TNF-a and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes

Sakamoto, Tomohiro, Janet Woodcock-Mitchell, Kousuke Marutsuka, John J. Mitchell, Burton E. Sobel, and Satoshi Fujii. TNF-a and insulin, alone and synergistically, induce plasminogen activator inhibitor-1 expression in adipocytes. Am. J. Physiol. 276 (Cell Physiol. 45): C1391– C1397, 1999.—Obesity is associated with hyperinsulinemia and elevated concentrations of tumor necrosis factor-a (TNF-a) in adipose tissue. TNF-a 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-a induces PAI-1, 3T3-L1 preadipocytes were differentiated into adipocytes and exposed to TNF-a for 24 h. TNF-a 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-a induction of PAI-1. Exposure of adipocytes to TNF-a or insulin alone over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF-a 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-a. Because induction of PAI-1 by TNF-a is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.