Exercise training is known to activate a number of transcriptional regulators and kinases in skeletal muscles that contribute to metabolic reprogramming, among which AMPK has profound effects on skeletal muscle gene expression and oxidative metabolism [35] and [36]. Narkar et al. have validated the belief that orally active AMPK agonist AICAR is sufficient as a single agent to improve running endurance in nonexercised mice [37]. Indeed, since AMPK is traditionally described as a central integrator of signal that controls energy balance, this should come as no surprise. In vivo studies have also proved that activation of AMPK was associated with increased skeletal muscle insulin sensitivity and prevention of obesity-related complications [38]. AMPK plays key roles in glucose and lipid metabolism by promoting mitochondrial biogenesis and fatty acid oxidation [37] and [39]. This link is likely to hold true in vivo, because regular aerobic exercise indeed results in elevated AMPK activity (Fig. 3C), as demonstrated by increased AMPK T172 phosphorylation, associated with increased glucose tolerance as determined by OGTT (Fig. 1E) and eliminated excess fat accumulation in skeletal muscle as determined by ORO staining (Fig. 2A).