The central nervous system plays a key part in regulating food intake through the brain-gut axis [30], with the hypothalamus acting as the central regulator, receiving both long- and short-term food intake and energy expenditure feedback from the periphery. The hypothalamus integrates these signals and acts through various downstream pathways to maintain energy balance. The hypothalamus is a master regulator of satiety, via production of pro-opiomelanocortin (POMC) and CART. POMC undergoes tissue-specific posttranslational cleavage, with the product depending on the endoproteases expressed in the tissue. In humans, leptin stimulates POMC conversion into α-MSH in the arcuate nucleus, which in turn binds to the MC4R, a key receptor involved in appetite control and energy homeostasis. Agouti-related peptide (AgRP) is an antagonist of MC4R. Mice overexpressing AgRP or MC4R knockout mice are hyperphagic and obese [71] and are insensitive to α-MSH. MC4R 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
