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

GS Hotamisligil, P Peraldi, A Budavari, R Ellis… - Science, 1996 - science.org
Science, 1996science.org
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 …
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.
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