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Chronic rosiglitazone treatment restores AMPK2 activity in insulin-resistant rat skeletal muscle

¹School of Medical Sciences, Royal Melbourne Institute of Technology University; ²St. Vincent's Institute and Department of Medicine, University of Melbourne, Melbourne; and ³Commonwealth Scientific and Industrial Research Organisation Health Sciences & Nutrition, Parkville, Victoria, Australia

Submitted 3 March 2005 ; accepted in final form 12 August 2005

Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor- (PPAR)-dependent and -independent effects. We tested the hypothesis that part of the insulin-sensitizing effect of RSG is mediated through the action of AMP-activated protein kinase (AMPK). First, we determined the effect of acute (30–60 min) incubation of L6 myotubes with RSG on AMPK regulation and palmitate oxidation. Compared with control (DMSO), 200 µM RSG increased (P < 0.05) AMPK1 activity and phosphorylation of AMPK (Thr¹⁷²). In addition, acetyl-CoA carboxylase (Ser²¹⁸) phosphorylation and palmitate oxidation were increased (P < 0.05) in these cells. To investigate the effects of chronic RSG treatment on AMPK regulation in skeletal muscle in vivo, obese Zucker rats were randomly allocated into two experimental groups: control and RSG. Lean Zucker rats were treated with vehicle and acted as a control group for obese Zucker rats. Rats were dosed daily for 6 wk with either vehicle (0.5% carboxymethylcellulose, 100 µl/100 g body mass), or 3 mg/kg RSG. AMPK1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPK2 activity was 25% lower in obese vs. lean animals (P < 0.05) but was normalized to control values after RSG treatment. ACC phosphorylation was decreased with obesity (P < 0.05) but restored to the level of lean controls with RSG treatment. Our data demonstrate that RSG restores AMPK signaling in skeletal muscle of insulin-resistant obese Zucker rats.

lipids; peroxisome proliferator-activated receptor-; thiazolidinedione; Zucker rats; adenosine monophosphate-activated protein kinase-2

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