Exercise provides clear beneficial effects for the prevention of numerous diseases. However, many of the molecular events responsible for the curative and protective role of exercise remain elusive. The recent discovery of FNDC5/irisin protein that is liberated by muscle tissue in response to exercise might be an important finding with regard to this unsolved mechanism. The most striking aspect of this myokine is its alleged capacity to drive brown-fat development of white fat and thermogenesis. However, the nature and secretion form of this new protein is controversial. The present study reveals that rat skeletal muscle secretes a 25 kDa form of FNDC5, while the 12 kDa/irisin theoretical peptide was not detected. More importantly, this study is the first to reveal that white adipose tissue (WAT) also secretes FNDC5; hence, it may also behave as an adipokine. Our data using rat adipose tissue explants secretomes proves that visceral adipose tissue (VAT), and especially subcutaneous adipose tissue (SAT), express and secrete FNDC5. We also show that short-term periods of endurance exercise training induced FNDC5 secretion by SAT and VAT. Moreover, we observed that WAT significantly reduced FNDC5 secretion in fasting animals. Interestingly, WAT of obese animals over-secreted this hormone, which might suggest a type of resistance. Because 72% of circulating FNDC5/irisin was previously attributed to muscle secretion, our findings suggest a muscle-adipose tissue crosstalk through a regulatory feedback mechanism.

Objective: The recently discovered peptide irisin has been hypothesized to be a regulator of body metabolism. The objective of this work was to evaluate whether circulating human irisin levels are modulated by body size and changes in adiposity during an energy restriction treatment and the subsequent weight regain.Methods: A group of 94 obese patients (50 men, 44 women; 49.4 6 9.4 years; BMI 35.6 6 4.5 kg/m 2 ) participated in a weight loss program following an 8-week hypocaloric diet (230% energy expenditure) with a weight maintenance follow-up. The patients were evaluated at 0, 8, and 24 weeks after starting treatment. In addition, 48 normal-weight subjects (16 men, 32 women; 35.71 6 8.8 years; BMI 22.9 6 2.2 kg/m 2 ) participated as controls. Plasma irisin, body weight, body composition, and hormones controlling energy homeostasis were measured.Results: Irisin levels were higher in obese subjects (353.1 6 18.6 ng/mL) than in those of normal-weight (198.4 6 7.8 ng/mL; P 0.001) and were also higher in men (340.9 6 20 ng/mL) than in women (267.6 6 12 ng/mL; P < 0.05). Moreover, irisin plasma levels were significantly correlated with high levels of direct and indirect adiposity markers, such as weight, BMI, waist circumference, and fat mass, as measured by bioimpedance, but not with height or leptin levels. Interestingly, irisin levels paralleled body weight reduction after the dietary treatment (week 8) and again returned to the baseline levels at 24 weeks in those patients regaining the lost weight.Conclusions: Irisin strongly reflects body fat mass, suggesting that the irisin circulating levels are conditioned by adiposity level. Am. J. Hum. Biol. 26:198-207, 2014.