title: IRS-3 mediates insulin-induced glucose uptake in differentiated IRS-2(-/-) brown adipocytes.
abstract: IRS-2 mediates insulin-induced glucose uptake in brown preadipocytes. Upon differentiation, basal IRS-3 expression increased concurrently with an enhancement in the IRS-3-associated phosphatidylinositol (PI) 3-kinase activity in the Triton-insoluble fraction in wild-type and IRS-2-deficient brown adipocytes stimulated with insulin. Moreover, insulin induced protein kinase B (Akt) and protein kinase C (PKC) zeta phosphorylation in both kinds of cells. More importantly, insulin induced glucose uptake in differentiated IRS-2-deficient brown adipocytes in a wortmannin-dependent manner. However, while insulin induced Akt phosphorylation occurred mainly in the cytosolic fraction, PKC zeta activation was constrained to the Triton-insoluble fraction. The reduction of IRS-3 expression by siRNA inhibited insulin-induced glucose uptake and also PKC zeta activation in differentiated IRS-2(-/-) brown adipocytes. In addition, inhibition of PKC zeta totally blunted insulin-induced glucose uptake in those cells. Our results provide evidences suggesting that IRS-3/PI 3-kinase/PKC zeta signaling is the main responsible for the insulin-induced glucose uptake observed upon differentiation of brown adipocytes lacking IRS-2.
authors.affiliation: Institute of Biochemistry/Department of Biochemistry and Molecular Biology, (CSIC/UCM), School of Pharmacy, Complutense University, 28040 Madrid, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Escribano
authors.forename: Mónica
authors.initials: M
authors.lastname: Arribas
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.forename: Manuel
authors.initials: M
authors.lastname: Benito
mesh_terms: D052437:Adipocytes, Brown / Q000166:cytology* / Q000187:drug effects*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D051379:Mice; D008954:Models, Biological; D017830:Octoxynol / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D000077191:Wortmannin; D047392:beta-Cyclodextrins / Q000494:pharmacology; D000099221:Protein Kinase C zeta
chemical_list: D000730:Androstadienes; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017830:Octoxynol; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011493:Protein Kinase C; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D000077191:Wortmannin; D047392:beta-Cyclodextrins; D000099221:Protein Kinase C zeta; C526298:Irs2 protein, mouse; C108872:Irs3 protein, mouse; C108732:methyl-beta-cyclodextrin