ADA Scientific Sessions 2025 Abstract · Jun 13, 2025
A Liver–Brown Fat Ketone Shuttle for Adaptive Thermogenesis
By MOAZZAMI Z, QUEATHEM E, CRAWFORD PA et al.
Introduction and Objective: During fasting, mammals decrease energy expending activities including thermogenesis by brown adipose tissue (BAT). However, it is unclear how BAT rewires its metabolism to simultaneously achieve energy conservation and body temperature maintenance in face of nutrient deprivation and cold stress. Here, we report that the utilization of liver-derived ketone bodies by BAT supports physiological adaptation to fasting. Methods: Metabolomics of arterial and venous blood collected from the left ventricle and the Sulzer’s vein, respectively, was carried out to determine nutrient flux in BAT. Liver-specific knockout of ketogenesis enzyme 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) and BAT-specific knockout of ketolysis enzyme 3-oxoacid CoA-transferase 1 (OXCT1) were generated in mice to perform a supply-demand analysis of ketones in BAT thermogenesis upon acute fasting and long-term intermittent fasting. Results: Compared to fed mice housed at room temperature, BAT from mice exposed to fasting and cold consumed more ketone bodies including acetoacetate (AcAc) and D-β-hydroxybutyrate (D-βOHB). Hepatic HMGCS2 deficiency sensitized animals to induced hypothermia, specifically when glucose and fatty acid metabolism was inhibited. Consumption of ketones by BAT contributed to systemic ketone clearance. OXCT1-dependent ketone flux into lipid elongation and desaturation in BAT safeguarded fasting-induced body temperature maintenance and ameliorated side effects associated with intermittent fasting. Conclusion: Fuel-switching to liver-produced ketone bodies in BAT during fasting confers survival advantage to mammals. Disclosure: Z. Moazzami: None. E. Queathem: None. P.A. Crawford: None. H. Ruan: None.