Neuronal ketone body utilization couples exercise and time-restricted feeding to cognitive enhancement

Objective: Ketone body metabolism is linked to brain health benefits, including delaying age-related cognitive decline. Exercise, particularly when combined with an overnight fast, stimulates ketone body turnover and improves brain metabolism and cognition. Yet, whether ketone metabolism is obligatory for this response is unknown. Here, we use chronic exercise via voluntary wheel running plus time-restricted feeding (VWR + TRF) to explore whether ketones mediate exercise-induced brain health benefits in middle-aged mice. Methods: To distinguish the roles of neuronal ketone metabolism vs. hepatic ketone production, we studied middle-age female neuronal-specific SCOT knockout mice and hepatocyte-specific HMGCS2 knockout mice, respectively. VWR + TRF was compared to sedentary ad-libitum fed mice to assess the impact on whole-body metabolism, cognition, and hippocampal molecular adaptations. VWR + TRF upregulated systemic lipid oxidation in all mice during the fasting period. Results: In female SCOT-Neuron-KO mice, we show impaired responses to VWR + TRF in indices of short- and long-term memory. Proteomic analysis of isolated hippocampi revealed that SCOT-Neuron-KO mice failed to globally upregulate key facilitators of synaptic function, including leucine-rich repeated transmembrane proteins, neurexins, and neuroligins. In female HMGCS2-Liver-KO mice, impaired responses to VWR + TRF in indices of short-term memory were paired with an upregulation in hippocampal ketogenesis machinery, suggesting potential in vivo evidence of cerebral ketogenesis, a mechanism mitigating an otherwise more pronounced behavioral phenotype. Conclusion: Together, these findings suggest that neuronal ketone body utilization is essential for, while hepatic-derived ketone bodies contribute to, the full cognitive and synaptic adaptations to VWR + TRF, supporting ketone metabolism as a key mechanistic link between metabolic state and brain health in midlife.