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J. Biol. Chem., Vol. 278, Issue 29, 26550-26557, July 18, 2003

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Hyperosmotic Stress Inhibits Insulin Receptor Substrate-1 Function by Distinct Mechanisms in 3T3-L1 Adipocytes^*

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

From the INSERM U 568 and l'Institut Fédératif de Recherches 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 02, France

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.

Received for publication, December 3, 2002 , and in revised form, April 30, 2003.

^* This work was supported by grants from INSERM (France), the University of Nice, the Fondation Bettencourt-Schueller, the Fondation pour la Recherche Médicale, the Région Provence-Alpes Côte d'Azur, the Conseil Général des Alpes Maritimes, and the Association pour la Recherche Contre le Cancer Grant 7449. This work was also supported by a grant from ALFEDIAM-Takeda Laboratories (Puteaux, France) (to J. F. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by fellowships from La Ligue Contre le Cancer and ALFEDIAM (France).

To whom correspondence should be addressed. Tel.: 33-4-93-37-77-99; Fax: 33-4-93-37-77-01; E-mail: tanti{at}unice.fr.

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