratory values similar to controls, and exhibited no evidence of adverse liver or kidney histopathology. Additionally, RTA 405 was well tolerated in streptozotocin-induced Type 1 diabetic rats and high-fat-diet-induced obese mice. The present results are consistent with the overall published body of data obtained with triterpenoids and provide further evidence that these molecules are well tolerated without adverse effects on hepatobiliary or renal function in rodent models of diabetes and obesity.

Effects of Diet-Induced Mild Obesity on Airway Hyperreactivity and Lung Inflammation in Mice

PubMed Central

Jung, Sun Hee; Kwon, Jang-Mi; Shim, Jae Won; Kim, Deok Soo; Jung, Hye Lim; Park, Moon Soo; Park, Soo-Hee; Lee, Jinmi; Lee, Won-Young

2013-01-01

Purpose Obesity has been suggested to be linked to asthma. However, it is not yet known whether obesity directly leads to airway hyperreactivity (AHR) or obesity-induced airway inflammation associated with asthma. We investigated obesity-related changes in adipokines, AHR, and lung inflammation in a murine model of asthma and obesity. Materials and Methods We developed mouse models of chronic asthma via ovalbumin (OVA)-challenge and of obesity by feeding a high-fat diet, and then performed the methacholine bronchial provocation test, and real-time PCR for leptin, leptin receptor, adiponectin, adiponectin receptor (adipor1 and 2), vascular endothelial growth factor (VEGF), transforming growth factor (TGF) β, and tumor necrosis factor (TNF) α in lung tissue. We also measured cell counts in bronchoalveolar lavage fluid. Results Both obese and lean mice chronically exposed to OVA developed eosinophilic lung inflammation and AHR to methacholine. However, obese mice without OVA challenge did not develop AHR or eosinophilic inflammation in lung tissue. In obese mice, lung mRNA expressions of leptin, leptin receptor, VEGF, TGF, and TNF were enhanced, and adipor1 and 2 expressions were decreased compared to mice in the control group. On the other hand, there were no differences between obese mice with or without OVA challenge. Conclusion Diet-induced mild obesity may not augment AHR or eosinophilic lung inflammation in asthma. PMID:24142648

Excess health care costs of obesity in adults with diabetes mellitus: a claims data analysis.

PubMed

von Lengerke, T; Hagenmeyer, E-G; Gothe, H; Schiffhorst, G; Happich, M; Häussler, B

2010-08-01

Body weight management is a key factor in diabetes mellitus. However, both behavioral and pharmacological innovations to manage obesity may imply additional costs. In order to provide further insights into the role of obesity in diabetes-associated resource consumption, this study aims to estimate incremental costs of concomitant obesity in German adult patients (≥ 18 years) with different types of diabetes. Adopting a third-party payer perspective, claims data from a German statutory sickness fund (N=1,094,496) were analyzed for costs of annual drug prescriptions and out- and inpatient care in adult beneficiaries with diabetes in 2004. Using diagnostic information, 37,570 beneficiaries with diabetes were identified. Concomitant obesity was assessed by ICD-10-codes (E66) in the claims data. Adjusting for sex, age, and micro- and macro-vascular complications, one generalized gamma regression model with the log link was performed for type 2 diabetes patients (N=24,562), type 1 diabetes patients (N=5,663), and an unclassified group (N=7,345), respectively. Overall, 33% of the patients with diabetes were identified as obese (type 2 diabetes: 34%, type 1 diabetes: 20%, unclassified: 38%). Affirming descriptive analyses, the generalized gamma regression models revealed that obesity is associated with significant increments in health care costs regardless of type of diabetes (type 2 diabetes: € 454, type 1 diabetes: € 812, unclassified: € 532). The interaction of obesity and macro-vascular complications was numerically stronger in type 1 than in type 2 diabetes but reached statistical significance only in type 2 diabetes (and the unclassified group). Moreover, concurrent macro- and micro-vascular complications were associated with higher incremental costs in all groups. Concomitant obesity is independently associated with incremental health care costs in adult patients with type 2 diabetes and, even more so, type 1 diabetes. Results are discussed with

Mortality as a function of obesity and diabetes mellitus.

PubMed

Pettitt, D J; Lisse, J R; Knowler, W C; Bennett, P H

1982-03-01

Mortality according to body mass index (weight/height2) was studied in 2197 Pima Indians aged 15-74 years, as part of the longitudinal study of diabetes begun in 1965 in the Gila River Indian Community of Arizona. The Pima Indians are a population with a high prevalence of obesity, and they have the highest known incidence of type II (non-insulin dependent) diabetes mellitus. Among males, mortality was greatest in those with a body mass index of at least 40 kg/m2, but obesity had little effect on mortality at body mass indices below 40 kg/m2. Age-specific death rates in women were not consistently related to obesity, although mortality in subjects with diabetes was higher than in those without. In men, diabetes had little effect on mortality. In this study, as in several other mortality studies, the lowest mortality rates were experienced by people with body weights well above those recommended as "desirable" by the Society of Actuaries in 1959. Thus, the applicability of the "desirable" weight standards in common use is questioned.

Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models

PubMed Central

Suzuki, M; Takeda, M; Kito, A; Fukazawa, M; Yata, T; Yamamoto, M; Nagata, T; Fukuzawa, T; Yamane, M; Honda, K; Suzuki, Y; Kawabe, Y

2014-01-01

Objective: Tofogliflozin, a highly selective inhibitor of sodium/glucose cotransporter 2 (SGLT2), induces urinary glucose excretion (UGE), improves hyperglycemia and reduces body weight in patients with Type 2 diabetes (T2D). The mechanisms of tofogliflozin on body weight reduction were investigated in detail with obese and diabetic animal models. Methods: Diet-induced obese (DIO) rats and KKAy mice (a mouse model of diabetes with obesity) were fed diets containing tofogliflozin. Body weight, body composition, biochemical parameters and metabolic parameters were evaluated. Results: In DIO rats tofogliflozin was administered for 9 weeks, UGE was induced and body weight gain was attenuated. Body fat mass decreased without significant change in bone mass or lean body mass. Food consumption (FC) increased without change in energy expenditure, and deduced total calorie balance (deduced total calorie balance=FC−UGE−energy expenditure) decreased. Respiratory quotient (RQ) and plasma triglyceride (TG) level decreased, and plasma total ketone body (TKB) level increased. Moreover, plasma leptin level, adipocyte cell size and proportion of CD68-positive cells in mesenteric adipose tissue decreased. In KKAy mice, tofogliflozin was administered for 3 or 5 weeks, plasma glucose level and body weight gain decreased together with a reduction in liver weight and TG content without a reduction in body water content. Combination therapy with tofogliflozin and pioglitazone suppressed pioglitazone-induced body weight gain and reduced glycated hemoglobin level more effectively than monotherapy with either pioglitazone or tofogliflozin alone. Conclusion: Body weight reduction with tofogliflozin is mainly due to calorie loss with increased UGE. In addition, tofogliflozin also induces a metabolic shift from carbohydrate oxidation to fatty acid oxidation, which may lead to prevention of fat accumulation and inflammation in adipose tissue and liver. Tofogliflozin may have the potential

Rice koji reduced body weight gain, fat accumulation, and blood glucose level in high-fat diet-induced obese mice

PubMed Central

Yoshizaki, Yumiko; Kawasaki, Chihiro; Cheng, Kai-Chun; Ushikai, Miharu; Amitani, Haruka; Asakawa, Akihiro; Okutsu, Kayu; Sameshima, Yoshihiro; Takamine, Kazunori

2014-01-01

Rice koji is considered a readily accessible functional food that may have health-promoting effects. We investigated whether white, yellow, and red koji have the anti-obesity effect in C57BL/6J mice fed a high-fat diet (HFD), which is a model for obesity. Mice were fed HFD containing 10% (w/w) of rice koji powder or steamed rice for 4 weeks. Weight gain, epididymal white adipose tissue, and total adipose tissue weight were significantly lower in all rice koji groups than in the HFD-rice group after 4 weeks. Feed efficiency was significantly reduced in the yellow koji group. Blood glucose levels were significantly lower in the white and red koji groups with HOMA-R and leptin levels being reduced in the white koji group. White and red koji increased glucose uptake and GLUT4 protein expression in L6 myotube cells. These results showed that all rice koji have the anti-obesity or anti-diabetes effects although the mechanisms may differ depending on the type of rice koji consumed. PMID:25237599

Rice koji reduced body weight gain, fat accumulation, and blood glucose level in high-fat diet-induced obese mice.

PubMed

Yoshizaki, Yumiko; Kawasaki, Chihiro; Cheng, Kai-Chun; Ushikai, Miharu; Amitani, Haruka; Asakawa, Akihiro; Okutsu, Kayu; Sameshima, Yoshihiro; Takamine, Kazunori; Inui, Akio

2014-01-01

Rice koji is considered a readily accessible functional food that may have health-promoting effects. We investigated whether white, yellow, and red koji have the anti-obesity effect in C57BL/6J mice fed a high-fat diet (HFD), which is a model for obesity. Mice were fed HFD containing 10% (w/w) of rice koji powder or steamed rice for 4 weeks. Weight gain, epididymal white adipose tissue, and total adipose tissue weight were significantly lower in all rice koji groups than in the HFD-rice group after 4 weeks. Feed efficiency was significantly reduced in the yellow koji group. Blood glucose levels were significantly lower in the white and red koji groups with HOMA-R and leptin levels being reduced in the white koji group. White and red koji increased glucose uptake and GLUT4 protein expression in L6 myotube cells. These results showed that all rice koji have the anti-obesity or anti-diabetes effects although the mechanisms may differ depending on the type of rice koji consumed.

Genetically obese (ob/ob) mice are resistant to the lethal effects of thioacetamide hepatotoxicity

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

Won, Young-Suk; Song, Ji-Won; Lim, Jong-Hwan

Obesity increases the risk of chronic liver diseases, including viral hepatitis, alcohol-induced liver disease, and non-alcoholic steatohepatitis. In this study, we investigated the effects of obesity in acute hepatic failure using a murine model of thioacetamide (TA)-induced liver injury. Genetically obese ob/ob mice, together with non-obese ob/+ littermates, were subjected to a single intraperitoneal injection of TA, and examined for signs of hepatic injury. ob/ob mice showed a significantly higher survival rate, lower levels of serum alanine aminotransferase and aspartate aminotransferase, and less hepatic necrosis and apoptosis, compared with ob/+ mice. In addition, ob/ob mice exhibited significantly lower levels ofmore » malondialdehyde and significantly higher levels of glutathione and antioxidant enzyme activities compared with their ob/+ counterparts. Bioactivation analyses revealed reduced plasma clearance of TA and covalent binding of [{sup 14}C]TA to liver macromolecules in ob/ob mice. Together, these data demonstrate that genetically obese mice are resistant to TA-induced acute liver injury through diminished bioactivation of TA and antioxidant effects. - Highlights: • ob/ob mice are resistant to lethal doses of thioacetamide, compared to ob/+ mice. • ob/ob mice show reduced oxidative stress and enhanced antioxidant enzyme activity. • ob/ob mice exhibit diminished bioactivation of thioacetamide.« less

Cutting Edge: Nonobese Diabetic Mice Deficient in Chromogranin A Are Protected from Autoimmune Diabetes.