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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. These proteins participate in insulin and insulin-like growth factor 1 signaling, as well as the actions of some cytokines, growth hormone, and prolactin. To more precisely define the specific role of IRS-1 in adipocyte biology, we established brown adipocyte cell lines from wild-type and IRS-1 knockout (KO) animals. Using differentiation protocols, both with and without insulin, preadipocyte cell lines derived from IRS-1 KO mice exhibited a marked decrease in differentiation and lipid accumulation (10 to 40%) compared to wild-type cells (90 to 100%). Furthermore, IRS-1 KO cells showed decreased expression of adipogenic marker proteins, such as peroxisome proliferator-activated receptor gamma (PPARgamma ), CCAAT/enhancer-binding protein alpha (C/EBPalpha ), fatty acid synthase, uncoupling protein-1, and glucose transporter 4. The differentiation deficit in the KO cells could be reversed almost completely by retrovirus-mediated reexpression of IRS-1, PPARgamma , or C/EBPalpha but not the thiazolidinedione troglitazone. Phosphatidylinositol 3-kinase (PI 3-kinase) assays performed at various stages of the differentiation process revealed a strong and transient activation in IRS-1, IRS-2, and phosphotyrosine-associated PI 3-kinase in the wild-type cells, whereas the IRS-1 KO cells showed impaired phosphotyrosine-associated PI 3-kinase activation, all of which was associated with IRS-2. Akt phosphorylation was reduced in parallel with the total PI 3-kinase activity. Inhibition of PI 3-kinase with LY294002 blocked differentiation of wild-type cells. Thus, IRS-1 appears to be an important mediator of brown adipocyte maturation. Furthermore, this signaling molecule appears to exert its unique role in the differentiation process via activation of PI 3-kinase and its downstream target, Akt, and is upstream of the effects of PPARgamma and C/EBPalpha .

* 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.

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.


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