MC4R and obesity due to melanocortin 4 receptor deficiency: MC4R-induced CRE activation in the hypothalamus is of prime importance for the regulation of mammalian metabolism, as highlighted by the finding that mutations in the MC4R gene are the most frequent monogenic cause of severe obesity in humans and targeted disruption of the MC4R gene in mice causes an obesity/diabetes syndrome36, 37, 38, 39.