In summary, we have characterized the signaling properties and the physiological consequences of a human obesity-associated MC4R mutation and conclude that this mutation had a defect in the activation of Gq/11α and when introduced into mice led to obesity, hyperphagia, and increased linear growth, with no significant direct effects on glucose metabolism or cardiac function, the latter of which are mediated by Gsα (61). Here, MC4R is linked to obesity disorder.