A critical assessment of the role of creatine in brown adipose tissue thermogenesis

Brown adipose tissue is specialized for non-shivering thermogenesis, combining lipolysis with an extremely active mitochondrial electron transport chain and a unique regulated uncoupling protein, UCP1, allowing unrestricted respiration. Current excitement focuses on the presence of brown adipose tissue in humans and the possibility that it may contribute to diet-induced thermogenesis, countering obesity and obesity-related disease as well as protecting cardio-metabolic health. In common with other tissues displaying a high, variable respiration, the tissue possesses a creatine pool and mitochondrial and cytosolic creatine kinase isoforms. Genetic and pharmacological manipulation of these components have pleiotropic effects that appear to influence diet- and cold-induced metabolism in vivo and modeled in vitro. These findings have been used to advance the concept of a UCP1-independent diet-induced thermogenic mechanism based on a dissipative hydrolysis of phosphocreatine in beige and brown adipose tissue. Here we review the in vivo and in vitro experimental basis for this hypothesis, and explore alternative explanations. We conclude that there is currently no convincing evidence for a significant futile creatine cycle in these tissues.