This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Steinberg, G. R. Articles by Kemp, B. E. Search for Related Content PubMed PubMed Citation Articles by Steinberg, G. R. Articles by Kemp, B. E. Related Collections Metabolism Obesity

The Suppressor of Cytokine Signaling 3 Inhibits Leptin Activation of AMP-Kinase in Cultured Skeletal Muscle of Obese Humans

St. Vincent’s Institute and Department of Medicine (G.R.S., M.B.C., B.E.K.), University of Melbourne, Fitzroy, Victoria 3065, Australia; Commonwealth Scientific and Industrial Research Organization (B.E.K.), Molecular and Health Technologies, Parkville, Victoria 3052, Australia; School of Exercise and Nutrition Sciences (A.J.M., D.C.-S.), Deakin University, Burwood, Victoria 3125, Australia; and Centre of Obesity Research and Education (P.E.O., J.B.D.), Monash University, Alfred Hospital, Melbourne, Victoria 3181, Australia

Address all correspondence and requests for reprints to: Gregory R. Steinberg, Ph.D., St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria 3065, Australia. E-mail: gsteinberg{at}svi.edu.au.

Context: Leptin is thought to regulate whole-body adiposity and insulin sensitivity, at least in part, by stimulating fatty acid metabolism via activation of AMP-kinase (AMPK) in skeletal muscle. Human obesity is associated with leptin resistance, and recent studies have demonstrated that hypothalamic expression of the suppressors of cytokine signaling 3 (SOCS3) regulates leptin sensitivity in rodents.

Objective: The objective of the study was to investigate the effects of leptin on fatty acid oxidation and AMPK signaling in primary myotubes derived from lean and obese skeletal muscle and evaluate the contribution of SOCS3 to leptin resistance and AMPK signaling in obese humans.

Results: We demonstrate that leptin stimulates AMPK activity and increases AMPK Thr172 and acetyl-CoA carboxylase-ß Ser222 phosphorylation and fatty acid oxidation in lean myotubes but that in obese subjects leptin-dependent AMPK signaling and fatty acid oxidation are suppressed. Reduced activation of AMPK was associated with elevated expression of IL-6 (3.5-fold) and SOCS3 mRNA (2.5-fold) in myotubes of obese subjects. Overexpression of SOCS3 via adenovirus-mediated infection in lean myotubes to a similar degree as observed in obese myotubes prevented leptin but not AICAR (5-amino-imidazole-4-carboxamide-1-ß-D-ribofuranoside) activation of AMPK signaling.

Conclusions: These data demonstrate that SOCS3 inhibits leptin activation of AMPK. These data suggest that this impairment of leptin signaling in skeletal muscle may contribute to the aberrant regulation of fatty acid metabolism observed in obesity and that pharmacological activation of AMPK may be an effective therapy to bypass SOCS3-mediated skeletal muscle leptin resistance for the treatment of obesity-related disorders.

This article has been cited by other articles:

				G. R. Steinberg and B. E. Kemp AMPK in Health and Disease Physiol Rev, July 1, 2009; 89(3): 1025 - 1078. [Abstract] [Full Text] [PDF]

				S. B. Jorgensen, J. Honeyman, J. S. Oakhill, D. Fazakerley, J. Stockli, B. E. Kemp, and G. R. Steinberg Oligomeric resistin impairs insulin and AICAR-stimulated glucose uptake in mouse skeletal muscle by inhibiting GLUT4 translocation Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E57 - E66. [Abstract] [Full Text] [PDF]

				G. Yang, L. Badeanlou, J. Bielawski, A. J. Roberts, Y. A. Hannun, and F. Samad Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome Am J Physiol Endocrinol Metab, July 1, 2009; 297(1): E211 - E224. [Abstract] [Full Text] [PDF]

				N. Cook, S. A. Fraser, M. Katerelos, F. Katsis, K. Gleich, P. F. Mount, G. R. Steinberg, V. Levidiotis, B. E. Kemp, and D. A. Power Low salt concentrations activate AMP-activated protein kinase in mouse macula densa cells Am J Physiol Renal Physiol, April 1, 2009; 296(4): F801 - F809. [Abstract] [Full Text] [PDF]

				K. L. Mullen, J. Pritchard, I. Ritchie, L. A. Snook, A. Chabowski, A. Bonen, D. Wright, and D. J. Dyck Adiponectin resistance precedes the accumulation of skeletal muscle lipids and insulin resistance in high-fat-fed rats Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2009; 296(2): R243 - R251. [Abstract] [Full Text] [PDF]

				K. Begriche, P. Letteron, A. Abbey-Toby, N. Vadrot, M.-A. Robin, A. Bado, D. Pessayre, and B. Fromenty Partial leptin deficiency favors diet-induced obesity and related metabolic disorders in mice Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E939 - E951. [Abstract] [Full Text] [PDF]

				Y. Wei, K. Chen, A. T. Whaley-Connell, C. S. Stump, J. A. Ibdah, and J. R. Sowers Skeletal muscle insulin resistance: role of inflammatory cytokines and reactive oxygen species Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2008; 294(3): R673 - R680. [Abstract] [Full Text] [PDF]

				B. Guerra, A. Santana, T. Fuentes, S. Delgado-Guerra, A. Cabrera-Socorro, C. Dorado, and J. A. L. Calbet Leptin receptors in human skeletal muscle J Appl Physiol, May 1, 2007; 102(5): 1786 - 1792. [Abstract] [Full Text] [PDF]