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and insulin, alone and synergistically, induce
plasminogen activator inhibitor-1 expression in adipocytes
Departments of 1 Medicine and 2 Molecular Physiology and Biophysics, University of Vermont College of Medicine, Burlington, Vermont 05446
Obesity is associated with hyperinsulinemia and elevated
concentrations of tumor necrosis factor-
(TNF-) in
adipose tissue. TNF- 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- induces PAI-1, 3T3-L1 preadipocytes were differentiated
into adipocytes and exposed to TNF- for 24 h. TNF- 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- induction of PAI-1. Exposure of adipocytes to TNF- or insulin alone
over 5 days increased PAI-1 production. These agonists exert synergistic effects. Results obtained suggest that TNF- 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-. Because induction of
PAI-1 by TNF- is potentiated synergistically by insulin, both agonists appear likely to contribute to the impairment of fibrinolytic system capacity typical in obese, hyperinsulinemic patients.
cytokine; insulin resistance; obesity; tumor necrosis factor-
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