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AMP-Activated Protein Kinase Is Not Down-Regulated in Human Skeletal Muscle of Obese Females

St. Vincent’s Institute (G.R.S., B.J.W.v.D., Z.C., S.M., D.J.C., B.E.K.) and Department of Medicine (G.R.S., D.J.C., B.E.K.), University of Melbourne, Fitzroy, Victoria 3065, Australia; Department of Human Biology and Nutritional Sciences (A.C.S., D.J.D.), University of Guelph, Ontario N1G 2W1, Canada; and Department of Medicine (G.J.F.H.), McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Address all correspondence and requests for reprints to: Gregory R. Steinberg, St. Vincent’s Institute, 9 Princes Street, Fitzroy, Victoria, Australia 3065. E-mail: gsteinberg{at}svi.edu.au.

Obesity in humans is associated with lipid accumulation in skeletal muscle, insulin and leptin resistance, and type 2 diabetes. AMP-activated protein kinase (AMPK) is an important regulator of fatty acid (FA) metabolism in skeletal muscle. To address the hypothesis that lipid accumulation in skeletal muscle of obese subjects may be due to down-regulation of AMPK, we measured mRNA and protein levels of AMPK isoforms, AMPK1 and -2 activity, AMPK kinase activity, acetyl-coenzyme A carboxylase (ACCß) expression and phosphorylation, and FA metabolism in biopsies of rectus abdominus muscle from lean and obese women. We also examined the effect of 5-aminoimidazole-4-carboxamide riboside (AICAR) on AMPK activity and the effects of AICAR and leptin on FA metabolism. Skeletal muscle of obese subjects had increased total FA uptake and triglyceride esterification, and leptin failed to stimulate FA oxidation. However, AMPK mRNA and protein expression, AMPK1 and -2 activities, AMPK kinase activity, ACCß phosphorylation, and FA oxidation were similar in lean and obese subjects. Moreover, AICAR increased AMPK2 activity, ACCß phosphorylation, and palmitate oxidation to a similar degree in muscle from lean and obese subjects. We conclude that the abnormal lipid metabolism and leptin resistance of skeletal muscle of obese subjects is not due to down-regulation of AMPK. In addition, the similar stimulation by AICAR of AMPK in skeletal muscle of lean and obese subjects suggests that direct pharmacological activation of AMPK may be a therapeutic approach for stimulating FA oxidation in the treatment of human obesity.

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