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

Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high -amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [beta OHB]) that correlated with liver beta OHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic beta OHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor alpha (PPAR alpha) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are pri-mary regulators of ketogenesis. Fgf21 expression and the PPAR alpha transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circa-dian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and crypto-chromes (CRYs) interfered with PPAR alpha transcriptional activity. Daily rhythms in the blood beta OHB level and in the expression of PPAR alpha target genes were significantly impaired in circadian clock-deficient Cry1,22(-/-) mice. These data suggest that blood beta OHB level is tightly controlled and that the circadian clock is a regulator of diet -induced ketogenesis.

Automated summary

The study reveals that caloric restriction and time-restricted feeding can induce rhythmic production of ketone bodies in the blood, which is regulated by PPARα and FGF21 and involves the circadian clock.