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1Diabetes Division, University of Texas Health Science Center at San Antonio; 2Texas Diabetes Institute, San Antonio; and 3Exercise Physiology and Metabolism Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, Texas
Submitted 7 September 2005 ; accepted in final form 8 December 2005
AMPK is a key regulator of fat and carbohydrate metabolism. It has been postulated that defects in AMPK signaling could be responsible for some of the metabolic abnormalities of type 2 diabetes. In this study, we examined whether insulin-resistant obese Zucker rats have abnormalities in the AMPK pathway. We compared AMPK and ACC phosphorylation and the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator PPAR
coactivator-1 (PGC-1) in gastrocnemius of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether 7 wk of exercise training on a treadmill reversed abnormalities in the AMPK pathway in obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with lean rats. Protein expression of the AMPK kinase LKB1 was also reduced in the muscle from obese rats by 43%. In obese rats, phosphorylation of ACC and protein expression of PGC-1
, two AMPK-regulated proteins, tended to be reduced by 50 (P = 0.07) and 35% (P = 0.1), respectively. There were no differences in AMPK1, -2, -
1, -2, and -3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPK1 protein content in the obese rats, although there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased LKB1 and PGC-1 protein content 2.8- and 2.5-fold, respectively, in the obese rats. LKB1 protein strongly correlated with hexokinase II activity (r = 0.75, P = 0.001), citrate synthase activity (r = 0.54, P = 0.02), and PGC-1 protein content (r = 0.81, P < 0.001). In summary, obese insulin-resistant rodents have abnormalities in the LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.
acetyl-CoA carboxylase; peroxisome proliferator-activated receptor- coactivator-1; exercise
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