Obesity is highly associated with insulin resistance and is the biggest risk 
factor for non-insulin-dependent diabetes mellitus. The molecular basis of this 
common syndrome, however, is poorly understood. It has been suggested that 
tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance 
in obesity, as it is overexpressed in the adipose tissues of rodents and humans 
and it blocks the action of insulin in cultured cells and whole animals. To 
investigate the role of TNF-alpha in obesity and insulin resistance, we have 
generated obese mice with a targeted null mutation in the gene encoding 
TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of 
TNF-alpha resulted in significantly improved insulin sensitivity in both 
diet-induced obesity and that resulting for the ob/ob model of obesity. The 
TNFalpha-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-alpha is 
an important mediator of insulin resistance in obesity through its effects on 
several important sites of insulin action.