title: Insulin receptor and IRS-1 co-immunoprecipitation with SOCS-3, and IKKα/β phosphorylation are increased in obese Zucker rat skeletal muscle.
abstract: OBJECTIVE
  We evaluated if selected pro-inflammatory cytokines and/or the protein suppressor of cytokine signaling 3 (SOCS-3) could account for decreased insulin-stimulated phosphatidylinositol 3-kinase (PI3-K) activity in the skeletal muscle of the obese Zucker rat.
  
  
  METHODS
  Eight lean and eight obese Zucker rats ~4weeks of age were obtained and allowed to feed ad libitum for 4weeks before undergoing hind limb perfusion in the presence of 500μU/ml insulin.
  
  
  RESULTS
  Insulin-stimulated skeletal muscle PI3-K activity and 3-O-methylglucose transport rates were reduced (P<0.05) in obese compared to lean animals. IRS-1 concentration remained unchanged although IRS-1 tyrosine phosphorylation was decreased (P<0.05), and IRS-1 serine phosphorylation (pS) was increased (P<0.05) in obese animals compared to lean animals. IKKα/β pS and JNK theronine/tyrosine phosphorylation was increased (P<0.05) in the obese animals. IκBα concentration was decreased (P<0.05) and IκBα pS was increased (P<0.05) in the obese compared to lean Zucker animals. SOCS-3 concentration and SOCS-3 co-immunoprecipitation with both insulin receptor β-subunit (IR-β) and IRS-1 were elevated (P<0.05) in obese compared to lean animals. IRS-1 co-immunoprecipitation with IR-β was reduced 56% in the obese animals.
  
  
  CONCLUSIONS
  Increased IKKα/β and JNK serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, while concurrent co-localization of SOCS-3 with both IR-β and IRS-1 may prevent IRS-1 from interacting with IR-β. These two mechanisms thusly may independently contribute to impairing insulin-stimulated PI3-K activation in the skeletal muscle of the obese Zucker rat.
authors.affiliation: Exercise Biochemistry Laboratory, Department of Kinesiology, California State University Northridge, CA 91330, USA.
authors.forename: Ilya A
authors.initials: IA
authors.lastname: Zolotnik
authors.forename: Tania Y
authors.initials: TY
authors.lastname: Figueroa
authors.forename: Ben B
authors.initials: BB
authors.lastname: Yaspelkis
mesh_terms: D000818:Animals; D051550:I-kappa B Kinase / Q000276:immunology* / Q000378:metabolism; D047468:Immunoprecipitation; D007328:Insulin / Q000276:immunology / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000032:analysis / Q000276:immunology*; D008297:Male; D018482:Muscle, Skeletal / Q000276:immunology* / Q000378:metabolism; D009765:Obesity / Q000276:immunology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011924:Rats, Zucker; D011972:Receptor, Insulin / Q000032:analysis / Q000276:immunology*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000032:analysis / Q000276:immunology*
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051550:I-kappa B Kinase