► Irisin is cleaved from fibronectin type III domain containing 5 (FNDC5). ► Plasma irisin levels are higher in obese compared to anorexia nervosa. ► Irisin correlates with body mass index, fat mass and fat free mass. ► Circulating irisin correlates with insulin but not ghrelin. ► Physiological function of irisin may be improvement of glucose tolerance. Irisin was recently identified as cleavage product of fibronectin type III domain containing 5 (FNDC5) and shown to increase energy expenditure in mice and humans and therefore was discussed as potential treatment option in obesity. However, the regulation of irisin under conditions of severely altered body weight such as anorexia nervosa and obesity remains to be investigated. We analyzed circulating irisin levels over a broad spectrum of body weight in 40 patients with anorexia nervosa (mean body mass index, BMI 12.6±0.7kg/m2), normal weight controls (22.6±0.9kg/m2) and obese patients with BMI of 30–40 (36.9±1.2kg/m2), 40–50 (44.9±1.1kg/m2) and >50 (70.1±2.7kg/m2, n=8/group). Correlation analyses were performed between irisin and different body indices, parameters of body composition and hormones involved in various homeostatic processes. Obese patients showed higher circulating irisin levels compared to normal weight and anorexic patients (p<0.05) resulting in a correlation of irisin with body weight (r=0.47, p<0.01) and BMI (r=0.50, p<0.001). Plasma irisin was also positively correlated with fat mass (r=0.48, p<0.01), body cell mass (r=0.45, p<0.01) and fat free mass (r=0.40, p<0.05). Insulin levels were positively correlated with irisin (r=0.45, p<0.01), whereas circulating ghrelin, cortisol, thyroid-stimulating hormone or C-reactive protein were not (p>0.05). These data indicate that circulating irisin is affected under conditions of altered BMI with highest levels in severely obese patients. The increase of irisin under conditions of obesity may indicate a physiological function to improve glucose tolerance which is often impaired in obese subjects.