While the Mc4r knockout mice exhibit marked obesity, resulting from hyperphagia and hypometabolism (Huszar et al., 1997; Butler and Cone, 2003; Butler, 2006), genetic disruption of the Mc3r lead to a modest obesity phenotype (Chen et al., 2000; Butler and Cone, 2002, 2003), suggesting that MC4R constitutes the major MCR receptor involved in energy homeostasis. This evidence concerns the gene MC4R and obesity due to melanocortin 4 receptor deficiency.