Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

Philippe Gual; Teresa Gonzalez; Thierry Grémeaux; Romain Barres; Yannick Le Marchand-Brustel; Jean-François Tanti

doi:10.1074/jbc.M212273200

Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

Philippe Gual, Teresa Gonzalez, Thierry Grémeaux, Romain Barres, Yannick Le Marchand-Brustel, Jean-François Tanti

64 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Biological Chemistry
Volume	278
Issue number	29
Pages (from-to)	26550-7
Number of pages	8
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.M212273200
Publication status	Published - 18 Jul 2003

Keywords

3T3 Cells
Adipocytes
Animals
Cell Membrane
Enzyme Activation
Insulin
Insulin Receptor Substrate Proteins
Insulin Resistance
Intracellular Signaling Peptides and Proteins
Mice
Osmotic Pressure
Phosphatidylinositol 3-Kinases
Phosphoproteins
Phosphorylation
Protein Kinase Inhibitors
Protein Kinases
Receptor, Insulin
Serine
Signal Transduction
Sirolimus
TOR Serine-Threonine Kinases
Tyrosine

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title = "Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes",

abstract = "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.",

keywords = "3T3 Cells, Adipocytes, Animals, Cell Membrane, Enzyme Activation, Insulin, Insulin Receptor Substrate Proteins, Insulin Resistance, Intracellular Signaling Peptides and Proteins, Mice, Osmotic Pressure, Phosphatidylinositol 3-Kinases, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Protein Kinases, Receptor, Insulin, Serine, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Tyrosine",

author = "Philippe Gual and Teresa Gonzalez and Thierry Gr{\'e}meaux and Romain Barres and {Le Marchand-Brustel}, Yannick and Jean-Fran{\c c}ois Tanti",

year = "2003",

month = jul,

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doi = "10.1074/jbc.M212273200",

language = "English",

volume = "278",

pages = "26550--7",

journal = "Journal of Biological Chemistry",

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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

SN - 0021-9258

VL - 278

SP - 26550

EP - 26557

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 29

ER -

Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

Abstract

Keywords

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