PROTECTION FROM OBESITY-INDUCED INSULIN-RESISTANCE IN MICE LACKING TNF-ALPHA FUNCTION

Obesity is highly associated with insulin resistance and is the bigges t risk factor for non-insulin-dependent diabetes mellitus(1-3). The mo lecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a can didate mediator of insulin resistance in obesity as it is overexpresse d in the adipose tissues of rodents and humans(4-10) and it blocks the action of insulin in cultured cells and whole animals(10-14). To inve stigate the role of TNF-alpha in obesity and insulin resistance, we ha ve generated obese mice with a targeted null mutation in the gene enco ding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensi tivity in both diet-induced obesity and that resulting for the ob/ob m odel of obesity. The TNF alpha-deficient obese mice had lower levels o f circulating free fatty acids, and were protected from the obesity-re lated reduction in the insulin receptor signalling in muscle and fat t issues, These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several impor tant sites of insulin action.