LEP and obesity due to melanocortin 4 receptor deficiency: MC4R plays an important role in controlling leptin's effects on food intake and body weight,48 and mice with disruption of the MC4R gene are severely obese.49 Multiple nonsense and missense mutations have now been identified in the human form of this gene, and these mutations are strongly associated with many obesity related traits.50,51 Indeed, MC4R is considered the first locus at which mutations are associated with a rare form of dominantly inherited morbid human obesity, and was the best known cause of human obesity before the era of genome wide association studies (GWAS).