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Am J Physiol Endocrinol Metab (December 13, 2005). doi:10.1152/ajpendo.00429.2005
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Submitted on September 7, 2005
Accepted on December 8, 2005

LKB1-AMPK Signaling in Muscle from Obese Insulin Resistant Zucker Rats and Effects of Training

Apiradee Sriwijitkamol1, John L Ivy2, Christine Christ-Roberts3, Ralph A DeFronzo1, Lawrence J Mandarino3, and Nicolas Musi1*

1 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Texas Diabetes Institute, San Antonio, TX, USA
2 Exercise Physiology and Metabolism Laboratory, Department of Kinesiology and Health Education, University of Texas at Austin, Austin, TX, USA
3 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

* To whom correspondence should be addressed. E-mail: nicolas.musi{at}uhs-sa.com.

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 acetyl CoA carboxylase (ACC) phosphorylation, as well as the protein content of the upstream AMPK kinase LKB1 and the AMPK-regulated transcriptional coactivator, peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC)-1, in gastrocnemius muscle of sedentary obese Zucker rats and sedentary lean Zucker rats. We also examined whether seven weeks of exercise training on a treadmill reversed abnormalities in the AMPK pathway in the obese Zucker rats. In the obese rats, AMPK phosphorylation was reduced by 45% compared with the lean rats. The protein expression of the AMPK kinase, LKB1, also was reduced in the muscle from the obese rats by 43%. In the obese rats, the phosphorylation of ACC and protein 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 {alpha}1, {alpha}2, {beta}1, {beta}2 and {gamma}3 protein content between the lean and obese Zucker rats. Training caused a 1.5-fold increase in AMPK {alpha}1 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 LKB1 and PGC-1 protein content by 2.8- and 2.5-fold 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 LKB1-AMPK-PGC-1 pathway in muscle, and these abnormalities can be restored by training.




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