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Functional Analysis of Tumor Necrosis Factor (TNF) Receptors in TNF--Mediated Insulin Resistance in Genetic Obesity¹

Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gökhan S. Hotamisligil, Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: ghotamis{at}hsph.harvard.edu

Although obesity has become the most common metabolic disorder in the developed world and is highly associated with insulin resistance and noninsulin-dependent diabetes mellitus, the molecular mechanisms underlying these disorders are not clearly understood. Tumor necrosis factor- (TNF-) is overexpressed in obesity and is a candidate mediator of obesity-induced insulin resistance. Complete lack of TNF- function through targeted mutations in TNF- gene or both of its receptors results in significant improvement of insulin sensitivity in dietary, chemical, or genetic models of rodent obesity. In this study, we have analyzed the in vivo role of TNF signaling from p55 [TNF receptor (TNFR) 1] and p75 (TNFR 2) TNFR in the development of insulin resistance by generating genetically obese mice (ob/ob) lacking p55 or p75 TNFRs. In the ob/ob mice, the absence of p55 caused a significant improvement in insulin sensitivity. p75 deficiency alone did not affect insulin sensitivity but might potentiate the effects of p55 deficiency in animals lacking both TNFRs. These results indicate that TNF- is a component of insulin resistance in the ob/ob model of murine obesity and p55 TNFR is the predominant receptor mediating its actions.