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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

AutorValverde, Ángela M.; Arribas, Mónica; Mur, Cecilia; Navarro, Paloma; Kahn, C. Ronald; Benito, Manuel
Fecha de publicación2003
EditorAmerican Society for Biochemistry and Molecular Biology
CitaciónJournal of Biological Chemistry 278(12): 10221-10231 (2003)
ResumenTo 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-1wt). 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 α-Akt, β-Akt, and γ-Akt isoforms upon insulin stimulation. Reconstitution of IRS-1-/- brown adipocytes with IRS-1wt restored the IRS-1/PI 3-kinase/Akt signaling pathway. Treatment of wild-type brown adipocytes with insulin for 24 h upregulated 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-1wt 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 a (C/EBPa) and its DNA binding activity in wild-type brown adipocytes but not in IRS-1-/- cells. However, insulin stimulation of both C/EBPα expression and binding activity was restored after IRS-1wt reconstitution of deficient cells. Retrovirus-mediated expression of C/EBPα and peroxisome proliferator-activated receptor γ in IRS-1-/- brown adipocytes up-regulated UCP-1 protein content and transactivated UCP-1 promoter regardless of insulin stimulation. Both C/EBPα and peroxisome proliferator-activated receptor γ reconstituted FAS mRNA expression, but only C/EBPα restored insulin sensitivity in the absence of IRS-1. Finally, reconstitution of IRS-1-/- brown adipocytes with the IRS-1 mutants IRS-1Phe-895, which lacks IRS-1/growth factor receptor binding protein 2 binding but not IRS-1/p85-PI 3-kinase binding, or with IRS-1Tyr-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.
Versión del editorhttps://doi.org/10.1074/jbc.M209363200
Identificadoresdoi: 10.1074/jbc.M209363200
issn: 0021-9258
e-issn: 1083-351X
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