Exercise and caloric restriction (CR) have been reported to have anti-ageing, anti-obesity, and health-promoting effects. Both interventions increase the level of dehydroepiandrosterone (DHEA) in muscle and blood, suggesting that DHEA might partially mediate these effects. In addition, it is thought that either 5'-adenosine monophosphate-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1 alpha) mediates the beneficial effects of exercise and CR. However, the effects of DHEA on AMPK activity and PGC-1 alpha expression remain unclear. Therefore, we explored whether DHEA in myotubes acts as an activator of AMPK and increases PGC-1 alpha. DHEA exposure increased glucose uptake but not the phosphorylation levels of Akt and PKC zeta/lambda in C2C12 myotubes. In contrast, the phosphorylation levels of AMPK were elevated by DHEA exposure. Finally, we found that DHEA induced the expression of the genes PGC-1 alpha and GLUT4. Our current results might reveal a previously unrecognized physiological role of DHEA; the activation of AMPK and the induction of PGC-1 alpha by DHEA might mediate its anti-obesity and health-promoting effects in living organisms. (C) 2015 Elsevier Inc. All rights reserved.