Deletion of Skeletal Muscle SOCS3 Prevents Insulin Resistance in Obesity
- Sebastian Beck Jorgensen1,2,
- Hayley M. O’Neill1,3,
- Lykke Sylow4,
- Jane Honeyman1,
- Kimberly A. Hewitt1,
- Rengasamy Palanivel3,
- Morgan D. Fullerton3,
- Lisa Öberg5,
- Anudharan Balendran5,
- Sandra Galic1,
- Chris van der Poel6,
- Ian A. Trounce7,
- Gordon S. Lynch6,
- Jonathan D. Schertzer3 and
- Gregory R. Steinberg1,3⇓
- 1St. Vincent’s Institute of Medical Research and Department of Medicine, University of Melbourne, Fitzroy, Victoria, Australia
- 2Diabetes Research Unit, Novo Nordisk A/S, Maaloev, Denmark
- 3McMaster University, Department of Medicine and Biochemistry and Biomedical Sciences, Hamilton, Ontario, Canada
- 4Department of Exercise and Sport Sciences, Section of Human Physiology, Molecular Physiology Group and Copenhagen Muscle Research Centre, Copenhagen, Denmark
- 5AstraZeneca R&D Mölndal, Mölndal, Sweden
- 6University of Melbourne, Basic and Clinical Myology Laboratory, Department of Physiology, Parkville, Victoria, Australia
- 7Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia
- Corresponding author: Gregory R. Steinberg,
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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0443/-/DC1.
- Received April 10, 2012.
- Accepted June 21, 2012.
- © 2013 by the American Diabetes Association.
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