Circadian clock controls rhythms in ketogenesis by interfering with PPARα transcriptional network.
Volha MezhninaOghogho P EbeigbeNikkhil VelingkaarAllan PoeYana SandlersRoman V KondratovPublished in: Proceedings of the National Academy of Sciences of the United States of America (2022)
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 [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic βOHB 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 α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. Fgf21 expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock-deficient Cry1,2 -/- mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.
Keyphrases
- transcription factor
- fatty acid
- insulin resistance
- poor prognosis
- gene expression
- physical activity
- heat shock
- randomized controlled trial
- binding protein
- weight loss
- high glucose
- diabetic rats
- genome wide identification
- genome wide
- high fat diet induced
- adipose tissue
- type diabetes
- long non coding rna
- ms ms
- resting state
- big data
- skeletal muscle
- blood pressure
- artificial intelligence
- functional connectivity
- deep learning
- heat shock protein