Molecular mechanisms of insulin resistance and the role of the adipocyte

• Published in: International Journal of Obesity Vol. 24; no. S4; pp. S23 - S27
• Main Author: Hotamisligil, G.S
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.11.2000
• Subjects: Adipocytes; Adipocytes - physiology; Adipose tissue; Adipose Tissue - physiology; animal disease models; Animals; atrophy; Body fat; brown adipose tissue; Diabetes; Diabetes Mellitus, Type 2 - etiology; Disease; Disease Models, Animal; fatty acid-binding proteins; Fatty acids; Gene Expression Regulation; homeostasis; homozygosity; hyperlipidemia; Hypertension; insulin; insulin receptors; Insulin Resistance; Kinases; loci; Mice; Mice, Transgenic; mutation; noninsulin-dependent diabetes mellitus; Obesity; Proteins; Public health; transforming growth factor beta; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - physiology; Tumor necrosis factor-TNF
• ISSN: 0307-0565; 1476-5497
• DOI: 10.1038/sj.ijo.0801497

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of diseases, including hypertension, dyslipidemias, cardiovascular problems and type 2 diabetes mellitus. However, the molecular mechanisms underlying abnormal insulin action and these other pathological states are not well understood. We have been focusing on cytokines, particularly TNFalpha and fatty acid binding proteins, as potential sites to study the molecular basis of these disorders. The role of TNFalpha in insulin resistance and other pathologies associated with obesity, have been examined in several experimental systems including obese mice with homozygous null mutations at the TNFalpha or TNF receptor loci. Analysis of these animals demonstrated that the genetic absence of TNF signaling in obesity: (i) significantly improves insulin receptor signaling capacity and consequently insulin sensitivity; (ii) prevents brown adipose tissue atrophy and beta3-adrenoreceptor deficiency and improves thermo-adaptive responses, (iii) decreases the elevated PAI-1 and TGFbeta production; and (iv) lowers hyperlipidemia and hyperleptinemia. Hence, abnormal TNFalpha action in adipocytes disturbs many aspects of metabolic homeostasis in obesity.