scholarly journals Adipocyte-specific deletion of IL-6 does not attenuate obesity-induced weight gain or glucose intolerance in mice

2019 ◽  
Vol 317 (4) ◽  
pp. E597-E604 ◽  
Author(s):  
Martin Whitham ◽  
Martin Pal ◽  
Tim Petzold ◽  
Marit Hjorth ◽  
Casey L. Egan ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Glucose Intolerance ◽  
Genetic Model ◽  
Whole Body ◽  
Littermate Control ◽  
Diet Induced Obesity ◽  
Marked Weight ◽  
Liver Insulin Resistance

It has been suggested that interleukin-6 (IL-6) produced by adipocytes in obesity leads to liver insulin resistance, although this hypothesis has never been definitively tested. Accordingly, we did so by generating adipocyte-specific IL-6-deficient (AdipoIL-6−/−) mice and studying them in the context of diet-induced and genetic obesity. Mice carrying two floxed alleles of IL-6 (C57Bl/6J) were crossed with Cre recombinase-overexpressing mice driven by the adiponectin promoter to generate AdipoIL-6−/− mice. AdipoIL-6−/− and floxed littermate controls were fed a standard chow or high-fat diet (HFD) for 16 wk and comprehensively metabolically phenotyped. In addition to a diet-induced obesity model, we also examined the role of adipocyte-derived IL-6 in a genetic model of obesity and insulin resistance by crossing the AdipoIL-6−/− mice with leptin-deficient ( ob/ob) mice. As expected, mice on HFD and ob/ob mice displayed marked weight gain and increased fat mass compared with chow-fed and ob/+ (littermate control) animals, respectively. However, deletion of IL-6 from adipocytes in either model had no effect on glucose tolerance or fasting hyperinsulinemia. We concluded that adipocyte-specific IL-6 does not contribute to whole body glucose intolerance in obese mice.

Female 5[beta]-reductase knockout mice are protected from diet induced obesity, insulin resistance and glucose intolerance

2016 ◽  
Author(s):  
Laura Gathercole ◽  
Matthew Chapman ◽  
Dean Larner ◽  
Petra Klusonova ◽  
Trevor Penning ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Knockout Mice ◽  
Diet Induced Obesity

scholarly journals Increased Tumor Growth in Mice with Diet-Induced Obesity: Impact of Ovarian Hormones

Endocrinology ◽  
2006 ◽  
Vol 147 (12) ◽  
pp. 5826-5834 ◽  
Author(s):  
Shoshana Yakar ◽  
Nomeli P. Nunez ◽  
Patricia Pennisi ◽  
Pnina Brodt ◽  
Hui Sun ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Tumor Growth ◽  
Glucose Intolerance ◽  
Tumor Development ◽  
Tumor Growth Rate ◽  
Obese Mice ◽  
Female Mice ◽  
Diet Induced Obesity ◽  
Body Adiposity ◽  
Obese Female

Obesity increases the risk of many cancers in both males and females. This study describes a link between obesity, obesity-associated metabolic alterations, and the risk of developing cancer in male and female mice. The goal of this study was to evaluate the relationship between gender and obesity and to determine the role of estrogen status in obese females and its effect on tumor growth. We examined the susceptibility of C57BL/6 mice to diet-induced obesity, insulin resistance/glucose intolerance, and tumors. Mice were injected sc with one of two tumorigenic cell lines, Lewis lung carcinoma, or mouse colon 38-adenocarcinoma. Results show that tumor growth rate was increased in obese mice vs. control mice irrespective of the tumor cell type. To investigate the effect of estrogen status on tumor development in obese females, we compared metabolic parameters and tumor growth in ovariectomized (ovx) and intact obese female mice. Obese ovx female mice developed insulin resistance and glucose intolerance similar to that observed in obese males. Our results demonstrate that body adiposity increased in ovx females irrespective of the diet administered and that tumor growth correlated positively with body adiposity. Overall, these data point to more rapid tumor growth in obese mice and suggest that endogenous sex steroids, together with diet, affect adiposity, insulin sensitivity, and tumor growth in female mice.

scholarly journals Role of Ventromedial Hypothalamus in Sucrose-Induced Obesity on Metabolic Parameters

2021 ◽  
pp. 097275312110057
Author(s):  
Archana Gaur ◽  
G.K. Pal ◽  
Pravati Pal
Keyword(s):  
Insulin Resistance ◽  
Weight Gain ◽  
Food Intake ◽  
Ventromedial Hypothalamus ◽  
Female Rats ◽  
Metabolic Parameters ◽  
Male Rats ◽  
Significant Weight Gain ◽  
The Metabolic Syndrome

Background: Obesity is because of excessive fat accumulation that affects health adversely in the form of various diseases such as diabetes, hypertension, cardiovascular diseases, and many other disorders. Our Indian diet is rich in carbohydrates, and hence the sucrose-induced obesity is an apt model to mimic this. Ventromedial hypothalamus (VMH) is linked to the regulation of food intake in animals as well as humans. Purpose: To understand the role of VMHin sucrose-induced obesity on metabolic parameters. Methods: A total of 24 adult rats were made obese by feeding them on a 32% sucrose solution for 10 weeks. The VMH nucleus was ablated in the experimental group and sham lesions were made in the control group. Food intake, body weight, and biochemical parameters were compared before and after the lesion. Results: Male rats had a significant weight gain along with hyperphagia, whereas female rats did not have a significant weight gain inspite of hyperphagia. Insulin resistance and dyslipidemia were seen in both the experimental and control groups. Conclusion: A sucrose diet produces obesity which is similar to the metabolic syndrome with insulin resistance and dyslipidemia, and a VMH lesion further exaggerates it. Males are more prone to this exaggeration.

Abstract 1766: Diet-Induced Obesity Causes Inflammation by Activating Toll-Like Receptor 4 Signaling and Downregulates AMPK in Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hwi Jin Ko ◽  
Dae Young Jung ◽  
Zhexi Ma ◽  
Jason K Kim
Keyword(s):  
Glucose Metabolism ◽  
Whole Body ◽  
Chow Diet ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Myocardial Glucose Metabolism ◽  
Cardiac Inflammation ◽  
Protein Levels ◽  
Diet Induced Obesity

Increasing evidence implicates the role of inflammation in diabetes and complications. Macrophages are shown to infiltrate adipose tissue in obesity, and inflammatory cytokines alter glucose metabolism in peripheral organs. Male C57BL/6 mice were fed high-fat diet (HFD; 55% fat by calories) or chow diet for 6 weeks, and heart samples were taken for analysis (n = 5~7). Chronic HFD increased whole body fat mass, measured by 1 H-MRS, by 3-fold, and elevated plasma IL-6 and TNF-α levels by 40%. Diet-induced obesity caused inflammation in heart and increased macrophage-specific CD68 levels by 5-fold (Fig. 1) (* P < 0.05 vs Chow). Diet-induced cardiac inflammation was associated with significant increases in toll-like receptor 4 (TLR4) and MyD88 levels in heart (Fig. 2). HFD also increased cardiomyocyte SOCS3 levels by more than 3-fold (Fig. 3). Myocardial glucose metabolism was measured using intravenous injection of 2-[ 14 C]deoxyglucose in awake mice (n = 6). Chronic HFD reduced myocardial glucose uptake by 50%, and this was associated with significant reductions in total GLUT4 and GLUT1 protein levels. Further, Thr 172 phosphorylation of AMPK, a critical regulator of energy balance, was markedly reduced in heart following HFD (Fig. 4). These results demonstrate that diet-induced obesity causes macrophage infiltration and inflammation in heart by increasing TLR4 signaling in cardiomyocytes. Similar to the effects of inflammation on peripheral glucose metabolism, diet-induced cardiac inflammation reduced myocardial glucose metabolism by downregulating AMPK and GLUT protein levels. Thus, our findings underscore an important role of inflammation in diabetic heart.

Distinct role of adiposity and insulin resistance in glucose intolerance: Studies in ventromedial hypothalamic-lesioned obese rats

Metabolism ◽  
2002 ◽  
Vol 51 (6) ◽  
pp. 716-723 ◽  
Author(s):  
Asako Kageyama ◽  
Tsutomu Hirano ◽  
Haruaki Kageyama ◽  
Toshimasa Osaka ◽  
Yoshio Namba ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Glucose Intolerance ◽  
Obese Rats ◽  
Distinct Role

scholarly journals TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexandre Moura-Assis ◽  
Pedro A. S. Nogueira ◽  
Jose C. de-Lima-Junior ◽  
Fernando M. Simabuco ◽  
Joana M. Gaspar ◽  
...  
Keyword(s):  
Dietary Fats ◽  
Whole Body ◽  
Metabolic Dysfunction ◽  
Diet Induced Obesity ◽  
Hypothalamic Inflammation ◽  
Novel Target ◽  
Tlr4 Activation ◽  
Leucine Rich Repeats ◽  
Body Energy

AbstractObesity and high-fat diet (HFD) consumption result in hypothalamic inflammation and metabolic dysfunction. While the TLR4 activation by dietary fats is a well-characterized pathway involved in the neuronal and glial inflammation, the role of its accessory proteins in diet-induced hypothalamic inflammation remains unknown. Here, we demonstrate that the knockdown of TLR4-interactor with leucine-rich repeats (Tril), a functional component of TLR4, resulted in reduced hypothalamic inflammation, increased whole-body energy expenditure, improved the systemic glucose tolerance and protection from diet-induced obesity. The POMC-specific knockdown of Tril resulted in decreased body fat, decreased white adipose tissue inflammation and a trend toward increased leptin signaling in POMC neurons. Thus, Tril was identified as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental obesity and its inhibition in the hypothalamus may represent a novel target for obesity treatment.

Expression of FOXC2 in adipose and muscle and its association with whole body insulin sensitivity

2004 ◽  
Vol 287 (4) ◽  
pp. E799-E803 ◽  
Author(s):  
Gina B. Di Gregorio ◽  
Rickard Westergren ◽  
Sven Enerback ◽  
Tong Lu ◽  
Philip A. Kern
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Tolerance Test ◽  
Intravenous Glucose Tolerance Test ◽  
Whole Body ◽  
Forkhead Transcription Factor ◽  
Intravenous Glucose ◽  
Insulin Resistant ◽  
Diet Induced Obesity ◽  
Tnf Α

FOXC2 is a winged helix/forkhead transcription factor involved in PKA signaling. Overexpression of FOXC2 in the adipose tissue of transgenic mice protected against diet-induced obesity and insulin resistance. We examined the expression of FOXC2 in fat and muscle of nondiabetic humans with varying obesity and insulin sensitivity. There was no relation between body mass index (BMI) and FOXC2 mRNA in either adipose or muscle. There was a strong inverse relation between adipose FOXC2 mRNA and insulin sensitivity, using the frequently sampled intravenous glucose tolerance test ( r = −0.78, P < 0.001). However, there was no relationship between muscle FOXC2 and any measure of insulin sensitivity. To separate insulin resistance from obesity, we examined FOXC2 expression in pairs of subjects who were matched for BMI but who were discordant for insulin sensitivity. Compared with insulin-sensitive subjects, insulin-resistant subjects had threefold higher levels of adipose FOXC2 mRNA ( P = 0.03). In contrast, muscle FOXC2 mRNA expression was no different between insulin-resistant and insulin-sensitive subjects. There was no association of adipose or muscle FOXC2 mRNA with either circulating or adipose-secreted TNF-α, IL-6, leptin, adiponectin, or non-esterified fatty acids. Thus adipose FOXC2 is more highly expressed in insulin-resistant subjects, and this effect is independent of obesity. This association between FOXC2 and insulin resistance may be related to the role of FOXC2 in PKA signaling.

scholarly journals Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1

2006 ◽  
Vol 291 (3) ◽  
pp. E517-E524 ◽  
Author(s):  
So-Young Park ◽  
You-Ree Cho ◽  
Hyo-Jeong Kim ◽  
Eun-Gyoung Hong ◽  
Takamasa Higashimori ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Glucose Intolerance ◽  
Fatty Acid Synthase ◽  
Visceral Obesity ◽  
Dominant Negative ◽  
Whole Body ◽  
Peripheral Tissues ◽  
Dominant Negative Mutation ◽  
Altered Glucose

Mice with liver-specific overexpression of dominant negative phosphorylation-defective S503A-CEACAM1 mutant (L-SACC1) developed chronic hyperinsulinemia resulting from blunted hepatic clearance of insulin, visceral obesity, and glucose intolerance. To determine the underlying mechanism of altered glucose homeostasis, a 2-h hyperinsulinemic euglycemic clamp was performed, and tissue-specific glucose and lipid metabolism was assessed in awake L-SACC1 and wild-type mice. Inactivation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) caused insulin resistance in liver that was mostly due to increased expression of fatty acid synthase and lipid metabolism, resulting in elevated intrahepatic levels of triglyceride and long-chain acyl-CoAs. Whole body insulin resistance in the L-SACC1 mice was further attributed to defects in insulin-stimulated glucose uptake in skeletal muscle and adipose tissue. Insulin resistance in peripheral tissues was associated with significantly elevated intramuscular fat contents that may be secondary to increased whole body adiposity (assessed by 1H-MRS) in the L-SACC1 mice. Overall, these results demonstrate that L-SACC1 is a mouse model in which chronic hyperinsulinemia acts as a cause, and not a consequence, of insulin resistance. Our findings further indicate the important role of CEACAM1 and hepatic insulin clearance in the pathogenesis of obesity and insulin resistance.

scholarly journals Multiomics reveal unique signatures of human epiploic adipose tissue related to systemic insulin resistance

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324603
Author(s):  
Laura Krieg ◽  
Konrad Didt ◽  
Isabel Karkossa ◽  
Stephan H Bernhart ◽  
Stephanie Kehr ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Gastric Bypass Surgery ◽  
Whole Body ◽  
Expression Levels ◽  
Entire Cohort ◽  
Fat Depots ◽  
Systemic Insulin Resistance ◽  
Whole Body Metabolism

ObjectiveHuman white adipose tissue (AT) is a metabolically active organ with distinct depot-specific functions. Despite their locations close to the gastrointestinal tract, mesenteric AT and epiploic AT (epiAT) have only scarcely been investigated. Here, we aim to characterise these ATs in-depth and estimate their contribution to alterations in whole-body metabolism.DesignMesenteric, epiploic, omental and abdominal subcutaneous ATs were collected from 70 patients with obesity undergoing Roux-en-Y gastric bypass surgery. The metabolically well-characterised cohort included nine subjects with insulin sensitive (IS) obesity, whose AT samples were analysed in a multiomics approach, including methylome, transcriptome and proteome along with samples from subjects with insulin resistance (IR) matched for age, sex and body mass index (n=9). Findings implying differences between AT depots in these subgroups were validated in the entire cohort (n=70) by quantitative real-time PCR.ResultsWhile mesenteric AT exhibited signatures similar to those found in the omental depot, epiAT was distinct from all other studied fat depots. Multiomics allowed clear discrimination between the IS and IR states in all tissues. The highest discriminatory power between IS and IR was seen in epiAT, where profound differences in the regulation of developmental, metabolic and inflammatory pathways were observed. Gene expression levels of key molecules involved in AT function, metabolic homeostasis and inflammation revealed significant depot-specific differences with epiAT showing the highest expression levels.ConclusionMulti-omics epiAT signatures reflect systemic IR and obesity subphenotypes distinct from other fat depots. Our data suggest a previously unrecognised role of human epiploic fat in the context of obesity, impaired insulin sensitivity and related diseases.

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