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.
