title: Regulation of SOCS-3 expression by leptin and its co-localization with insulin receptor in rat skeletal muscle cells.
abstract: Obesity is a well-defined risk factor for the development of insulin resistance in target tissues, such as skeletal muscle, and thus type 2 diabetes. This may occur due to endocrine effects mediated by adipokines including leptin, the product of the obese (ob) gene, whose circulating levels positively correlate with body mass index. Induction of suppressor of cytokine-3 (SOCS-3) protein expression has been implicated as a possible mechanism of leptin-induced insulin resistance. Here, we show that treatment of rat skeletal muscle cells with leptin activated the SOCS-3 gene promoter and caused a time-dependent increase in both SOCS-3 mRNA and protein content. Confocal microscopy demonstrated increased co-localization of SOCS-3 with insulin receptor in leptin-treated cells and we confirmed a direct interaction between these two proteins by showing increased coimmunoprecipitation of SOCS-3 and insulin receptor after exposure of cells to leptin. However, the expected functional consequences were not observed, as we saw no change in basal or insulin-stimulated glucose uptake and phosphorylation of GSK3beta, Akt (T308 and S473) or ERK1/2. In summary, leptin induced SOCS-3 expression and its association with the insulin receptor in rat skeletal muscle cells but functional significance of this increase was not apparent upon measuring glucose uptake.
authors.affiliation: Department of Biology, York University, Toronto, M3J 1P3 Ontario, Canada.
authors.forename: Megumi
authors.initials: M
authors.lastname: Eguchi
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Gillis
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Natalia
authors.initials: N
authors.lastname: Lyakhovsky
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: John C
authors.initials: JC
authors.lastname: McDermott
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D007328:Insulin / Q000494:pharmacology; D020738:Leptin / Q000494:pharmacology*; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism*; D054411:Receptors, Leptin; D015398:Signal Transduction / Q000187:drug effects; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000378:metabolism*; D013997:Time Factors
chemical_list: D007328:Insulin; C515448:LEPR protein, human; D020738:Leptin; D012333:RNA, Messenger; D054411:Receptors, Leptin; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C515447:leptin receptor, mouse; D011972:Receptor, Insulin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D005947:Glucose