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.