Ablation of AMP-Activated Protein Kinase α2 Activity Exacerbates Insulin Resistance Induced by High-Fat Feeding of Mice

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 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 similar to 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. Diabetes 57: 2958-2966, 2008