Chronic rosiglitazone treatment restores AMPKalpha2 activity in insulin-resistant rat skeletal muscle.
Rosiglitazone (RSG) is an insulin-sensitizing thiazolidinedione (TZD) that exerts peroxisome proliferator-activated receptor-gamma (PPARgamma)-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 microM RSG increased (P < 0.05) AMPKalpha1 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 microl/100 g body mass), or 3 mg/kg RSG. AMPKalpha1 activity was similar in muscle from lean and obese animals and was unaffected by RSG treatment. AMPKalpha2 activity was approximately 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.
Lessard
Sarah J
SJ
School of Medical Sciences, RMIT University, Melbourne, Victoria, Australia.
Chen
Zhi-Ping
ZP
Watt
Matthew J
MJ
Hashem
Michael
M
Reid
Julianne J
JJ
Febbraio
Mark A
MA
Kemp
Bruce E
BE
Hawley
John A
JA
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007333:Insulin Resistance; D009097:Multienzyme Complexes / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy* / Q000201:enzymology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage*
D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases