The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-Kinase in cultured skeletal muscle of obese humans

Steinberg, Gregory R., McAinch, Andrew J., Chen, Michael B., O`Brien, Paul E., Dixon, John B., Cameron-Smith, David and Kemp, Bruce 2006, The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-Kinase in cultured skeletal muscle of obese humans, Journal of clinical endocrinology and metabolism, vol. 91, no. 9, pp. 3592-3597, doi: 10.1210/jc.2006-0638.

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Title The suppressor of cytokine signaling 3 inhibits leptin activation of AMP-Kinase in cultured skeletal muscle of obese humans
Author(s) Steinberg, Gregory R.
McAinch, Andrew J.
Chen, Michael B.
O`Brien, Paul E.
Dixon, John B.
Cameron-Smith, David
Kemp, Bruce
Journal name Journal of clinical endocrinology and metabolism
Volume number 91
Issue number 9
Start page 3592
End page 3597
Publisher Endocrine Society
Place of publication Baltimore, MD
Publication date 2006
ISSN 0021-972X
Summary 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.
Language eng
DOI 10.1210/jc.2006-0638
Field of Research 110602 Exercise Physiology
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2006, by The Endocrine Society
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Document type: Journal Article
Collection: School of Exercise and Nutrition Sciences
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