Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes
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Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes. / Gual, Philippe; Gonzalez, Teresa; Grémeaux, Thierry; Barres, Romain; Le Marchand-Brustel, Yannick; Tanti, Jean-François.
In: Journal of Biological Chemistry, Vol. 278, No. 29, 18.07.2003, p. 26550-7.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes
AU - Gual, Philippe
AU - Gonzalez, Teresa
AU - Grémeaux, Thierry
AU - Barres, Romain
AU - Le Marchand-Brustel, Yannick
AU - Tanti, Jean-François
PY - 2003/7/18
Y1 - 2003/7/18
N2 - 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.
AB - 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.
KW - 3T3 Cells
KW - Adipocytes
KW - Animals
KW - Cell Membrane
KW - Enzyme Activation
KW - Insulin
KW - Insulin Receptor Substrate Proteins
KW - Insulin Resistance
KW - Intracellular Signaling Peptides and Proteins
KW - Mice
KW - Osmotic Pressure
KW - Phosphatidylinositol 3-Kinases
KW - Phosphoproteins
KW - Phosphorylation
KW - Protein Kinase Inhibitors
KW - Protein Kinases
KW - Receptor, Insulin
KW - Serine
KW - Signal Transduction
KW - Sirolimus
KW - TOR Serine-Threonine Kinases
KW - Tyrosine
U2 - 10.1074/jbc.M212273200
DO - 10.1074/jbc.M212273200
M3 - Journal article
C2 - 12730242
VL - 278
SP - 26550
EP - 26557
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 29
ER -
ID: 45577497