LKB1-AMPK signaling in muscle from obese insulin-resistant Zucker rats and effects of training

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 gamma 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 PGC1 alpha, two AMPK-regulated proteins, tended to be reduced by 50 ( P = 0.07) and 35% ( P = 0.1), respectively. There were no differences in AMPK alpha 1, -alpha 2, -alpha 1, -alpha 2, and -alpha 3 protein content between lean and obese rats. Training caused a 1.5-fold increase in AMPK alpha 1 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 alpha 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 alpha 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.