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- Title
Ablation of AMP-activated protein kinase alpha2 activity exacerbates insulin resistance induced by high-fat feeding of mice.
- Authors
Fujii N; Ho RC; Manabe Y; Jessen N; Toyoda T; Holland WL; Summers SA; Hirshman MF; Goodyear LJ; Fujii, Nobuharu; Ho, Richard C; Manabe, Yasuko; Jessen, Niels; Toyoda, Taro; Holland, William L; Summers, Scott A; Hirshman, Michael F; Goodyear, Laurie J
- Abstract
<bold>Objective: </bold>We determined whether muscle AMP-activated protein kinase (AMPK) has a role in the development of insulin resistance.<bold>Research Design and Methods: </bold>Muscle-specific transgenic mice expressing an inactive form of the AMPK alpha2 catalytic subunit (alpha2i 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.<bold>Results: </bold>Compared with wild-type mice, glucose tolerance in alpha2i 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 microU/ml) was measured in isolated soleus muscles. On the control diet, insulin-stimulated glucose transport was reduced by approximately 50% in alpha2i 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 alpha2i TG mice. High-fat feeding in alpha2i TG mice was accompanied by decreased expression of insulin signaling proteins in gastrocnemius muscle.<bold>Conclusions: </bold>The lack of skeletal muscle AMPK alpha2 activity exacerbates the development of glucose intolerance and insulin resistance caused by high-fat feeding and supports the thesis that AMPK alpha2 is an important target for the prevention/amelioration of skeletal muscle insulin resistance through lifestyle (exercise) and pharmacologic (e.g., metformin) treatments.
- Publication
Diabetes, 2008, Vol 57, Issue 11, p2958
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db07-1187