Irisin: ‘fat’ or artefact

Abstract

SummarySoon after the discovery of the muscle-derived factor irisin, a great controversy arose in the literature regarding certain inconsistencies in the regulation of the fibronectin type III domain containing 5 protein (FNDC5/irisin) after exercise, as well as the unpredicted association of circulating irisin levels with parameters of adiposity in humans. Due to these questionable findings, doubts as to the identity of the soluble portion of FNDC5 as well as the real role of irisin and its possible therapeutic applications in the treatment of obesity and diabetes have proliferated. We recently postulated that FNDC5/irisin is an adipokine expressed and secreted by white adipose tissue in rats and humans. Its circulating concentration correlates with adiposity in humans among independent cohorts of patients. Further analysis, focused on obesity-related metabolic disorders, has shown that irisin could play a role in promoting insulin resistance or act as an adaptive response to counteract disturbances in glucose and lipid homoeostasis in obesity. Overall, this leads us to raise the question whether the new factor, increased in circulation of obese patients, is really irisin-reflecting fat mass or it is an artefact. Therefore, the current review is focused on the potential participation of adipose tissue in irisin circulating levels, and the role of irisin in metabolic pathologies associated with obesity in an attempt to clarify the controversy generated by these recently published reports.

Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

“…Supporting this interpretation, the antibody used in our study also recognizes the secreted FNDC5/irisin protein, as indicated by positive staining of fixed plasma proteins inside blood vessels (data not shown). In fact, antibodies (as ours) against the endogenous portion of FNDC5 protein have been previously shown to recognize secreted irisin, which has led to the proposal that the full-length FNDC5/irisin may be secreted [50]. Further supporting our interpretation, immunostaining has been successfully used to visualize irisin bound on the cell surface of recombinant irisin-treated 3T3-L1 adipocytes, which has suggested the existence of a yet-to-be-identified irisin receptor on the adipocyte cell membrane [51].…”

Serum irisin and its regulation by hyperinsulinemia in women with polycystic ovary syndrome

“…In the human data, a decrease in serum irisin concentration at the end of an 8-week energy restriction program (70% of the daily energy requirements) positively correlated with the decreased concentration of total cholesterol, apolipoprotein B and the total cholesterol/high-density lipoprotein cholesterol ratio in patients with metabolic syndrome [23]. Crujeirais et al postulated that irisin acts as an adaptive response to counteract disturbances in glucose and lipid homoeostasis in obesity [24]. Based on previously reported human data, we can hypothesize that elevated serum irisin at baseline and after insulin infusion may represent a compensatory mechanism to maintain proper energy balance in the insulin resistant state observed in PCOS women.…”

Irisin is more strongly predicted by muscle oxidative potential than adiposity in non-diabetic men

“…Numerous aspects of irisin biology thus remain highly controversial, as recently reviewed in [9]. Some of the controversies include the following: (1) Although at first suggested to be a myokine, more recent studies question its production by muscle and instead suggest it might primarily be an adipokine [2,26].…”

“…(3) Studies on the impact of physical activity are contradictory, some showing irisin is increased after a physical effort [5,7,15,32], others not [16,29,32]. (4) The impact of obesity and/or diabetes is contradictory [8,15,21,31], although recent work tends to support a positive association with circulating irisin levels [9]. A possible explanation for some of the contradictory results between published reports could reside in which cleavage product of FNDC5 is actually released and detected using the various kits available for its measurement [12,[26][27][28].…”