Further, acute exercise is a powerful stimulator of skeletal BU 4061T muscle PGC1-a, mediated in part by sympathetic activation, and downstream targets of PGC1-a include FNDC5 and subsequently irisin. Accordingly, we directly assessed the influence of tonic sympathetic activity and the responses to acute sympathetic activation of circulating FGF21 and irisin in adult men. Decreasing basal sympathetic activity did not influence FGF21 or irisin, however, consistent with cell and animal studies, FGF21 increased in response to acute sympathetic activation. Noteworthy, the magnitude of increase in circulating FGF21 was positively related to the magnitude of increase in circulating epinephrine. Peroxisome proliferator-activated receptor alpha in the liver and PPARc in white adipose tissue are both activators of FGF21, and, in turn, both will respond to the increase in free fatty acids resulting from sympathetically mediated lipolysis. It is plausible that the increase in FGF21 we report was due to sympathetic activation and the subsequent lipolysis. From a teleological perspective, weight gain is associated with increased sympathetic activity, usually accompanied by increased b-adrenergic receptor mediated energy expenditure to defend body composition. It seems feasible, at least initially, this increased sympathetic drive may also be targeting activation and formation of thermogenic adipose tissue. We surmised that sympathetic activation may also contribute, at least in part, to the previously reported responses of FGF21 and irisin/FNDC5 to exercise training. This was based on previous studies reporting increases in all of these potential regulators following either acute or short-term exercise training in animals and humans. Sprint-interval training is a lowvolume, high-intensity alternative to traditional, endurance exercise training. It has been shown repeatedly to evoke favorable and significant physiological adaptations that have positive implications for both health and athletic performance. While sympathetic activation following sprint-interval training was not assessed in the current study, previous studies in humans confirm that sprint exercise activates the sympathetic nervous system. In the current study, sprint interval training decreased circulating FGF21 and did not affect skeletal muscle FNDC5 protein content. However, circulating irisin was decreased in males and increased in females. To our knowledge, this is the first investigation to report on the influence of exercise training on FNDC5 protein content in human skeletal muscle. Ten weeks of endurance exercise increased FNDC5 mRNA in obese men while FNDC5 mRNA did not change following 21 weeks of endurance exercise in normal weight men. In animal models, exercise training increased FNDC5 mRNA in mice, but decreased FNDC5 mRNA and protein content in pigs. In C2C12 myotubes, administration of AICAR, an exercise mimetic, decreased FNDC5 mRNA.