The hunt for the molecular mechanism of brown fat thermogenesis.

This review focuses on research that my colleagues and I carried out from 1972 to 1986 that led to the identification of the original uncoupling protein and the development of the current model for the acute regulation of brown fat thermogenesis. An important consequence of the early stages of this research was the realization that brown fat mitochondria demonstrated the key principles of Peter Mitchell's Chemiosmotic Hypothesis with exquisite precision and simplicity, that a regulatable proton conductance was necessary and sufficient to control respiration and hence thermogenesis, and that fatty acids provided not only the substrate for thermogenesis, but also acted as a self-regulating second (or third) messenger. These studies have provided the basis for 30 years of subsequent research by numerous groups into the structure and mechanism of UCP1, and its role in non-shivering thermogenesis in multiple species, including man.