Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans

Abstract

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.

Irisin and FNDC5: effects of 12-week strength training, and relations to muscle phenotype and body mass composition in untrained women

“…Still, a role for irisin in browning of adipocytes in human subjects cannot be ruled out. Different deposits of human adipocyte have been shown to respond differently to irisin exposure (Lee et al 2014), which may indicate that the negative results presented by Raschke et al (2013) and Norheim et al (2014) was an artefact of adipocyte sampling.…”

“…In contrast to these negative findings, several studies also seem to suggest that irisin is a training-responsive myokine in humans (Huh et al 2012;Kraemer et al 2013;Norheim et al 2014; Lee et al 2014). These aberrances may of course be caused by per-chance statistical errors or technical flaws, perhaps related to dubious quantification of s-irisin (Raschke et al 2013;Erickson 2013).…”

“…However, they may also hint towards between-groups or even between-individuals differences in irisin biology, for which observations have been made (Timmons et al 2012;Boström et al 2012;Pekkala et al 2013). Recently, Lee et al (2014) revitalized the potential significance of irisin in human medicine by demonstrating its natural induction in response to hypothermia and exercise, in turn inducing browning gene expression programs in adipocytes.…”

Horizons in the Pharmacotherapy of Obesity

“…Therefore, it is important not only to acutely activate thermogenesis in brown adipocytes but also to increase their number and their capacity for thermogenesis [64]. Among the approaches being investigated are mimetics of irisin and fibroblast growth factor-21 [65,66], though recent work casts doubt on the role of irisin because many studies have used commercial ELISA kits to detect irisin that cross-react with other proteins [67].…”

Obese with higher FNDC5/Irisin levels have a better metabolic profile, lower lipopolysaccharide levels and type 2 diabetes risk

“…The body weight, free fat mass and triglycerides have been related to FNDC/ irisin (5,30,37), indicating that body composition, especially body fat, and serum lipids could has influence about levels of this peptides, however, it is important to mention that these correlations presented a fragile "r" values. Although several metabolic glycemic control variables has been associated to FNDC5/ irisin levels, to our knowledge, it is the first time that neck circumference (a practice factor related to insulin resistance) (38) and a developing risk T2DM global index are inversely related to FNDC5/irisin levels, indicating, once again, that in humans, the levels of this peptides is fully combined with insulin resistance and glucose tolerance, as observed in animals and in vitro studies (1,39). Based on insulin sensibility and resistance observed between groups it would be expected that correlation with others markers of glucose homeostasis were observed besides neck circumference, however, it is important to cite that there are trend statistic between FNDC5/irisin and HOMA-S (p = 0.07), Quicki index (p = 0.08) and TYG index (p = 0.07), what indicate that results go in this direction, perhaps in a higher sample of subjects these results could be significant.…”