Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes

doi:10.1128/MCB.21.1.319-329.2001

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Molecular and Cellular Biology, January 2001, p. 319-329, Vol. 21, No. 1
0270-7306/01/$04.00+0 DOI: 10.1128/MCB.21.1.319-329.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Essential Role of Insulin Receptor Substrate 1 in Differentiation of Brown Adipocytes

Mathias Fasshauer,¹^,² Johannes Klein,¹^,³ Kristina M. Kriauciunas,¹ Kohjiro Ueki,¹ Manuel Benito,⁴ and C. Ronald Kahn¹^,^*

Research Division, Joslin Diabetes Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215¹; Department of Internal Medicine III, University of Leipzig, 04103 Leipzig,² and Department of Internal Medicine I, Medical University of Lübeck, 23538 Lübeck,³ Germany; and Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain⁴

Received 31 May 2000/Returned for modification 12 July 2000/Accepted 11 October 2000

The most widely distributed members of the family of insulin receptor substrate (IRS) proteins are IRS-1 and IRS-2. Theseproteins participate in insulin and insulin-like growth factor1 signaling, as well as the actions of some cytokines, growthhormone, and prolactin. To more precisely define the specificrole of IRS-1 in adipocyte biology, we established brown adipocytecell lines from wild-type and IRS-1 knockout (KO) animals. Usingdifferentiation protocols, both with and without insulin, preadipocytecell lines derived from IRS-1 KO mice exhibited a marked decreasein differentiation and lipid accumulation (10 to 40%) comparedto wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showeddecreased expression of adipogenic marker proteins, such as peroxisomeproliferator-activated receptor gamma (PPAR $gamma$ ), CCAAT/enhancer-bindingprotein alpha (C/EBP $alpha$ ), fatty acid synthase, uncoupling protein-1,and glucose transporter 4. The differentiation deficit in theKO cells could be reversed almost completely by retrovirus-mediatedreexpression of IRS-1, PPAR $gamma$ , or C/EBP $alpha$ but not the thiazolidinedionetroglitazone. Phosphatidylinositol 3-kinase (PI 3-kinase) assaysperformed at various stages of the differentiation process revealeda strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associatedPI 3-kinase in the wild-type cells, whereas the IRS-1 KO cellsshowed impaired phosphotyrosine-associated PI 3-kinase activation,all of which was associated with IRS-2. Akt phosphorylation wasreduced in parallel with the total PI 3-kinase activity. Inhibitionof PI 3-kinase with LY294002 blocked differentiation of wild-typecells. Thus, IRS-1 appears to be an important mediator of brownadipocyte maturation. Furthermore, this signaling molecule appearsto exert its unique role in the differentiation process via activationof PI 3-kinase and its downstream target, Akt, and is upstreamof the effects of PPAR $gamma$ and C/EBP $alpha$ .

^* Corresponding author. Mailing address: Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215. Phone: (617) 732-2635.Fax: (617) 732-2593. E-mail: c.ronald.{at}joslin.harvard.edu.

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