Circadian clock controls rhythms in ketogenesis by interfering with PPARa transcriptional network

Ketone bodies, intermediates in energy metabolism and signaling, have attracted significant attention due to their role in health and disease. We performed around the clock study on ketone bodies and ketogenesis with mice on different diets. We found that caloric restriction, a dietary intervention that improves metabolism and longevity, induced high amplitude circadian rhythms in blood ßOHB. The blood ßOHB rhythms resulted from rhythmic ketogenesis in the liver controlled by the interaction between the circadian clock and PPAR? transcriptional networks. This interaction results in transcriptional reprogramming of in beta-oxidation and ketogenesis enzymes. The reprogramming is impaired in circadian clock mutant mice. The circadian clock gated ketogenesis contributes to the diet impact on health and longevity. Overall design: RNA-seq analysis of liver transcriptome of mice on calorie restriction (CR) diet versus ad libitum (AL) fed mice.