Tumor necrosis factor α is a key component in the obesity-linked elevation of plasminogen activator inhibitor 1

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 β (TGF-β). 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 α (TNF-α) 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-α 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-β mRNAs. Studies in which exogenous TNF-α was infused into lean mice lacking individual TNFRs indicate that TNF-α signaling of PAI-1 in adipose tissue can be mediated by either the p55 or the p75 TNFR. However, TNF-α signaling of TGF-β mRNA expression in adipose tissue is mediated exclusively via the p55 TNFR. Our results suggest that TNF-α is a common link between the insulin resistance and elevated PAI-1 and TGF-β in obesity. The chronic elevation of TNF-α in obesity thus may directly promote the development of the complex cardiovascular risk profile associated with this condition.