Slc6a19 deficiency improves insulin sensitivity and preserves cardiac function in mice during diet-induced obesity

Recently, novel inbred mouse strains that are genetically distinct from the commonly used models have been developed from wild-caught mice. These wild-derived inbred strains have been included in many of the large-scale genomic projects, but their potential as models of altered obesity and diabetes susceptibility has not been assessed. We examined obesity and diabetes-related traits in response to high-fat feeding in two of these strains, PWD/PhJ (PWD) and WSB/EiJ (WSB), in comparison with C57BL/6J (B6). Young PWD mice displayed high fasting insulin levels, although they had normal insulin sensitivity. PWD mice subsequently developed a much milder and delayed-onset obesity compared with B6 mice but became as insulin resistant. PWD mice had a robust first-phase and increased second-phase glucose-stimulated insulin secretion in vivo, rendering them more glucose tolerant. WSB mice were remarkably resistant to diet-induced obesity and maintained very low fasting insulin throughout the study. WSB mice exhibited more rapid glucose clearance in response to an insulin challenge compared with B6 mice, consistent with their low percent body fat. Interestingly, in the absence of a measurable in vivo insulin secretion, glucose tolerance of WSB mice was better than B6 mice, likely due to their enhanced insulin sensitivity. Thus PWD and WSB are two obesity-resistant strains with unique insulin secretion phenotypes. PWD mice are an interesting model that dissociates hyperinsulinemia from obesity and insulin resistance, whereas WSB mice are a model of extraordinary resistance to a high-fat diet.

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The Reproductive Axis Retains Normal Insulin Sensitivity in the Setting of Diet-Induced Obesity and Infertility

10.1210/endo-meetings.2010.part1.p7.p1-347 ◽

2010 ◽

pp. P1-347-P1-347

Author(s):

S Wu ◽

K Brothers ◽

S Divall ◽

F Wondisford ◽

A Wolfe

Keyword(s):

Insulin Sensitivity ◽

Diet Induced Obesity ◽

Reproductive Axis

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Rosiglitazone Improves Insulin Sensitivity and Baroreflex Gain in Rats with Diet‐induced Obesity

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1051.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Ding Zhao ◽

Virginia L. Brooks

Keyword(s):

Insulin Sensitivity ◽

Diet Induced Obesity

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Increasing endogenous PPARγ ligands improves insulin sensitivity and protects against diet-induced obesity without side effects of thiazolidinediones

10.21203/rs.3.rs-490889/v1 ◽

2021 ◽

Author(s):

Yu-Hua Tseng ◽

Lee-Ming Chuang ◽

Yi-Cheng Chang ◽

Meng-Lun Hsieh ◽

Lun Tsou ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Insulin Sensitivity ◽

Side Effects ◽

Knockout Mice ◽

Fasting Glucose ◽

Binding Mode ◽

Fluid Retention ◽

Diet Induced Obesity

Abstract Insulin resistance and obesity are pivotal features of type 2 diabetes mellitus. Peroxisome proliferator-activated receptor γ (PPARγ) is a master transcriptional regulator of systemic insulin sensitivity and energy balance. The anti-diabetic drug thiazolidinediones are potent synthetic PPARγ ligands and insulin sensitizers with undesirable side effects including increased adiposity, fluid retention, and osteoporosis, which limit their clinical use. We and others have proved that 15-keto-PGE2 is an endogenous natural PPARγ ligand. 15-keto-PGE2 is catalyzed by prostaglandin reductase 2 (PTGR2) to become inactive metabolites. We found that 15-keto-PGE2 level is increased in Ptgr2 knockout mice. Ptgr2 knockout mice were protected from diet-induced obesity, insulin resistance, and hepatic steatosis without fluid retention nor reduced bone mineral density. Diet-induced obese mice have drastically reduced 15-keto-PGE2 levels compared to lean mice. Administration of 15-keto-PGE2 markedly improved insulin sensitivity and prevented diet-induced obesity in mice. We demonstrated that 15-keto-PGE2 activates PPARγ through covalent binding to its cysteine 285 residue at helix 3, which restrained its binding pocket between helix 3 and β-sheets of the PPARγ ligand binding domain. This binding mode differs from the helix12-dependent binding mode of thiazolidinediones. We further identified a small-molecule PTGR2 inhibitor BPRPT245, which interferes the interaction between the substrate-binding sites of PTGR2 and 15-keto-PGE2. BPRPT245 increased 15-keto-PGE2 concentration, activated PPARγ, and promoted glucose uptake in adipocytes. BPRPT245 also prevented diet-induced obesity, improved insulin sensitivity and glucose tolerance, lowers fasting glucose without fluid retention and osteoporosis. In humans, reduced serum 15-keto-PGE2 levels were observed in patients with type 2 diabetes compared with controls. Furthermore, serum 15-keto-PGE2 levels correlate inversely with insulin resistance and fasting glucose in non-diabetic humans. In conclusion, we identified a new therapeutic approach to improve insulin sensitivity and protect diet-induced obesity through increasing endogenous natural PPARγ ligands without side effects of thiazolidinediones.

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DPP4 deletion in adipose tissue improves hepatic insulin sensitivity in diet-induced obesity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00323.2019 ◽

2020 ◽

Vol 318 (5) ◽

pp. E590-E599 ◽

Cited By ~ 6

Author(s):

Tania Romacho ◽

Henrike Sell ◽

Ira Indrakusuma ◽

Diana Roehrborn ◽

Tamara R. Castañeda ◽

...

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Glucose Tolerance ◽

Hepatic Insulin Sensitivity ◽

Dipeptidyl Peptidase 4 ◽

Diet Induced Obesity ◽

Hepatic Fat ◽

Igf Binding ◽

Igf Binding Protein

Besides a therapeutic target for type 2 diabetes, dipeptidyl peptidase 4 (DPP4) is an adipokine potentially upregulated in human obesity. We aimed to explore the role of adipocyte-derived DPP4 in diet-induced obesity and insulin resistance with an adipose tissue-specific knockout (AT-DPP4-KO) mouse. Wild-type and AT-DPP4-KO mice were fed for 24 wk with a high fat diet (HFD) and characterized for body weight, glucose tolerance, insulin sensitivity by hyperinsulinemic-euglycemic clamp, and body composition and hepatic fat content. Image and molecular biology analysis of inflammation, as well as adipokine secretion, was performed in AT by immunohistochemistry, Western blot, real-time-PCR, and ELISA. Incretin levels were determined by Luminex kits. Under HFD, AT-DPP4-KO displayed markedly reduced circulating DPP4 concentrations, proving AT as a relevant source. Independently of glucose-stimulated incretin hormones, AT-DPP4-KO had improved glucose tolerance and hepatic insulin sensitivity. AT-DPP4-KO displayed smaller adipocytes and increased anti-inflammatory markers. IGF binding protein 3 (IGFBP3) levels were lower in AT and serum, whereas free IGF1 was increased. The absence of adipose DPP4 triggers beneficial AT remodeling with decreased production of IGFBP3 during HFD, likely contributing to the observed, improved hepatic insulin sensitivity.

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Inhibition of HDAC3 promotes ligand-independent PPARγ activation by protein acetylation

Journal of Molecular Endocrinology ◽

10.1530/jme-14-0066 ◽

2014 ◽

Vol 53 (2) ◽

pp. 191-200 ◽

Cited By ~ 52

Author(s):

Xiaoting Jiang ◽

Xin Ye ◽

Wei Guo ◽

Hongyun Lu ◽

Zhanguo Gao

Keyword(s):

Insulin Sensitivity ◽

Posttranslational Modifications ◽

Target Genes ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Histone Deacetylase 3 ◽

Protein Inhibition ◽

Diet Induced Obesity ◽

Exogenous Ligands

Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor whose activation is dependent on a ligand. PPARγ activation by exogenous ligands, such as thiazolidinediones (TZDs), is a strategy in the treatment of type 2 diabetes mellitus for the improvement of insulin sensitivity. In addition to a ligand, PPARγ function is also regulated by posttranslational modifications, such as phosphorylation, sumoylation, and ubiquitination. Herein, we report that the PPARγ protein is modified by acetylation, which induces the PPARγ function in the absence of an external ligand. We observed that histone deacetylase 3 (HDAC3) interacted with PPARγ to deacetylate the protein. In immunoprecipitation assays, the HDAC3 protein was associated with the PPARγ protein. Inhibition of HDAC3 using RNAi-mediated knockdown or HDAC3 inhibitor increased acetylation of the PPARγ protein. Furthermore, inhibition of HDAC3 enhanced the expression of PPARγ target genes such as adiponectin and aP2. The expression was associated with an increase in glucose uptake and insulin signaling in adipocytes. HDAC3 inhibition enhanced lipid accumulation during differentiation of adipocytes. PPARγ acetylation was also induced by pioglitazone and acetylation was required for PPARγ activation. In the absence of TZDs, the acetylation from HDAC3 inhibition was sufficient to induce the transcriptional activity of PPARγ. Treating diet-induced obesity mice with HDAC3 inhibitor or pioglitazone for 2 weeks significantly improved high-fat-diet-induced insulin resistance. Our results indicate that acetylation of PPARγ is a ligand-independent mechanism of PPARγ activation. HDAC3 inhibitor is a potential PPARγ activator for the improvement of insulin sensitivity.

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Cafeteria diet inhibits insulin clearance by reduced insulin-degrading enzyme expression and mRNA splicing

Journal of Endocrinology ◽

10.1530/joe-13-0177 ◽

2013 ◽

Vol 219 (2) ◽

pp. 173-182 ◽

Cited By ~ 28

Author(s):

P Brandimarti ◽

J M Costa-Júnior ◽

S M Ferreira ◽

A O Protzek ◽

G J Santos ◽

...

Keyword(s):

Skeletal Muscle ◽

Insulin Secretion ◽

Alternative Splicing ◽

Insulin Sensitivity ◽

Glucose Homeostasis ◽

Insulin Clearance ◽

Cafeteria Diet ◽

Mrna Levels ◽

Insulin Degrading Enzyme ◽

Diet Induced Obesity

Insulin clearance plays a major role in glucose homeostasis and insulin sensitivity in physiological and/or pathological conditions, such as obesity-induced type 2 diabetes as well as diet-induced obesity. The aim of the present work was to evaluate cafeteria diet-induced obesity-induced changes in insulin clearance and to explain the mechanisms underlying these possible changes. Female Swiss mice were fed either a standard chow diet (CTL) or a cafeteria diet (CAF) for 8 weeks, after which we performed glucose tolerance tests, insulin tolerance tests, insulin dynamics, and insulin clearance tests. We then isolated pancreatic islets for ex vivo glucose-stimulated insulin secretion as well as liver, gastrocnemius, visceral adipose tissue, and hypothalamus for subsequent protein analysis by western blot and determination of mRNA levels by real-time RT-PCR. The cafeteria diet induced insulin resistance, glucose intolerance, and increased insulin secretion and total insulin content. More importantly, mice that were fed a cafeteria diet demonstrated reduced insulin clearance and decay rate as well as reduced insulin-degrading enzyme (IDE) protein and mRNA levels in liver and skeletal muscle compared with the control animals. Furthermore, the cafeteria diet reduced IDE expression and alternative splicing in the liver and skeletal muscle of mice. In conclusion, a cafeteria diet impairs glucose homeostasis by reducing insulin sensitivity, but it also reduces insulin clearance by reducing IDE expression and alternative splicing in mouse liver; however, whether this mechanism contributes to the glucose intolerance or helps to ameliorate it remains unclear.

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Effects of food pattern change and physical exercise on cafeteria diet-induced obesity in female rats

British Journal Of Nutrition ◽

10.1017/s0007114511006933 ◽

2012 ◽

Vol 108 (8) ◽

pp. 1511-1518 ◽

Cited By ~ 18

Author(s):

Jéferson F. Goularte ◽

Maria B. C. Ferreira ◽

Gilberto L. Sanvitto

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Physical Exercise ◽

Energy Intake ◽

Liver Weight ◽

Cafeteria Diet ◽

Chow Diet ◽

Diet Induced Obesity ◽

Visceral Adipose

Obesity affects a large number of people around the world and appears to be the result of changes in food intake, eating habits and physical activity levels. Changes in dietary patterns and physical exercise are therefore strongly recommended to treat obesity and its complications. The present study tested the hypothesis that obesity and metabolic changes produced by a cafeteria diet can be prevented with dietary changes and/or physical exercise. A total of fifty-six female Wistar rats underwent one of five treatments: chow diet; cafeteria diet; cafeteria diet followed by a chow diet; cafeteria diet plus exercise; cafeteria diet followed by a chow diet plus exercise. The duration of the experiment was 34 weeks. The cafeteria diet resulted in higher energy intake, weight gain, increased visceral adipose tissue and liver weight, and insulin resistance. The cafeteria diet followed by the chow diet resulted in energy intake, body weight, visceral adipose tissue and liver weight and insulin sensitivity equal to that of the controls. Exercise increased total energy intake at week 34, but produced no changes in the animals' body weight or adipose tissue mass. However, insulin sensitivity in animals subjected to exercise and the diet was similar to that of the controls. The present study found that exposure to palatable food caused obesity and insulin resistance and a diet change was sufficient to prevent cafeteria diet-induced obesity and to maintain insulin sensitivity at normal levels. In addition, exercise resulted in normal insulin sensitivity in obese rats. These results may help to develop new approaches for the treatment of obesity and type 2 diabetes mellitus.

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