Effects of AMPK activation on insulin sensitivity and metabolism in leptin-deficient ob/ob mice

Research output: Contribution to journalJournal articleResearchpeer-review

Robby Zachariah Tom, Pablo M Garcia-Roves, Rasmus J O Sjögren, Lake Q Jiang, Maria H Holmström, Atul S Deshmukh, Elaine Vieira, Alexander V Chibalin, Marie Björnholm, Juleen R Zierath

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 (AMPKγ3(R225Q)) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKγ3(R225Q) (γ3(R225Q)) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKγ3(R225Q) prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-γ3(R225Q)) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-γ3(R225Q) mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean γ3(R225Q) mice, but not in ob/ob-γ3(R225Q) mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from γ3(R225Q) 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-γ3(R225Q) mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKγ3(R225Q) 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 AMPKγ3(R225Q) mutation.

Original languageEnglish
JournalDiabetes
Volume63
Issue number5
Pages (from-to)1560-71
Number of pages12
ISSN0012-1797
DOIs
Publication statusPublished - May 2014

    Research areas

  • Acetyl-CoA Carboxylase/metabolism, Adenylate Kinase/metabolism, Animals, Female, Glucagon/metabolism, Insulin/metabolism, Insulin Resistance/physiology, Leptin/genetics, Lipid Metabolism, Male, Mice, Mice, Obese, Muscle, Skeletal/drug effects, Obesity/metabolism, Phosphorylation/drug effects

ID: 218626868