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 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.
Samad
F
F
The Scripps Research Institute, Department of Vascular Biology, 10550 North Torrey Pines Road, VB-3, La Jolla, CA 92037, USA.
Uysal
K T
KT
Wiesbrock
S M
SM
Pandey
M
M
Hotamisligil
G S
GS
Loskutoff
D J
DJ
D000818:Animals; D005786:Gene Expression Regulation; D007333:Insulin Resistance; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000097:blood* / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D012307:Risk Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D017395:Plasminogen Activator Inhibitor 1; D018124:Receptors, Tumor Necrosis Factor; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha