Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes.
In 3T3-L1 adipocytes, hyperosmotic stress was found to inhibit insulin signaling, leading to an insulin-resistant state. We show here that, despite normal activation of insulin receptor, hyperosmotic stress inhibits both tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1-associated phosphoinositide 3 (PI 3)-kinase activity in response to physiological insulin concentrations. ... Insulin-induced membrane ruffling, which is dependent on PI 3-kinase activation, was also markedly reduced. These inhibitory effects were associated with an increase in IRS-1 Ser307 phosphorylation. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307. The inhibition of mTOR completely reversed the inhibitory effect of hyperosmotic stress on insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase activation. In addition, prolonged osmotic stress enhanced the degradation of IRS proteins through a rapamycin-insensitive pathway and a proteasome-independent process. These data support evidence of new mechanisms involved in osmotic stress-induced cellular insulin resistance. Short-term osmotic stress induces the phosphorylation of IRS-1 on Ser307 by an mTOR-dependent pathway. This, in turn, leads to a decrease in early proximal signaling events induced by physiological insulin concentrations. On the other hand, prolonged osmotic stress alters IRS-1 function by inducing its degradation, which could contribute to the down-regulation of insulin action.
Mesh Terms:
1-Phosphatidylinositol 3-Kinase, 3T3 Cells, Adipocytes, Animals, Cell Membrane, Enzyme Activation, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Mice, Osmotic Pressure, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Protein Kinases, Receptor, Insulin, Serine, Signal Transduction, Sirolimus, Tyrosine
1-Phosphatidylinositol 3-Kinase, 3T3 Cells, Adipocytes, Animals, Cell Membrane, Enzyme Activation, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Mice, Osmotic Pressure, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Protein Kinases, Receptor, Insulin, Serine, Signal Transduction, Sirolimus, Tyrosine
J. Biol. Chem.
Date: Jul. 18, 2003
PubMed ID: 12730242
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