Fujii, NobuharuHo, Richard C.Manabe, YasukoJessen, NielsToyoda, TaroHolland, WilliamSummers, Scott A.Hirshman, Michael F.Goodyear, Laurie2013-01-072008Fujii, Nobuharu, Richard C. Ho, Yasuko Manabe, Niels Jessen, Taro Toyoda, William L. Holland, Scott A. Summers, Michael F. Hirshman, and Laurie J. Goodyear. 2008. Ablation of AMP-activated protein kinase \(\alpha\)2 activity exacerbates insulin resistance induced by high-fat feeding of mice. Diabetes 57(11): 2958-2966.0012-1797http://nrs.harvard.edu/urn-3:HUL.InstRepos:10140027Objective: 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 \(\alpha\)2 catalytic subunit (\(\alpha\)2i 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 \(\alpha\)2i 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 \(\mu\)U/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by \(\sim\)50% in \(\alpha\)2i 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 \(\alpha\)2i TG mice. High-fat feeding in \(\alpha\)2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle. Conclusions: The lack of skeletal muscle AMPK \(\alpha\)2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK \(\alpha\)2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.en-USJournal Article2013-01-0710.2337/db07-1187