mutations have been found in about 5.8% of adults with severe childhood-onset obesity [72]. In another report it has been shown that resequencing MC4R resulted in the identification of low-frequency coding variants that explain approximately 2 to 3% of cases of severe obesity [73]. Common variants near MC4R are associated with fat mass, weight and risk of obesity [74]. POMC deficiency could also lead to obesity (due to lack of binding at MC4R), hypocortisolism (due to the lack of binding of ACTH to the MC2R in the adrenal gland), and alteration of pigment (due to lack of binding at MC1R in the skin). This syndrome is defined by severe early onset obesity, adrenal insufficiency, and red hair [75]. In rodent models of cancer [76] and renal failure [77], MC4R antagonists attenuate cachexia by maintaining appetite, lean body mass, and basal energy expenditure [78]. Thus, MC4R antagonists may be useful to treat cachexia [79] while MC4R agonists are being developed to treat obesity.
