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J Biol Chem. 2003 Aug 29;278(35):33377-83. Epub 2003 Jun 13.

Bi-directional regulation of brown fat adipogenesis by the insulin receptor.

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  • 1Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.

Abstract

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 IRlox 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.

PMID:
12807888
DOI:
10.1074/jbc.M303056200
[PubMed - indexed for MEDLINE]
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