AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (α) and two regulatory subunits (β and γ), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the γ3 subunit (AMPKγ3R225Q) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3R225Q (γ3R225Q) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle–specific expression of AMPKγ3R225Q prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3R225Q) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3R225Q mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3R225Q mice, but not in ob/ob-γ3R225Q mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3R225Q mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-γ3R225Q mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3R225Q are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKγ3R225Q mutation.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db13-0670/-/DC1.
P.M.G.-R. is currently affiliated with the Diabetes and Obesity Laboratory, Institut D’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Esther Koplowitz Centre, and with CIBERDEM, Barcelona, Spain.
A.S.D. is currently affiliated with the Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany.
E.V. is currently affiliated with CIBERDEM, Barcelona, Spain.
- Received April 25, 2013.
- Accepted January 26, 2014.
- © 2014 by the American Diabetes Association.
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