title: Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity.
abstract: Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin signal transduction in adipose tissue and the liver. Skeletal muscle is an important tissue for controlling energy expenditure and whole-body insulin sensitivity; however, the physiological importance of SOCS3 in this tissue has not been examined. Therefore, we generated mice that had SOCS3 specifically deleted in skeletal muscle (SOCS MKO). The SOCS3 MKO mice had normal muscle development, body mass, adiposity, appetite, and energy expenditure compared with wild-type (WT) littermates. Despite similar degrees of obesity when fed a high-fat diet, SOCS3 MKO mice were protected against the development of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance.
authors.affiliation: St. Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia. gsteinberg@mcamster.ca
authors.forename: Sebastian Beck
authors.initials: SB
authors.lastname: Jorgensen
authors.forename: Hayley M
authors.initials: HM
authors.lastname: O'Neill
authors.forename: Lykke
authors.initials: L
authors.lastname: Sylow
authors.forename: Jane
authors.initials: J
authors.lastname: Honeyman
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Hewitt
authors.forename: Rengasamy
authors.initials: R
authors.lastname: Palanivel
authors.forename: Morgan D
authors.initials: MD
authors.lastname: Fullerton
authors.forename: Lisa
authors.initials: L
authors.lastname: Öberg
authors.forename: Anudharan
authors.initials: A
authors.lastname: Balendran
authors.forename: Sandra
authors.initials: S
authors.lastname: Galic
authors.forename: Chris
authors.initials: C
authors.lastname: van der Poel
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Schertzer
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
mesh_terms: D000818:Animals; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D010766:Phosphorylation; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014280:Triglycerides