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      IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance.

      Science (New York, N.Y.)

      Adipocytes, metabolism, Adipose Tissue, Animals, Cells, Cultured, Insulin, pharmacology, Insulin Receptor Substrate Proteins, Insulin Resistance, physiology, Male, Mice, Muscle, Skeletal, Obesity, Phosphoproteins, Phosphorylation, Rats, Rats, Zucker, Receptor, Insulin, antagonists & inhibitors, Serine, Signal Transduction, Tumor Necrosis Factor-alpha

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          Abstract

          Tumor necrosis factor-alpha (TNF-alpha) 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-alpha 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-alpha-mediated inhibition of IR signaling, whereas transfected 32D cells that express IRS-1 were very sensitive to this effect of TNF-alpha. An inhibitory form of IRS-1 was observed in muscle and fat tissues from obese rats. These results indicate that TNF-alpha induces insulin resistance through an unexpected action of IRS-1 to attenuate insulin receptor signaling.

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          8571133

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