MC4R and obesity disorder: In humans, loss-of-function mutations in Mc4r are associated with hyperphagia, severe early-onset obesity, increased longitudinal growth, fasting hyperinsulinemia, and increased lean mass [8–10], a phenotype that closely mirrors that seen in Mc4r-deficient mice [11], supporting an essential role for the melanocortin system in energy homeostasis across mammalian species [12].