PMID- 36161962
OWN - NLM
STAT- MEDLINE
DCOM- 20220928
LR  - 20230327
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 119
IP  - 40
DP  - 2022 Oct 4
TI  - Circadian clock controls rhythms in ketogenesis by interfering with PPARalpha 
      transcriptional network.
PG  - e2205755119
LID - 10.1073/pnas.2205755119 [doi]
LID - e2205755119
AB  - 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 [betaOHB]) that correlated with liver betaOHB level. 
      Time-restricted feeding, another periodic fasting-based diet, also led to 
      rhythmic betaOHB 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 (PPARalpha) and 
      its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are 
      primary regulators of ketogenesis. Fgf21 expression and the PPARalpha 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 PPARalpha transcriptional activity. 
      Daily rhythms in the blood betaOHB level and in the expression of PPARalpha target genes 
      were significantly impaired in circadian clock-deficient Cry1,2(-/-) mice. These 
      data suggest that blood betaOHB level is tightly controlled and that the circadian 
      clock is a regulator of diet-induced ketogenesis.
FAU - Mezhnina, Volha
AU  - Mezhnina V
AD  - Center for Gene Regulation in Health and Disease and Department of Biological 
      Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 
      44115.
FAU - Ebeigbe, Oghogho P
AU  - Ebeigbe OP
AD  - Center for Gene Regulation in Health and Disease and Department of Biological 
      Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 
      44115.
FAU - Velingkaar, Nikkhil
AU  - Velingkaar N
AUID- ORCID: 0000-0003-1571-0833
AD  - Center for Gene Regulation in Health and Disease and Department of Biological 
      Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 
      44115.
FAU - Poe, Allan
AU  - Poe A
AUID- ORCID: 0000-0003-2151-9074
AD  - Center for Gene Regulation in Health and Disease and Department of Biological 
      Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 
      44115.
FAU - Sandlers, Yana
AU  - Sandlers Y
AD  - Department of Chemistry, Cleveland State University, Cleveland, OH 44115.
FAU - Kondratov, Roman V
AU  - Kondratov RV
AUID- ORCID: 0000-0003-3449-745X
AD  - Center for Gene Regulation in Health and Disease and Department of Biological 
      Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 
      44115.
LA  - eng
GR  - R01 AG039547/AG/NIA NIH HHS/United States
GR  - S10 OD010381/OD/NIH HHS/United States
GR  - S10 OD025252/OD/NIH HHS/United States
GR  - R01AG039547/HHS | NIH | National Institute on Aging (NIA)/
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20220926
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (ARNTL Transcription Factors)
RN  - 0 (Cryptochromes)
RN  - 0 (Ketone Bodies)
RN  - 0 (PPAR alpha)
RN  - TZP1275679 (3-Hydroxybutyric Acid)
SB  - IM
MH  - 3-Hydroxybutyric Acid/metabolism
MH  - ARNTL Transcription Factors/genetics/metabolism
MH  - Animals
MH  - *Circadian Clocks/genetics
MH  - Circadian Rhythm/genetics
MH  - Cryptochromes/metabolism
MH  - *Gene Regulatory Networks
MH  - *Ketone Bodies/metabolism
MH  - Liver/metabolism
MH  - Mice
MH  - *PPAR alpha/genetics/metabolism
PMC - PMC9546578
OTO - NOTNLM
OT  - aging
OT  - caloric restriction
OT  - circadian rhythms
OT  - fatty acid metabolism
OT  - metabolism
COIS- The authors declare no competing interest.
EDAT- 2022/09/27 06:00
MHDA- 2022/09/28 06:00
PMCR- 2023/03/26
CRDT- 2022/09/26 18:36
PHST- 2022/09/26 18:36 [entrez]
PHST- 2022/09/27 06:00 [pubmed]
PHST- 2022/09/28 06:00 [medline]
PHST- 2023/03/26 00:00 [pmc-release]
AID - 202205755 [pii]
AID - 10.1073/pnas.2205755119 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2205755119. doi: 
      10.1073/pnas.2205755119. Epub 2022 Sep 26.