Objectives: Brown adipose tissue (BAT) dissipates the energy of circulating metabolites into heat and this capacity can be leveraged to combat obesity and its associated metabolic complications. Common dietary weight-loss interventions such as ketogenic diet (KD) or intermittent fasting involve ketogenesis, thus making ketones a major contributor to fuel supply. We hypothesized that ketones fuel BAT thermogenesis in ketosis and inhibition of hepatic ketogenesis or BAT utilization of ketone diminishes thermogenesis.
Methods: To establish the dispensability of ketogenesis for BAT thermogenesis, liver-specific HMGCS2 (rate-limiting enzyme for ketogenesis) KO mice and WT controls were cold-challenged (fasted). Compensatory routes in the absence of ketogenesis were determined in two separate experiments by inhibiting fatty acids (FAs) uptake and glycolysis followed by a cold tolerance test. Ketone levels were measured in BAT-deficient (Myf5-Cre+; Ppargflox/flox) models after an overnight fast. BAT-specific OXCT1 KO (key enzyme for ketolysis) mice were characterized under different ketotic states including KD and streptozotocin (STZ)-induced diabetes. Additionally, BAT dysfunction was developed by housing OXCT1 KO animals at thermoneutrality (TN) or by aging them.
Results: HMGCS2 KO mice were cold insensitive, but inhibition of FAs uptake or glycolysis rendered these animals more sensitive to cold. BAT paucity induced by PPARγ KO resulted in higher levels of ketone. Loss of OXCT1-dependent ketolysis in BAT did not affect ketone levels in KD or STZ, but it improved cold tolerance in KD. Moreover, OXCT1-KO mice were prone to develop ketosis when BAT function is impaired by TN and aging.
Conclusions: Loss of hepatic ketogenesis requires mice to compensatorily utilize fatty acids and glucose for BAT thermogenesis to maintain body temperature. Under ketogenic conditions, BAT is a major consumer of circulating ketones via terminal oxidation or yet-to-be-characterized alternative metabolic pathways. Understanding the regulatory role of ketones in BAT thermogenesis extends and refines common dietary interventions to better tackle metabolic disorders.
Funding Sources: This work was partially supported by NIH R01 AI139420, R01 AI162791, and the Integrative Biology & Physiology Accelerator Program.
