Mammalian cellular machinery has evolved to function best at ~37 °C, making maintenance of core body temperature (at ~37 °C) critical for optimal organ function. The physiological importance of thermoregulation has been appreciated for many years, but our mechanistic understanding of the diversity and functioning of thermogenic mechanisms has advanced considerably in the past century. A brief analysis by Prusiner and Poe (published in 1968) marked a pivotal shift in thermoregulation research, transitioning from a coarse physiological perspective to biochemical interpretations of thermogenic pathways.

In the thermoneutral zone, core body temperature is sustained with minimal metabolic effort, facilitated by anatomical features and baseline metabolism. The thermoneutral zone is a subjective temperature range that might be around 20–22 °C for a lean, lightly clothed man. When environmental temperatures drop below the thermoneutral zone, the body activates a series of thermoregulatory mechanisms to preserve core temperature and re-establish thermal homeostasis. Physiologically, thermogenic mechanisms are classified as shivering thermogenesis, which occurs in muscle, and non-shivering thermogenesis (NST). NST comprises a group of processes that use different energy sources and mechanisms that ultimately converge in the release of heat. Prusiner and Poe distinguished the molecular mechanisms of thermogenic pathways and proposed a classification scheme based on the biochemical origins of metabolic heat rather than a one based on physiology. In addition, several other suggestions presented in their paper have had lasting implications for ongoing research on futile cycles and thermogenesis. Specifically, the authors highlighted two points that remain relevant for contemporary studies: first, the relative thermogenic contribution of ATP synthesis versus ATP hydrolysis, and second, the thermogenic role of the ATP-consuming futile cycle.