To further explore the role of MC4R signaling pathways in the regulation of energy balance, we examined in detail the physiological consequences in mice and signaling properties of one mutant MC4R that is associated with early-onset obesity in humans and has been reported to have relatively intact Gsα signaling (MC4RF51L, phenylalanine 51 to leucine) (23). Here, GNAS is linked to obesity due to melanocortin 4 receptor deficiency.