SIM1 and obesity due to melanocortin 4 receptor deficiency: Our results are in agreement with published literature that strongly associates monogenic forms of obesity, characterized by severe, early-onset obesity, with loss-of-function mutations in genes of the hypothalamic leptin–melanocortin pathway, which plays a critical role in the regulation of food intake and body weight (41), e.g., POMC (42–51), LEPR (52–69), PCSK1 (70–77), SIM1 (78–87), and tubby-like protein TUB (88–92).