Cetacean loss of the master adipose tissue regulator β3-adrenergic receptor may underlie their thick blubber and an Oligocene radiation and dispersal

Blubber is a hydrostatic pressure-resistant and insulating vascularized layer of subcutaneous adipose tissue beneath the skin found in cetaceans, pinnipeds, and sirenians. Little is known about the molecular genetics of blubber formation, and it is unclear when the blubber observed today began to develop during the evolution of the marine mammal groups. Here we screen for genes lost in cetaceans and find that ADRB3 (β₃-adrenergic receptor), a gene essential for adipose tissue lipolysis and thermogenesis, acquired inactivating mutations in crown cetaceans 20 million years after its downstream effector uncoupling protein 1 (UCP1) gained partial loss-of-function mutations in semi-aquatic stem cetaceans. Both in vivo and in vitro experiments indicate that cetacean ADRB3 is not functional, suggesting that crown cetaceans abolished cold-induced non-shivering thermogenesis to favor lipid storage for thermal insulation. Our study supports that cetacean blubber evolved stepwise along their transition to an aquatic environment and implies that ADRB3 loss was critical for the radiation and dispersal of toothed and baleen whales.