Majority of studies in human and animals showed that lower circulating levels of irisin were associated with obesity (135, 137) and T2DM (136, 140–145), but so far with inconsistent and controversial results; the opposite trend was also found in subjects with obesity (136, 138), metabolic syndrome (146), and T2DM (147). This evidence concerns the gene FNDC5 and obesity due to melanocortin 4 receptor deficiency.