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-alpha (TNF-alpha) is overexpressed in 
obesity and is a candidate mediator 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 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-alpha is a component of insulin resistance in the 
ob/ob model of murine obesity and p55 TNFR is the predominant receptor mediating 
its actions.