Kt. Uysal et al., FUNCTIONAL-ANALYSIS OF TUMOR-NECROSIS-FACTOR (TNF) RECEPTORS IN TNF-ALPHA-MEDIATED INSULIN-RESISTANCE IN GENETIC OBESITY, Endocrinology, 139(12), 1998, pp. 4832-4838
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.