Rediscovery of cold-activated brown adipose tissue (BAT) in humans has boosted research interest in identifying BAT activators for metabolic benefits. Of particular interest are cytokines capable of fat browning. Irisin, derived from FNDC5, is an exercise-induced myokine that drives brown-fat-like thermogenesis in murine white fat. Here we explored whether cold exposure is an afferent signal for irisin secretion in humans and compared it with FGF21, a brown adipokine in rodents. Cold exposure increased circulating irisin and FGF21. We found an induction of irisin secretion proportional to shivering intensity, in magnitude similar to exercise-stimulated secretion. FNDC5 and/or FGF21 treatment upregulated human adipocyte brown fat gene/protein expression and thermogenesis in a depot-specific manner. These results suggest exercise-induced irisin secretion could have evolved from shivering-related muscle contraction, serving to augment brown fat thermogenesis in concert with FGF21. Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis that is exploitable in obesity therapeutics development.

This study reveals for the first time a strong positive association between plasma FGF21 levels and BMD in healthy women, suggesting the association between bone loss and high FGF21 states in animals may not be directly translated to humans in physiologic states. We hypothesize that FGF21 may increase bone mass particularly in women through paracrine mechanisms in the bone-adipose interface.

Vitamin D deficiency and its adverse skeletal sequelae are well recognized in the general population. Recent observation of high prevalence of low vitamin D states and their associations with worse clinical outcomes in critically ill populations have sparked interest in the role of supplementation for these patients. High-dose vitamin D efficaciously increases serum levels, but its impact on clinical outcome has not been examined. This article will review results from observational studies on prevalence and outcomes of hypovitaminosis D in critically ill patients, as well as caveats of vitamin D interventional trials. Improved understanding of vitamin D metabolism in critical illness will clarify the therapeutic potential of this pleiotropic hormone and facilitate implementation of cost-effective clinical trials.