Mammalian adipose tissue thermogenesis evolved in eutherian mammals

Heat production in fat tissue, a trait also known as adipose tissue thermogenesis, evolved over two stages in mammals, fully developing in eutherian mammals after the group’s evolutionary divergence from marsupials, according to a new study. The results could provide insights that inform future therapies related to metabolism and obesity. Many organisms produce heat internally to regulate body temperature. It is thought that the evolution of the ability to maintain high body temperatures provided evolutionary advantages, including adaptability to a wider range of environments and the ability to maintain optimal metabolism. For example, brown adipose tissue (BAT), the main organ for nonshivering thermogenesis (NST) in mammals, enables newborns, small-sized species, and hibernators to increase heat output to overcome cold stress. Expression of the thermogenic uncoupling protein 1 (UCP1) is crucial for heat production in BAT thermogenesis. However, while BAT thermogenesis is considered a key trait in eutherian mammals, its evolutionary origin is unknown.

To investigate the evolutionary origins, Susanne Keipert and colleagues employed a comparative genomics approach combined with ancient protein reconstructions. According to Keipert et al., although mouse UCP1 is thermogenic, the adipose tissue of marsupials expresses a nonthermogenic UCP1 variant, and only the ancestral eutherian UCP1 possessed thermogenic capabilities. This finding suggests that UCP1 gained thermogenic activity after the marsupial-eutherian mammal split roughly 150 million years ago. Transcriptome sequencing of marsupial opossum adipose tissue indicates that UCP1-mediated thermogenesis likely involved two stages: a prethermogenic stage where adipose tissue appears to have first undergone a rewiring linking nonthermogenic UCP1 expression in adipose tissue to cold stress in the common therian ancestor. This was followed by the acquisition of thermogenic function only after placental mammals diverged from marsupials. “BAT and beige adipose tissue have undergone an explosion of research in the past 15 years owing to their role as regulators of metabolism and potential for treating human obesity. However, despite their importance in activating NST, human therapies that target the pathways occurring in these tissues remain rare,” write Katherine Grabek and Ryan Sprenger in a related Perspective. “The approach of Keipert et al., using comparative genomics across a wider range of mammals, could thereby provide new insights on NST and endothermy that inform future therapies.”