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Originally published In Press as doi:10.1074/jbc.M004046200 on May 26, 2000

J. Biol. Chem., Vol. 275, Issue 33, 25494-25501, August 18, 2000
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Essential Role of Insulin Receptor Substrate-2 in Insulin Stimulation of Glut4 Translocation and Glucose Uptake in Brown Adipocytes*

Mathias FasshauerDagger §, Johannes KleinDagger §||**, Kohjiro UekiDagger , Kristina M. KriauciunasDagger , Manuel BenitoDagger Dagger , Morris F. WhiteDagger , and C. Ronald KahnDagger §§

From the Dagger  Research Division, Joslin Diabetes Center, and the Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, the || Medical University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany, and the Dagger Dagger  Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain

Insulin and insulin-like growth factor I signals are mediated via phosphorylation of a family of insulin receptor substrate (IRS) proteins, which may serve both complementary and overlapping functions in the cell. To study the metabolic effects of these proteins in more detail, we established brown adipocyte cell lines from wild type and various IRS knockout (KO) animals and characterized insulin action in these cells in vitro. Preadipocytes derived from both wild type and IRS-2 KO mice could be fully differentiated into mature brown adipocytes. In differentiated IRS-2 KO adipocytes, insulin-induced glucose uptake was decreased by 50% compared with their wild type counterparts. This was the result of a decrease in insulin-stimulated Glut4 translocation to the plasma membrane. This decrease in insulin-induced glucose uptake could be partially reconstituted in these cells by retrovirus-mediated re-expression of IRS-2, but not overexpression of IRS-1. Insulin signaling studies revealed a total loss of IRS-2-associated phosphatidylinositol (PI) 3-kinase activity and a reduction in phosphotyrosine-associated PI 3-kinase by 30% (p < 0.05) in the KO cells. The phosphorylation and activity of Akt, a major downstream effector of PI 3-kinase, as well as Akt-dependent phosphorylation of glycogen synthase kinase-3 and p70S6 kinase were not affected by the lack of IRS-2; however, there was a decrease in insulin stimulation of Akt associated with the plasma membrane. These results provide evidence for a critical role of IRS-2 as a mediator of insulin-stimulated Glut4 translocation and glucose uptake in adipocytes. This occurs without effects in differentiation, total activation of Akt and its downstream effectors, but may be caused by alterations in compartmentalization of these downstream signals.

* This work was supported in part by National Institutes of Health Grants DK 5545, DK 33201, and DK 36836 (to the Joslin Diabetes and Endocrinology Research Center).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ The first two authors contributed equally to this work.

Supported by a grant from the Studienstiftung des deutschen Volkes.

** Supported by a grant from the Deutsche Forschungsgemeinschaft.

§§ To whom correspondence should be addressed: Dept. of Research, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Tel.: 617-732-2635; Fax: 617-732-2593; E-mail: c.ronald.kahn@joslin.harvard.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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