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dc.contributor.authorMur, Cecilia-
dc.contributor.authorValverde, Ángela M.-
dc.contributor.authorKahn, C. Ronald-
dc.contributor.authorBenito, Manuel-
dc.identifierdoi: 10.2337/diabetes.51.3.743-
dc.identifierissn: 0012-1797-
dc.identifiere-issn: 1939-327X-
dc.identifier.citationDiabetes 51(3): 743-754 (2002)-
dc.description.abstractImmortalized brown adipocyte cell lines have been generated from fetuses of mice deficient in the insulin-like growth factor I receptor gene (IGF-IR-/-), as well as from fetuses of wild-type mice (IGF-IR+/+). These cell lines maintained the expression of adipogenic-and thermogenic-differentiation markers and show a multilocular fat droplets phenotype. IGF-IR-/- brown adipocytes lacked IGF-IR protein expression; insulin receptor (IR) expression remained unchanged as compared with wild-type cells. Insulin-induced tyrosine autophosphorylation of the IR β-chain was augmented in IGF-IR-deficient cells. Upon insulin stimulation, tyrosine phosphorylation of (insulin receptor substrate-1) IRS-1 was much higher in IGF-IR-/- brown adipocytes, although IRS-1 protein content was reduced. In contrast, tyrosine phosphorylation of IRS-2 decreased in IGF-IR-deficient cells; its protein content was unchanged as compared with wild-type cells. Down-stream, the association IRS-1/growth factor receptor binding protein-2 (Grb-2) was augmented in the IGF-IR-/- brown adipocyte cell line. However, SHC expression and SHC tyrosine phosphorylation and its association with Grb-2 were unaltered in response to insulin in IGF-IR-deficient brown adipocytes. These cells also showed an enhanced activation of mitogen-activated protein kinase (MAPK) kinase (MEK1/2) and p42/p44 mitogen-activated protein kinase (MAPK) upon insulin stimulation. In addition, the lack of IGF-IR in brown adipocytes resulted in a higher mitogenic response (DNA synthesis, cell number, and proliferating cell nuclear antigen expression) to insulin than wild-type cells. Finally, cells lacking IGF-IR showed a much lower association between IR or IRS-1 and phosphotyrosine phosphatase 1B (PTP1B) and also a decreased PTP1B activity upon insulin stimulation. However, PTP1B/Grb-2 association remained unchanged in both cell types, regardless of insulin stimulation. Data presented here provide strong evidence that IGF-IR-deficient brown adipocytes show an increased insulin sensitivity via IRS-1/Grb-2/MAPK, resulting in an increased mitogenesis in response to insulin.-
dc.description.sponsorshipThis work was supported by grant PM97-0050 from the Ministerio de Educación y Cultura, Spain.-
dc.publisherAmerican Diabetes Association-
dc.titleIncreased insulin sensitivity in IGF-I receptor-deficient brown adipocytes-
dc.description.versionPeer Reviewed-
dc.contributor.funderMinisterio de Educación y Cultura (España)-
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