EVOTHERM · Reconstructing the Molecular Evolution of Non-Shivering Thermogenesis

Non-shivering thermogenesis (NST) is one of the most fascinating evolutionary achievements, enabling high body temperatures and successful radiation of mammals and birds into cold environments. Yet, the evolutionary origin and molecular innovations enabling NST are unknown. Using comparative approaches, my laboratory has recently transformed our view on mammalian NST by demonstrating that the thermogenic function of the mammalian heater protein, uncoupling protein 1 (UCP1), has only emerged late during mammalian evolution in the stem placental ancestor. With this ground-breaking framework, I aim to reconstruct the molecular innovations of UCP1-based NST in placental mammals, and explore the unknown molecular basis of NST in non-placental mammals and birds, thereby advancing our understanding on the evolution of thermogenesis in vertebrates. Specifically, I will 1) Determine critical structure-function motifs of UCP1 that enabled heat production and that have been tuned through placental species radiation to adapt thermoregulatory demands of various ecological niches; 2) Characterize molecular networks governing NST on an evolutionary scale by comparative transcriptomics of extant placental and marsupial heater organs; 3) Explore alternative thermogenic mechanisms in marsupials; 4) Delineate the functional evolution of muscle-based NST in amniotes by reconstructing ancestral key variants of sarcolipin, the proclaimed key player of muscle thermogenesis. In addition to cutting-edge molecular and bioenergetic techniques for assessing thermogenesis, which we have all mastered in my laboratory, our reconstruction of ancestral thermogenic proteins allows us to look back hundreds of millions of years into the evolutionary past of vertebrate thermogenesis. To identify unknown thermogenic mechanisms and consolidate them in vivo, we take advantage of the latest Crispr-CAS technologies to generate unique non-model organisms, such as the first UCP1 knockout marsupial.