A Mouse Model of Metabolic Syndrome; Increase in Visceral Adipose Tissue Precedes the Development of Fatty Liver and Insulin Resistance in High-Fat Diet-Fed Male KK/Ta Mice

Abstract Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. Obesity is associated with dyslipidemia and insulin resistance, which may in part be mediated by inflammation and alterations to immune cell subsets within the adipose tissue. ET-1 promotes inflammation via the ET-1 type A (ETA) receptor, and blockade of ETA receptors improves dyslipidemia in patients with chronic kidney disease. We hypothesized that ET-1 causes dyslipidemia and inflammation within the adipose tissue of obese mice. To test this hypothesis, C57BL/6J mice were fed either normal diet (NMD) or high fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle or atrasentan (ETA receptor antagonist, 10mg/kg/day). HFD mice had significantly higher fat mass than NMD mice, with no significant effect of treatment with atrasentan. HFD mice had significantly higher circulating non-esterified free fatty acids, an effect that was ameliorated in mice treated with atrasentran (1.03±0.07 vs 0.58±0.02 mEq/L, p<0.05). Atrasentan-treated mice had significantly attenuated increase in liver triglycerides compared to non-treated HFD mice (3.8±0.7 vs 7.5±1.3mg/dL respectively, p<0.05). Mice treated with atrasentan had significantly improved glucose tolerance (10150±1031 vs 6563±975 AUC, p<0.05) and insulin tolerance (-2796±386 vs -9825±319 AUC, p<0.05) compared to non-treated insulin-resistant HFD mice. Plasma adiponectin, an insulin sensitizing adipokine that is inversely associated with adiposity and insulin resistance, was significantly increased in atrasentan-treated mice compared to non-treated HFD (4.8±0.1326 vs 6.5±0.3 µg/ml, p<0.05), with no differences in plasma insulin levels. Gene expression analysis of visceral fat showed improved expression of genes negatively associated with insulin resistance that were downregulated in non-treated HFD mice vs. NMD (IRS-1, PPAR-gamma, GLUT4, and adiponectin). Flow cytometric analyses of visceral adipose tissue indicated that HFD mice had a significantly higher number of both CD4+ and CD8+ T cells compared to NMD mice, which was attenuated by treatment with atrasentan. Further, eosinophils, which are important in maintaining adipose tissue health and reducing inflammation, were significantly decreased in HFD mice compared to NMD. Atrasentan treatment abolished the decrease in eosinophils. Taken together, these data indicate that ETA receptor blockade improves peripheral glucose homeostasis, dyslipidemia, and liver triglyceride levels, and also attenuates the proinflammatory immune profile in visceral adipose tissue. These data suggest a potential use for ETA receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

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Blimp-1 in adipose resident Tregs controls adipocyte beiging and obesity

10.1101/2019.12.14.874693 ◽

2019 ◽

Author(s):

Lisa Y. Beppu ◽

Xiaoyao Qu ◽

Giovanni J. Marrero ◽

Allen N. Fooks ◽

Adolfo B. Frias ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Caloric Intake ◽

Transcriptional Regulator ◽

High Fat ◽

Diet Induced Obesity ◽

Visceral Adipose

ABSTRACTCrosstalk between the immune system and adipocytes is critical for maintaining tissue homeostasis and regulating chronic systemic inflammation during diet-induced obesity (DIO). How visceral adipose tissue resident regulatory T cells (aTregs) signal to adipocytes in the visceral adipose tissue (VAT) is not understood. Here we show that Treg-specific ablation of the transcriptional regulator Blimp-1 resulted in increased insulin sensitivity, decreased body weight and increased Ucp-1 in adipocytes in high fat diet (HFD)-fed mice. Mechanistically, we demonstrate that Blimp-1 drives IL-10 production in Tregs, thus suppressing beiging and energy expenditure in adipocytes. Moreover, IL-10 mRNA expression positively correlated with increasing body weight in humans. These findings reveal a surprising relationship between aTregs and adipocytes in promoting insulin resistance during excessive caloric intake, placing Blimp-1-regulated IL-10 expression by aTregs at a critical juncture in the development of obesity and its associated comorbidities in mice and humans.SUMMARYHere we show that ablation of Blimp-1 in adipose tissue resident Tregs (aTregs) leads to decreased IL-10 production, resulting in increased Ucp-1 expression and beiging by adipocytes and protection from diet-induced obesity and insulin resistance.

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Galectin-3 Deletion Enhances Visceral Adipose Tissue Inflammation and Dysregulates Glucose Metabolism in Mice on a High-Fat Diet

Serbian Journal of Experimental and Clinical Research ◽

10.1515/sjecr-2016-0030 ◽

2016 ◽

Vol 17 (3) ◽

pp. 231-240 ◽

Cited By ~ 1

Author(s):

Ilija Jeftic ◽

Marina Miletic-Kovacevic ◽

Nemanja Jovicic ◽

Jelena Pantic ◽

Nebojsa Arsenijevic ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

High Fat ◽

Galectin 3 ◽

Visceral Adipose

Abstract Obesity and type 2 diabetes mellitus (T2DM) constitute major health problems worldwide. Increased visceral adiposity enhances the risk of insulin resistance and type 2 diabetes. The mechanisms involved in obesity-associated chronic inflammation in metabolic tissues (metaflammation) that lead to insulin resistance and dysregulated glucose metabolism are incompletely defined. Galectin-3 (Gal-3), a β-galactoside-binding lectin, modulates immune/inflammatory responses and specifically binds to metabolic danger molecules. To dissect the role of Gal-3 in obesity and diabetes, Gal-3-deficient (LGALS3-/-) and wild-type (WT) C57Bl/6 male mice were placed on a high-fat diet (HFD, 60% kcal fat) or a standard chow diet (10% kcal fat) for 6 months and metabolic, histological and immunophenotypical analyses of the visceral adipose tissue were performed. HFD-fed LGALS3-/- mice had higher body weights and more body weight gain, visceral adipose tissue (VAT), hyperglycaemia, hyperinsulinemia, insulin resistance and hyperlipidemia than diet-matched WT mice. Compared to WT mice, the enlarged VAT in obese LGALS3-/- mice contained larger adipocytes. Additionally, we demonstrate enhanced inflammation in the VAT of LGALS3-/- mice compared with diet-matched WT mice. The VAT of LGALS3-/- mice fed a HFD contained more numerous dendritic cells and proinflammatory F4/80+CD11c+CD11b+ and F4/80high macrophages. In contrast to WT mice, the numbers of CXCR3+ and CD8+ T cells were increased in the VAT of Gal-3-deficient mice after 6 months of high-fat feeding. We provide evidence that Gal-3 ablation results in enhanced HFD-induced adiposity, inflammation in the adipose tissue, insulin resistance and hyperglycaemia. Thus, Gal-3 represents an important regulator of obesity-associated immunometabolic alterations.

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Relationship of visceral adipose tissue with surrogate insulin resistance and liver markers in individuals with metabolic syndrome chronic complications

Therapeutic Advances in Endocrinology and Metabolism ◽

10.1177/2042018820958298 ◽

2020 ◽

Vol 11 ◽

pp. 204201882095829

Author(s):

Vanessa Bullón-Vela ◽

Itziar Abete ◽

Josep A. Tur ◽

Jadwiga Konieczna ◽

Dora Romaguera ◽

...

Keyword(s):

Risk Factors ◽

Insulin Resistance ◽

Metabolic Syndrome ◽

Adipose Tissue ◽

Fatty Liver ◽

Visceral Adipose Tissue ◽

Chronic Complications ◽

Glutamyl Transferase ◽

Visceral Adipose ◽

Receiver Operating

Background: Visceral adipose tissue (VAT) has a hazardous influence on systemic inflammation, insulin resistance and an adverse metabolic profile, which increases the risk of developing non-alcoholic fatty liver disease (NAFLD) and chronic complications of diabetes. In our study we aimed to evaluate the association of VAT and the triglyceride glucose (TyG) as a proxy of insulin resistance surrogated with metabolic and liver risk factors among subjects diagnosed with metabolic syndrome (MetS). Methods: A cross-sectional study was performed including 326 participants with MetS (55–75 years) from the PREDIMED-Plus study. Liver-status markers, VAT and TyG were assessed. Participants were stratified by tertiles according to VAT ( n = 254) and TyG ( n = 326). A receiver operating characteristic curve was used to analyse the efficiency of TyG for VAT. Results: Subjects with greater visceral fat depots showed worse lipid profile, higher homeostatic model assessment for insulin resistance (HOMA-IR), TyG, alanine transaminase (ALT), fibroblast growth factor-21 (FGF-21), fatty liver index (FLI) and hepatic steatosis index (HSI) compared with participants in the first tertile. The multi-adjusted linear-regression analyses indicated that individuals in the third tertile of TyG (>9.1−10.7) had a positive association with HOMA-IR [ β = 3.07 (95% confidence interval (CI) 2.28−3.86; p trend < 0.001)], ALT [ β = 7.43 (95% CI 2.23−12.63; p trend = 0.005)], gamma glutamyl transferase (GGT) [ β = 14.12 (95% CI 3.64−24.61; p trend = 0.008)], FGF-21 [ β = 190.69 (95% CI 93.13−288.25; p trend < 0.001)], FLI [ β = 18.65 (95% CI 14.97−22.23; p trend < 0.001)] and HSI [ β = 3.46 (95% CI, 2.23−4.68; p trend < 0.001)] versus participants from the first tertile. Interestingly, the TyG showed the largest area under the receiver operating curve (AUC) for women (AUC = 0.713; 95% CI 0.62−0.79) compared with men (AUC = 0.570; 95% CI 0.48−0.66). Conclusions: A disrupted VAT enlargement and impairment of TyG are strongly associated with liver status and cardiometabolic risk factors linked with NAFLD in individuals diagnosed with MetS. Moreover, the TyG could be used as a suitable and reliable marker estimator of VAT.

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The dual FXR/TGR5 agonist INT-767 counteracts nonalcoholic steatohepatitis and visceral adipose tissue dysfunction in a rabbit model of high fat diet-induced metabolic syndrome

Endocrine Abstracts ◽

10.1530/endoabs.49.ep377 ◽

2017 ◽

Author(s):

Paolo Comeglio ◽

Ilaria Cellai ◽

Sandra Filippi ◽

Annamaria Morelli ◽

Erica Sarchielli ◽

...

Keyword(s):

Metabolic Syndrome ◽

Adipose Tissue ◽

Visceral Adipose Tissue ◽

Nonalcoholic Steatohepatitis ◽

High Fat Diet ◽

Rabbit Model ◽

High Fat ◽

Adipose Tissue Dysfunction ◽

Visceral Adipose

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A Mouse Model of Metabolic Syndrome: Insulin Resistance, Fatty Liver and Non-Alcoholic Fatty Pancreas Disease (NAFPD) in C57BL/6 Mice Fed a High Fat Diet

Journal of Clinical Biochemistry and Nutrition ◽

10.3164/jcbn.09-83 ◽

2010 ◽

Vol 46 (3) ◽

pp. 212-223 ◽

Cited By ~ 227

Author(s):

Julio C. Fraulob ◽

Rebeca Ogg-Diamantino ◽

Caroline Fernandes-Santos ◽

Marcia Barbosa Aguila ◽

Carlos A. Mandarim-de-Lacerda

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Mouse Model ◽

Fatty Liver ◽

High Fat Diet ◽

High Fat ◽

Pancreas Disease ◽

Fatty Pancreas

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Trans-palmitoleic Acid Reduces Adiposity via Increased Lipolysis in a Rodent Model of Diet-Induced Obesity

British Journal Of Nutrition ◽

10.1017/s0007114521001501 ◽

2021 ◽

pp. 1-24

Author(s):

L. Irasema Chávaro-Ortiz ◽

Brenda D. Tapia-Vargas ◽

Mariel Rico-Hidalgo ◽

Ruth Gutiérrez-Aguilar ◽

María E. Frigolet

Keyword(s):

Adipose Tissue ◽

Lipid Metabolism ◽

Visceral Adipose Tissue ◽

High Fat Diet ◽

Palmitoleic Acid ◽

Rodent Model ◽

Adipocyte Size ◽

High Fat ◽

Diet Induced Obesity ◽

Visceral Adipose

Abstract Obesity is defined as increased adiposity, which leads to metabolic disease. The growth of adipose tissue depends on its capacity to expand, through hyperplasia or hypertrophy, in order to buffer energy surplus. Also, during the establishment of obesity, adipose tissue expansion reflects adipose lipid metabolism (lipogenesis and/or lipolysis). It is well known that dietary factors can modify lipid metabolism promoting or preventing the development of metabolic abnormalities that concur with obesity. Trans-palmitoleic acid (TP), a biomarker of dairy consumption, has been associated with reduced adiposity in clinical studies. Thus, we aimed to evaluate the effect of TP over adiposity and lipid metabolism-related genes in a rodent model of diet-induced obesity (DIO). To fulfil this aim, we fed C57BL/6 mice with a Control or a High Fat diet, added with or without TP (3g/kg diet), during 11 weeks. Body weight and food intake were monitored, fat pads were weighted, histology of visceral adipose tissue was analysed, and lipid metabolism-related gene expression was explored by qPCR. Results show that TP consumption prevented weight gain induced by high fat diet, reduced visceral adipose tissue weight, and adipocyte size, while increasing the expression of lipolytic molecules. In conclusion, we show for the first time that TP influences adipose tissue metabolism, specifically lipolysis, resulting in decreased adiposity and reduced adipocyte size in a DIO mice model.

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Estrogens Protect against High-Fat Diet-Induced Insulin Resistance and Glucose Intolerance in Mice

Endocrinology ◽

10.1210/en.2008-0971 ◽

2009 ◽

Vol 150 (5) ◽

pp. 2109-2117 ◽

Cited By ~ 244

Author(s):

Elodie Riant ◽

Aurélie Waget ◽

Haude Cogo ◽

Jean-François Arnal ◽

Rémy Burcelin ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Intolerance ◽

High Fat Diet ◽

Chow Diet ◽

High Fat ◽

Normal Chow ◽

Visceral Adipose ◽

Deficient Mice ◽

Normal Chow Diet

Although corroborating data indicate that estrogens influence glucose metabolism through the activation of the estrogen receptor α (ERα), it has not been established whether this pathway could represent an effective therapeutic target to fight against metabolic disturbances induced by a high-fat diet (HFD). To this end, we first evaluated the influence of chronic 17β-estradiol (E2) administration in wild-type ovariectomized mice submitted to either a normal chow diet or a HFD. Whereas only a modest effect was observed in normal chow diet-fed mice, E2 administration exerted a protective effect against HFD-induced glucose intolerance, and this beneficial action was abolished in ERα-deficient mice. Furthermore, E2 treatment reduced HFD-induced insulin resistance by 50% during hyperinsulinemic euglycemic clamp studies and improved insulin signaling (Akt phosphorylation) in insulin-stimulated skeletal muscles. Unexpectedly, we found that E2 treatment enhanced cytokine (IL-6, TNF-α) and plasminogen activator inhibitor-1 mRNA expression induced by HFD in the liver and visceral adipose tissue. Interestingly, although the proinflammatory effect of E2 was abolished in visceral adipose tissue from chimeric mice grafted with bone marrow cells from ERα-deficient mice, the beneficial effect of the hormone on glucose tolerance was not altered, suggesting that the metabolic and inflammatory effects of estrogens can be dissociated. Eventually comparison of sham-operated with ovariectomized HFD-fed mice demonstrated that endogenous estrogens levels are sufficient to exert a full protective effect against insulin resistance and glucose intolerance. In conclusion, the regulation of the ERα pathway could represent an effective strategy to reduce the impact of high-fat diet-induced type 2 diabetes.

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