Insulin is a potent inducer of adipogenesis, and differentiation of adipocytes requires many components of the insulin signaling pathway, including the insulin receptor substrate IRS-1 and phosphatidylinositol 3-kinase (PI3K). Brown pre-adipocytes in culture exhibit low levels of insulin receptor (IR), and during differentiation there is both an increase in total IR levels and a shift in the alternatively spliced forms of IR from the A isoform (-exon 11) to the B isoform (+exon 11). Brown pre-adipocyte cell lines from insulin receptor-deficient mice exhibit dramatically impaired differentiation and an inability to regulate alternative splicing of the insulin receptor. Surprisingly, re-expression of either splice isoform of IR in the IR-deficient cells fails to rescue differentiation in these cells. Likewise, overexpression of IR in control IR1ox cells also results in inhibition of differentiation and a failure to accumulate expression of the adipogenic markers peroxisome proliferator-activated receptor gamma, Glut4, and fatty acid synthase, although cells overexpressing IR retain the ability to activate PI3K and down-regulate mitogen-activated protein kinase ( MAPK) phosphorylation. Thus, differentiation of brown adipocytes requires a timed and regulated expression of IR, and either the absence or overabundance of insulin receptors in these cells dramatically inhibits differentiation.
机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Chan, GK
Deckelbaum, RA
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Deckelbaum, RA
Bolivar, I
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Bolivar, I
Goltzman, D
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Goltzman, D
Karaplis, AC
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McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, CanadaMcGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Chan, GK
Deckelbaum, RA
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Deckelbaum, RA
Bolivar, I
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Bolivar, I
Goltzman, D
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机构:McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
Goltzman, D
Karaplis, AC
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McGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, CanadaMcGill Univ, Dept Med, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada