Beck Jørgensen, Sebastian2; O'Neill, Hayley M3; Sylow, Lykke9; Honeyman, Jane3; Hewitt, Kimberly A3; Palanivel, Rengasamy5; Fullerton, Morgan D5; Öberg, Lisa6; Balendran, Anudharan6; Galic, Sandra3; van der Poel, Chris7; Trounce, Ian A8; Lynch, Gordon S7; Schertzer, Jonathan D5; Steinberg, Gregory R5
1 PhD, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet2 Diabetes Research Unit, Novo Nordisk A/S3 St. Vincent's Institute of Medical Research and Department of Medicne, University of Melbourne, Fitzroy, Victoria4 Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet5 McMaster University, Department of Medicine and Biochemistry and Biomedical Sciences, Hamilton, Ontario6 AstraZeneca R&D Mölndal, Mölndal7 University of Melbourne, Basic and Clinical Myology Laboratory, Department of Physiology, Parkville, Victoria8 Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria9 Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, Københavns Universitet
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.