AMPK Signaling in Muscle from Obese Insulin Resistant Zucker Rats and Effects of Training
Abstract Number: 57-OR
Authors: APIRADEE SRIWIJITKAMOL, RALPH A. DEFRONZO, JOHN L. IVY, LAWRENCE J. MANDARINO, NICOLAS MUSI
Institutions: San Antonio, TX; Austin, TX
Results: AMP-activated protein kinase (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, as well as the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcription factor PGC-1 in gastrocnemius muscle of sedentary obese Zucker rats (n=5) and sedentary lean Zucker rats (n=5). We also examined whether seven weeks of exercise training on a treadmill reversed abnormalities in the AMPK pathway in the obese Zucker rats (n=7). In the obese rats, AMPK phosphorylation was reduced by 45% compared with the lean rats (p<0.05). The expression of the AMPK kinase, LKB1, was also reduced in the muscle from the obese rats by 43% (p<0.05). In the obese rats, the phosphorylation of ACC and expression of PGC-1, two AMPK regulated proteins, tended to be reduced by 50% (p=0.07) and by 35% (p=0.1), respectively. There were no differences in AMPK α1, α2, β1, β2 and γ3 protein content between the lean and obese Zucker rats. Training caused a 1.5-fold increase in AMPK α1 protein content in the obese rats, whereas there was no effect of training on AMPK phosphorylation and the other AMPK isoforms. Furthermore, training also significantly increased PGC-1 and LKB1 protein content by 2.5- (p<0.05) and 2.8-fold (p<0.05) in the obese rats, respectively. 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 AMPK pathway in muscle, and these abnormalities can be restored by training.