Both FGF21and irisin/FNDC5 have been mechanistically linked to the conversion of white to beige adipose tissue. In light of the potential clinical significance of FGF21 and irisin/FNDC5 for the treatment of obesity, an understanding of their regulation is of obvious importance. In this regard, we have considered two potential regulators/perturbations that are not necessarily mutually exclusive: the sympathetic nervous system and sprint interval exercise training. Stimulation of sympathetic activity via cold exposure is a well-known activator of beige fat in humans. There is some evidence from experimental animals suggesting that the sympathetic nervous system may also have a direct regulatory role pertaining to FGF21, and indirectly to irisin/FNDC5 via stimulation of peroxisome R428 proliferator-activated receptor gamma co-activator 1-alpha. Further, exercise, perhaps via intermittent increased sympathetic activation, may also stimulate FGF21 and/or irisin/ FNDC5, although the evidence is somewhat contradictory depending on species and type of exercise. In the current manuscript we present two studies. Study 1 is a retrospective analysis of plasma collected during a previously published study ; we address the new hypothesis that the sympathetic nervous system is an important physiological regulator of FGF21 and irisin in adult males. In Study 2 we performed a prospective investigation in which we examined the hypothesis that short-term sprint interval training would increase skeletal muscle FNDC5 protein content, and increase circulating concentrations of irisin and FGF21 in adult males and females. FGF21 and irisin/FNDC5 have been mechanistically linked to the conversion of white adipose to thermogenic beige adipose tissue, however the physiological control of these regulators is both important to clarify and, at the moment, poorly understood. The novel findings of this manuscript are: 1) basal sympathetic activity does not influence circulating FGF21 or irisin; 2) FGF21 is increased in response to acute sympathetic activation; 3) sprint interval training decreases FGF21, does not affect skeletal muscle FNDC5, and results in a sexual dimorphic response in systemic irisin. The sympathetic nervous system is a well-known activator of beige adipose in adult humans. Combined use of positron emission tomography and computed tomography scanning during administration of fluorodeoxyglucose is currently the gold standard non-invasive method of quantifying beige fat activation ; b-adrenergic receptor blockade decreases the metabolic activity of beige fat, thus rendering its detection extremely difficult. It seems plausible that the sympathetic nervous system may also contribute to the regulation of FGF21 and/or irisin/FNDC5 as part of the coordinated control of the “browning” of adipocytes. Data from cell and animal studies support this notion. Administration of a non-selective b-adrenergic receptor agonist increases FGF21 mRNA and secretion in rodents, and b3-adrenergic receptor stimulation increases FGF21 gene expression in the white and brown adipose tissue of mice.