While the physiological role of FNDC5/irisin in mediating responses to exercise is unquestionable, and there is also strong evidence of altered FNDC5/irisin regulation in clinical scenarios of metabolic disorders associated with diabetes, obesity and metabolic syndrome in humans, the available methods for determining irisin are still under debate [73]. This evidence concerns the gene FNDC5 and obesity due to melanocortin 4 receptor deficiency.