Bi-directional regulation of brown fat adipogenesis by the insulin receptor.
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.
Entingh
Amelia J
AJ
Department of Cellular and Molecular Physiology, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Massachusetts 02215, USA.
Taniguchi
Cullen M
CM
Kahn
C Ronald
CR
D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology; D002454:Cell Differentiation; D004396:Coloring Agents / Q000494:pharmacology; D015536:Down-Regulation; D005091:Exons; D051275:Glucose Transporter Type 4; D006720:Homozygote; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D020033:Protein Isoforms; D011972:Receptor, Insulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors
D001391:Azo Compounds; D004396:Coloring Agents; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C495693:Slc2a4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; C011049:oil red O