Why do many mammalian organs including the heart lose regenerative potential during the perinatal window remains enigmatic. Through phylogenetic analysis of non-model vertebrate species and mechanistic studies in zebrafish and mice, we provide evidence to support critical roles of two major thermogenic neurohormonal pathways and a novel downstream transcription factor in suppressing heart regenerative capacity, and implicate that the limited regenerative capacity in various adult mammalian tissues may be a tradeoff for the acquisition of endothermy in ontogeny and phylogeny.