RT Journal Article
SR Electronic
T1 IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance
JF Science
JO Science
FD American Association for the Advancement of Science
SP 665
OP 670
DO 10.1126/science.271.5249.665
VO 271
IS 5249
A1 Hotamisligil, Gökhan S.
A1 Peraldi, Pascal
A1 Budavari, Adriane
A1 Ellis, Ramsey
A1 White, Morris F.
A1 Spiegelman, Bruce M.
YR 1996
UL http://science.sciencemag.org/content/271/5249/665.abstract
AB Tumor necrosis factor-α (TNF-α) is an important mediator of insulin resistance in obesity and diabetes through its ability to decrease the tyrosine kinase activity of the insulin receptor (IR). Treatment of cultured murine adipocytes with TNF-α was shown to induce serine phosphorylation of insulin receptor substrate 1 (IRS-1) and convert IRS-1 into an inhibitor of the IR tyrosine kinase activity in vitro. Myeloid 32D cells, which lack endogenous IRS-1, were resistant to TNF-α-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-α. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-α induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.