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

Abstract

Objective: We determined if 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 diet (10% kcal fat) 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 approximately 50% in α2i TG mice compared with wild type mice. High fat feeding partially decreased insulin-stimulated glucose transport in wild type mice, while the high fat feeding resulted in a full blunting of insulin-stimulated glucose transport in the α2iTG 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.