Furthermore, in humans with gain-of-function MC4R mutations, Lotta et al. [49] have shown that such mutations can present biased MC4R-signaling through MAPK activation and recruitment of β-arrestin, which correlates with their lower body mass index and protection against obesity, type-2 diabetes, and coronary artery disease. Here, MC4R is linked to obesity due to melanocortin 4 receptor deficiency.