Protection from obesity-induced insulin resistance in mice lacking TNF-α function

Abstract

Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus^1,2,3. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-α is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans^{4,5,6,7,8,9,10} and it blocks the action of insulin in cultured cells and whole animals^{10,11,12,13,14}. To investigate the role of TNF-α in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-α and those encoding the two receptors for TNF-α. The absence of TNF-α resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFα-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-α is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.