Although MC4RF51L had relatively intact coupling to Gsα/cAMP signaling, mice with homozygous MC4RF51L mutation developed severe obesity associated with hyperphagia and impaired anorectic responses to melanocortin agonist, as well as increased linear growth, without primary effects on cold tolerance, glucose metabolism, or cardiovascular responses to melanocortin administration. This evidence concerns the gene GNAS and obesity due to melanocortin 4 receptor deficiency.