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Essential Role of Insulin-Like Growth Factor I Receptor in Insulin-Induced Fetal Brown Adipocyte Differentiation

Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular, Centro Mixto, Facultad de Farmacia, Ciudad Universitaria, 28040 Madrid, Spain

Address all correspondence and requests for reprints to: Dr. Angela M. Valverde, Instituto de Bioquímica/Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Ciudad Universitaria, 28040 Madrid, Spain. E-mail: valverde{at}farm.ucm.es.

To define the specific role of IGF-I receptor (IGF-IR) in adipogenic and thermogenic differentiation of brown adipocytes during late fetal life, we have established immortalized brown adipocyte cell lines from fetuses of IGF-IR-deficient mice (IGF-IR^-/-) as well as from wild-type mice (IGF-IR^+/+). IGF-IR^-/- cells showed an increased insulin sensitivity regarding insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation despite a substantial reduction in IRS-1 protein content. Furthermore, insulin-induced total and IRS-1-associated phosphatidylinositol 3-kinase activities were augmented in IGF-IR-deficient cells compared with wild-type cells. Downstream phosphatidylinositol 3-kinase activation of Akt, but not p70s6 kinase, were elicited at lower doses of insulin in IGF-IR^-/- brown adipocytes. Activation of protein kinase C by insulin was similar in both cell types as was insulin-induced glucose uptake. Treatment of wild-type brown adipocytes with insulin for 12 h up-regulated fatty acid synthase (FAS) and adipocyte determination and differentiation (ADD1/SREBP) mRNAs; this effect was impaired in the absence of IGF-IR. At the protein level, insulin increased FAS content and the amount of the mature form of adipocyte determination and differentiation (ADD1/SREBP) in the nucleus in wild-type cells, but not in IGF-IR^-/- cells. Furthermore, 24 h of insulin stimulation induced the expression of both uncoupling protein-1 and CCAAT/enhancer-binding protein (C/EBP) in wild-type brown adipocytes; these effects were abolished in IGF-I-R^-/- cells. Retrovirus-mediated reexpression of peroxisomal proliferator-activated receptor (PPAR) in IGF-IR^-/- brown adipocytes could overcome FAS mRNA impairment, bypassing insulin signaling. However, insulin further increased FAS mRNA expression in C/EBP-IGF-IR^-/- cells, but not in PPAR-IGF-IR^-/- cells. In addition, fetal brown adipocytes lacking IGF-IR up-regulated uncoupling protein-1 expression in the absence of insulin when PPAR, but not C/EBP, was overexpressed. These data provide strong evidence for a critical role of IGF-IR in the differentiation of the brown adipocyte phenotype in fetal life; this effect is mimicked by PPAR in an insulin-independent manner.

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