ALTERED GENE-EXPRESSION FOR TUMOR-NECROSIS-FACTOR-ALPHA AND ITS RECEPTORS DURING DRUG AND DIETARY MODULATION OF INSULIN-RESISTANCE

As obesity is a major risk factor for noninsulin-dependent diabetes me llitus, adipose tissue may generate a mediator that influences the act ivity of insulin on various target tissues. Recent evidence suggests t hat a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve thi s role. This study investigates whether the expression of TNF alpha an d its receptors is modulated during drug treatment to reduce insulin r esistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked di abetes (KKA(y)) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly inc reased in fat tissues of the obese diabetic animals. In muscle from th ese diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R 2 were significantly elevated, although R2 transcript abundance was le ss elevated than in fat. We also observed that the overexpression of m RNA for TNF alpha and both of its receptors could be at least partly n ormalized by treatment of the diabetic animals with the insulin-sensit izing agent pioglitazone. Treating of the obese diabetic animals by fo od restriction reduced the expression of mRNA for TNF R2 in muscle, bu t not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduc tion of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by thera pies that reverse the disorder.