Among them, mutations in the leptin gene (ob/ob mice) or in the leptin receptor gene (db/db mice, fa/fa rats), leading to the deficiency of the related proteins, produce extreme obesity in rodents (9, 32–35) as well as in humans (36–39), due to hyperphagia, decreased energy expenditure, and insulin-resistance. Here, LEP is linked to obesity due to melanocortin 4 receptor deficiency.