Ketones Improve the Mitochondrial Coupling Efficiency of Brown Adipocytes

Brown adipose tissue (BAT) thermogenesis is an energy-demanding response, and this capacity can be leveraged to dissipate excess energy in obesity and its associated metabolic complications. Therefore, understanding the regulatory mechanisms of BAT mitochondrial uncoupling and thermogenesis is crucial. Ketone bodies are endogenous metabolites mainly found during starvation and carbohydrate restriction; however, their regulatory role on BAT thermogenesis is elusive. In this study, we aim to investigate the potential metabolic reprogramming induced by ketones on BAT. We hypothesize that ketones are alternative fuels for BAT during energy/carbohydrate shortage and decrease mitochondrial uncoupling to counterbalance the systemic energy deficit. In mice, ketogenic diet reduces core body temperature by 0.4˚C. Using Seahorse respirometry in differentiated brown adipocytes, we found that ketones improve mitochondrial coupling efficiency (ATP-linked respiration/ basal respiration) by 30%, implying an attempt to decrease thermogenesis. The gene Oxct1, encoding succinyl-CoA:3-ketoacid CoA transferase that is required for ketolysis, is abundantly expressed by brown adipocytes. BAT-specific Oxct1 knockout renders mice more resistant to cold-induced decrease in core body temperature during fasting or ketogenic diet, via mechanisms independent of UCP1. Together, our data suggest that ketones potentially communicate hunger to brown adipocytes, thus promoting mitochondrial coupling efficiency for energy conservation.