IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance

Hotamışlıgil, Gökhan S.; Peraldi, Pascal; Budavari, Adriane I.; Ellis, Ramsey; White, Morris F.; Spiegelman, Bruce M.

doi:10.1126/science.271.5249.665

Cited by 2,433 publications

(1,755 citation statements)

References 18 publications

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“…Cell culture experiments have demonstrated that insulin-induced tyrosine phosphorylation of the β-subunit of the insulin receptor and IRS-1 are reduced in the presence of TNF-α [3,27]. TNF-α promotes serine phosphorylation of IRS-1, which interferes with insulin-induced tyrosine phosphorylation and subsequent insulin signalling and action [28,29]. Data on the dietary intervention used in the current study are consistent with the amelioration of such inhibitory effects.…”

Section: Dietary Interventionsupporting

confidence: 74%

Diet but not aerobic exercise training reduces skeletal muscle TNF-a in overweight humans

et al. 2004

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Aims/hypothesis. Our aim was to test the hypothesis that TNF-α protein levels in skeletal muscle are important in mediating the improvements in glucose homeostasis that are associated with diet and exercise regimens intended to reduce cardiovascular risk. Methods. We recruited 20 people with a body mass index of 32.1±1.2 kg/m 2 (mean ± SEM) and one other component of the metabolic syndrome. The average age was 51.2±8.1 years (mean ± SD). Of the 20 subjects, 6 were men and 14 were women. All subjects completed an 8-week control period, followed by randomisation to 8 weeks of moderate cycling exercise (30 min, three times per week) or to a diet with the following characteristics: low in saturated fat, high in fibre, low glycaemic index, rich in complex carbohydrates.Results. Diet induced a small reduction in body mass index (3.0±0.7%, p<0.05), although weight loss was not intended. Exercise training increased maximum oxygen consumption by 12±6% (p<0.05). Both interventions reduced fasting plasma insulin levels by about 20%. Diet reduced skeletal muscle TNF-α protein by 54±10% (p<0.05), an effect that was independent (p=0.94 in covariate analysis) of the small concurrent weight loss (−2.8±0.7 kg). Levels of GLUT4 protein were unchanged in the diet group. In contrast, exercise training did not significantly change TNF-α protein expression, but GLUT4 protein expression increased by 105±37% (p<0.05). Conclusions/interpretation. These data indicate that the metabolic benefits of a diet aimed at cardiovascular risk reduction are associated with a decrease in skeletal muscle TNF-α protein.

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Section: Dietary Interventionsupporting

confidence: 74%

Diet but not aerobic exercise training reduces skeletal muscle TNF-a in overweight humans

et al. 2004

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“…Our results show that increased serine phosphorylation of IR, IRS-1 and IRS-2 could be one of these mechanisms. Previous studies clearly showed that an increase in IR and IRSs serine phosphorylation could induce insulin resistance, pointing to this as an important mechanism in the control of insulin signalling [45,46,47]. It has been reported that activation of PKC induces serine phosphorylation of IR, which can inhibit its tyrosine kinase activity, leading to a decrease in insulin-induced PI3-kinase activity [48,49].…”

Section: Discussionmentioning

confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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“…TNF is known to reduce adipose tissue mass by decreasing PPARG production, stimulating lipolysis and repressing genes involved in the uptake and metabolism of lipids and glucose [37][38][39][40][41]. Considering all this, the higher insulin sensitivity that we observed in our study in WAT and that was associated with higher expression of genes mediating insulin sensitivity (Irs1, Slc2a4, adiponectin) and lipogenesis (Srebf1, Fasn, Pparg) may be secondary to the tissue TNF and IL1B depletion, and might contribute to the increase in adipocyte volume seen in C3H/HeJ mice despite lower food intake.…”

Section: Discussionmentioning

confidence: 99%

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

et al. 2007

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Aims/hypothesis Inflammation is associated with obesity and has been implicated in the development of diabetes and atherosclerosis. During gram-negative bacterial infection, lipopolysaccharide causes an inflammatory reaction via toll-like receptor 4 (TLR4), which has an essential function in the induction of innate and adaptative immunity. Our aim was to determine what role TLR4 plays in the development of metabolic phenotypes during high-fat feeding. Materials and methods We evaluated metabolic consequences of a high-fat diet in TLR4 mutant mice (C3H/HeJ) and their respective controls. Results TLR4 inactivation reduced food intake without significant modification of body weight, but with higher epididymal adipose tissue mass and adipocyte hypertrophy. It also attenuated the inflammatory response and increased glucose transport and the expression levels of adiponectin and lipogenic markers in white adipose tissue. In addition, TLR4 inactivation blunted insulin resistance induced by lipopolysaccharide in differentiated adipocytes. Increased feeding efficiency in TLR4 mutant mice was associated with lower mass and lower expression of uncoupling protein 1 gene in brown adipose tissue. Finally, TLR4 inactivation slowed the development of hepatic steatosis, reducing the liver triacylglycerol content and also expression levels of lipogenic and fibrosis markers. Conclusions/interpretation TLR4 influences white adipose tissue inflammation and insulin sensitivity, as well as liver fat storage, and is important in the regulation of metabolic phenotype during a fat-enriched diet.

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IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance

Cited by 2,433 publications

References 18 publications

Diet but not aerobic exercise training reduces skeletal muscle TNF-a in overweight humans

Diet but not aerobic exercise training reduces skeletal muscle TNF-a in overweight humans

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet

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