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Submitted on March 23, 2006
Accepted on June 26, 2006
St Vincent's Institute and Department of Medicine, University of Melbourne, 41 Victoria Parade, Fitzroy, Vic 3065; Commonwealth Scientific and Industrial Research Organization, Molecular & Health Technologies, 343 Royal Parade, Parkville, Vic 3052; School of Exercise and Nutrition Sciences, Deakin University, Burwood, Vic 3125; Centre of Obesity Research and Education, Monash University, Alfred Hospital, Melbourne, Vic 3181, Australia
* To whom correspondence should be addressed. 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: To investigate the effects of leptin on fatty acid oxidation and AMPK signaling in primary myotubes derived from lean and obese skeletal muscle and to 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 ACC
Ser222 phosphorylation and fatty acid oxidation in lean myotubes but that in obese subjects leptin dependent AMPK signaling and fatty acid oxidation is suppressed. Reduced activation of AMPK was associated with elevated expression of interleukin-6 (
3.5 fold) and SOCS3 mRNA (2.5-fold) in myotubes of obese subjects. Over-expression of SOCS3 via adenovirus-mediated infection in lean myotubes to a similar degree as observed in obese myotubes prevented leptin but not AICAR 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.
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