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J. Biol. Chem., Vol. 278, Issue 12, 10221-10231, March 21, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/12/10221    most recent M209363200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Valverde, A. M. Articles by Benito, M. Search for Related Content PubMed PubMed Citation Articles by Valverde, A. M. Articles by Benito, M. Social Bookmarking                      What's this?

Insulin-induced Up-regulated Uncoupling Protein-1 Expression Is Mediated by Insulin Receptor Substrate 1 through the Phosphatidylinositol 3-Kinase/Akt Signaling Pathway in Fetal Brown Adipocytes^*

Angela M. Valverde, Mónica Arribas, Cecilia Mur, Paloma Navarro, Sebastián Pons^§, Anne-Marie Cassard-Doulcier^¶, C. Ronald Kahn^§, and Manuel Benito

From the  Departamento de Bioquímica y Biología Molecular, Centro Mixto Consejo Superior de Investigaciones Científicas/Universidad Complutense de Madrid, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain, ^§ Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, and ^¶ Centre de Recherches sur l'Endocrinologie Moléculaire et le Dévelopment, CNRS, 92190 Meudon, France

To investigate the role of insulin receptor substrate-1 (IRS-1) and its downstream signaling in insulin-induced thermogenic differentiation of brown adipocytes, we have reconstituted IRS-1-deficient fetal brown adipocytes (IRS-1^/) with wild-type IRS-1 (IRS-1^wt). The lack of IRS-1 resulted in the inability of insulin to induce IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity and Akt phosphorylation in IRS-1^/ brown adipocytes. In addition, these cells showed an impairment in activating -Akt, -Akt, and -Akt isoforms upon insulin stimulation. Reconstitution of IRS-1^/ brown adipocytes with IRS-1^wt restored the IRS-1/PI 3-kinase/Akt signaling pathway. Treatment of wild-type brown adipocytes with insulin for 24 h up-regulated uncoupling protein-1 (UCP-1) expression and transactivated the UCP-1 promoter; this effect was abolished in the absence of IRS-1 or in the presence of an Akt inhibitor and further recovered after IRS-1^wt reconstitution. Neither UCP-2 nor UCP-3 was up-regulated by insulin in wild-type and IRS-1-deficient brown adipocytes. Insulin stimulated the expression of CCAAT/enhancer-binding protein  (C/EBP) and its DNA binding activity in wild-type brown adipocytes but not in IRS-1^/ cells. However, insulin stimulation of both C/EBP expression and binding activity was restored after IRS-1^wt reconstitution of deficient cells. Retrovirus-mediated expression of C/EBP and peroxisome proliferator-activated receptor  in IRS-1^/ brown adipocytes up-regulated UCP-1 protein content and transactivated UCP-1 promoter regardless of insulin stimulation. Both C/EBP and peroxisome proliferator-activated receptor  reconstituted FAS mRNA expression, but only C/EBP restored insulin sensitivity in the absence of IRS-1. Finally, reconstitution of IRS-1^/ brown adipocytes with the IRS-1 mutants IRS-1^Phe-895, which lacks IRS-1/growth factor receptor binding protein 2 binding but not IRS-1/p85-PI 3-kinase binding, or with IRS-1^{Tyr-608/Tyr-628/Tyr-658}, which only binds p85-PI 3-kinase, induced UCP-1 expression and transactivated the UCP-1 promoter. These data provide strong evidence for an essential role of IRS-1 through the PI 3-kinase/Akt signaling pathway inducing UCP-1 gene expression by insulin.

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