Ablation of AMP-activated protein kinase α 2 activity exacerbates insulin resistance induced by high-fat feeding of mice

Nobuharu Fujii, Richard C. Ho, Yasuko Manabe, Niels Jessen, Taro Toyoda, William L. Holland, Scott A. Summers, Michael F. Hirshman, Laurie J. Goodyear

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


OBJECTIVE-We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance. RESEARCH DESIGN AND METHODS-Muscle-specific transgenic mice expressing an inactive form of the AMPK α2 catalytic subunit (α2i TG) and their wild-type littermates were fed either a high-fat (60% kcal fat) or a control (10% kcal fat) diet for 30 weeks. RESULTS-Compared with wild-type mice, glucose tolerance in α2i TG mice was slightly impaired on the control diet and significantly impaired on the high-fat diet. To determine whether the whole-body glucose intolerance was associated with impaired insulin sensitivity in skeletal muscle, glucose transport in response to submaximal insulin (450 (μU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by - 50% in α2i TG mice compared with wild-type mice. High-fat feeding partially decreased insulin-stimulated glucose transport in wild-type mice, while high-fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the α2i TG mice. High-fat feeding in α2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle. CONCLUSIONS-The lack of skeletal muscle AMPK α2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK α2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.

Original languageEnglish (US)
Pages (from-to)2958-2966
Number of pages9
Issue number11
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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