Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
Level 5 - mechanism / opinion, no new human data
Animal mechanistic study (mice) with no human data.
PubMed 36161962 · doi:10.1073/pnas.2205755119
What was done
Investigators evaluated the regulation of ketone body production (beta-hydroxybutyrate, βOHB) in mice subjected to caloric restriction (CR) and time-restricted feeding (TRF). They analyzed daily oscillations in blood and liver βOHB levels alongside hepatic expression of fatty acid oxidation genes, ketogenesis genes, and the PPARα target Fgf21. Molecular interactions between core circadian clock proteins (CLOCK, BMAL1, CRYs) and PPARα transcriptional activity were tested, including validation in circadian clock-deficient Cry1,2 -/- mice.
What was found
CR induced high-amplitude daily rhythms in circulating βOHB that correlated with liver βOHB levels and coincided with circadian expression of fatty acid oxidation, ketogenesis genes, Fgf21, and the PPARα transcriptional network. TRF induced rhythmic βOHB with lower amplitude than CR. Mechanistically, CLOCK, BMAL1, and CRY proteins interfered with PPARα transcriptional activity. In Cry1,2 -/- mice, daily rhythms in blood βOHB levels and PPARα target gene expression were significantly impaired. No exact numerical values or statistics were reported in the abstract.
Why it matters
This study delineates a direct molecular link between core circadian clock machinery and hepatic ketogenesis, demonstrating that daily oscillations in ketone bodies under dietary restriction are clock-regulated via PPARα modulation.
Limits
All findings are derived from mouse models; human translational relevance is untested. The abstract omits sample sizes (n), numerical effect sizes, variance, and exact dietary intervention durations.
Cited by
- supports Mice subjected to time-restricted feeding have elevated levels of ketone bodies.