Browning of white fat: does irisin play a role in humans?

Abstract

The discovery of irisin as an exercise-regulated myokine inducing browning of WAT has gained interest as a potential new strategy to combat obesity and its associated disorders, such as type 2 diabetes. However, there are inconsistencies regarding the relevance of irisin in humans. The regulation of FNDC5 mRNA expression by exercise and contraction could not be reproduced by a number of human studies using several exercise protocols and in vitro approaches. Furthermore, the nature of FNDC5 fragments and the presence of irisin in humans are questionable and probably contribute to conflicting data obtained with commercially available ELISA kits. Most importantly, the information regarding the concentration of circulating irisin in humans is not clear, as different studies using different kits measure irisin levels in a wide range. Data about the role of irisin in states of human obesity and metabolic diseases are conflicting and, in some cases, changes in irisin levels have been observed; they were only moderate in 10-20%. Independent of the presence and regulation of FNDC5/irisin in humans, the application of recombinant irisin could still represent a therapeutic strategy to fight obesity. However, the current data obtained from human cell models reveal that FNDC5/irisin has no effect on browning of the major WAT depots in humans and is likely to selectively target a small subpopulation of adipocytes, which are located in classical BAT regions, such as the supraclavicular adipose tissue. Thus, other candidates, such as BMP7 or CNPs, seem to be more prominent candidates as inducers of browning in humans.

Human Brown Adipose Tissue: What We Have Learned So Far

“…Exogenous administration of this peptide hormone, which was named "Irisin," led to the browning of subcutaneous adipose tissue depots in mice (91). Irisin expression was shown to be correlated to exercise in humans in some, but not all, studies (92). A recent article (93) convincingly demonstrated, however, that shivering leads to an increase in Irisin levels in humans, and it might thus provide a link between shivering and nonshivering thermogenesis in response to cold.…”

Exercise regulation of adipose tissue

“…8,[28][29][30] First, it is surprising that exercise training would lead to the induction of a thermogenic, heat-producing cell type such as beige cells, since the contracting muscles generate significant amounts of heat during exercise. 8,30 Second, exercise is an energy-consuming process, so it is perplexing that exercise would induce the expression of cells that inherently increase energy expenditure, resulting in even greater fuel requirements for the organism.…”

Mitochondrial Actions for Fat Browning and Energy Expenditure in White Adipose Tissue

“…These data strongly suggest the activation of browning and thermogenic genes by irisin. Nevertheless, irisin efficacy in browning WAT depots in humans is still under debate [157,158].…”

“…These data strongly suggest the activation of browning and thermogenic genes by irisin. Nevertheless, irisin efficacy in browning WAT depots in humans is still under debate [157,158].Fibroblast growth factor 21 (FGF21), expressed predominantly in liver, WAT, BAT and pancreas, has emerged as an important metabolic regulator that induces weight loss in obese mouse models through increases in energy expenditure without alterations in food intake [159,160]. FGF21 is considered the only known cold-induced secreted protein that functions to increase the appearance of brite adipocytes in WAT depots in an autocrine/paracrine manner, increasing the expression of thermogenic genes in fat tissues, partially via the enhancement adipose tissue PGC1-α protein level [159].…”