Obesity is associated with a cluster of abnormalities, including hypertension, 
insulin resistance, hyperinsulinemia, and elevated levels of both plasminogen 
activator inhibitor 1 (PAI-1) and transforming growth factor beta (TGF-beta). 
Although these changes may increase the risk for accelerated atherosclerosis and 
fatal myocardial infarction, the underlying molecular mechanisms remain to be 
defined. Although tumor necrosis factor alpha (TNF-alpha) has been implicated in 
the insulin resistance associated with obesity, its role in other disorders of 
obesity is largely unknown. In this report, we show that in obese (ob/ob) mice, 
neutralization of TNF-alpha or deletion of both TNF receptors (TNFRs) results in 
significantly reduced levels of plasma PAI-1 antigen, plasma insulin, and 
adipose tissue PAI-1 and TGF-beta mRNAs. Studies in which exogenous TNF-alpha 
was infused into lean mice lacking individual TNFRs indicate that TNF-alpha 
signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the 
p75 TNFR. However, TNF-alpha signaling of TGF-beta mRNA expression in adipose 
tissue is mediated exclusively via the p55 TNFR. Our results suggest that 
TNF-alpha is a common link between the insulin resistance and elevated PAI-1 and 
TGF-beta in obesity. The chronic elevation of TNF-alpha in obesity thus may 
directly promote the development of the complex cardiovascular risk profile 
associated with this condition.