Effects of AMPK Activation on Insulin Sensitivity and Metabolism in Leptin-Deficient ob/ob Mice

  1. Juleen R. Zierath1,2
  1. 1Integrative Physiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  2. 2Integrative Physiology, Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
  1. Corresponding author: Juleen R. Zierath, juleen.zierath{at}ki.se.
  1. R.Z.T. and P.M.G.-R. contributed equally to this work.

Abstract

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. AMPKγ3R225Q3R225Q) 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/ob3R225Q) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob3R225Q 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/ob3R225Q 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/ob3R225Q 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.

Footnotes

  • 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.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 63 no. 5 1560-1571
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