Functional variants of the melanocortin-4 receptor associated with the Odontoceti and Mysticeti suborders of cetaceans

Cetaceans, a group of mammals adapted to the aquatic environment that descended from terrestrial artiodactyls, exhibit tremendous interspecific differences in a number of phenotypes, including feeding behavior, such as filter feeding in the Mysticeti vs prey-hunting Odontoceti, and size, with the smallest cetacean, the vaquita, at 1.4 meters and the largest, the blue whale, reaching 33 meters. The Melanocortin-4 receptor (MC4R) regulates food intake, energy balance, and somatic growth in both mammals and teleosts. In this study, we examined allelic variants of the MC4R in cetaceans. We sequenced the MC4R from 20 cetaceans, and pharmacologically characterized 17 of these protein products. Results identified a single variation at amino acid 156 in the MC4R from representative species of major cetacean lineages uniquely associated with the toothed whales or Odontoceti (arginine at 156) and baleen whales or Mysticeti (glutamine at 156). The Q156 receptor variant found in the larger baleen whales was functionally less responsive to its endogenous anorexigenic ligand, α-MSH. Furthermore, the R156 receptor variant showed greater constitutive activity and a higher affinity for ligand. These data suggest that the MC4R may be one gene involved in the evolution of feeding ecology, energy balance, and body size in cetaceans.