FUNCTIONAL-ANALYSIS OF TUMOR-NECROSIS-FACTOR (TNF) RECEPTORS IN TNF-ALPHA-MEDIATED INSULIN-RESISTANCE IN GENETIC OBESITY

Although obesity has become the most common metabolic disorder in the developed world and is highly associated with insulin resistance and n oninsulin-dependent diabetes mellitus, the molecular mechanisms underl ying these disorders are not clearly understood. Tumor necrosis factor -alpha (TNF-alpha) is overexpressed in obesity and is a candidate medi ator of obesity-induced insulin resistance. Complete lack of TNF-alpha function through targeted mutations in TNF-alpha 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 rec eptor (TNFR) 1] and p75 (TNFR 2) TNFR in the development of insulin re sistance by generating genetically obese mice (ob/ob) lacking p55 or p 75 TNFRs. In the ob lob mice, the absence of p55 caused a significant improvement in insulin sensitivity. p75 deficiency alone did not affec t insulin sensitivity but might potentiate the effects of p55 deficien cy in animals lacking both TNFRs. These results indicate that TNF-alph a is a component of insulin resistance in the ob/ob model of murine ob esity and p55 TNFR is the predominant receptor mediating its actions.