TNF-alpha and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes.
Obesity is associated with hyperinsulinemia and elevated concentrations of tumor necrosis factor-alpha (TNF-alpha) in adipose tissue. TNF-alpha has been implicated as an inducer of the synthesis of plasminogen activator inhibitor-1 (PAI-1), the primary physiological inhibitor of fibrinolysis, mediated by plasminogen activators in cultured adipocytes. To identify mechanism(s) through which TNF-alpha induces PAI-1, 3T3-L1 preadipocytes were differentiated into adipocytes and exposed to TNF-alpha for 24 h. TNF-alpha selectively increased the synthesis of PAI-1 without increasing activity of plasminogen activators. Both superoxide (generated by xanthine oxidase plus hypoxanthine) and hydrogen peroxide were potent inducers of PAI-1, and hydroxyl radical scavengers completely abolished the TNF-alpha induction of PAI-1. Exposure of adipocytes to TNF-alpha or insulin alone over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF-alpha stimulates PAI-1 production by adipocytes, an effect potentiated by insulin, and that adipocyte generation of reactive oxygen centered radicals mediates the induction of PAI-1 production by TNF-alpha. Because induction of PAI-1 by TNF-alpha is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.
Sakamoto
T
T
Department of Medicine, University of Vermont College of Medicine, Burlington, Vermont 05446, USA.
Woodcock-Mitchell
J
J
Marutsuka
K
K
Mitchell
J J
JJ
Sobel
B E
BE
Fujii
S
S
D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D013890:Thiourea; C019107:tetramethylthiourea