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

Obesity is associated with a cluster of abnormalities, including hypertensi on, insulin resistance, hyperinsulinemia, and elevated levels of both plasm inogen activator inhibitor 1 (PAI-1) and transforming growth factor beta (T GF-beta), Although these changes may increase the risk for accelerated athe rosclerosis and fatal myocardial infarction, the underlying molecular mecha nisms remain to be defined. Although tumor necrosis factor alpha (TNF-alpha ) has been implicated in the insulin resistance associated with obesity, it s 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 o f both TNF receptors (TNFRs) results in significantly reduced levels of pla sma PAI-1 antigen, plasma insulin, and adipose tissue PAI-1 and TGF-beta mR NAs, Studies in which exogenous TNF-alpha was infused into lean mice lackin g individual TNFRs indicate that TNF-alpha signaling of PAI-1 in adipose ti ssue 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 exclusi vely 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 thi s condition.