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Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism.

Cell metabolism | Apr 4, 2017

The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, ∼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.

Pubmed ID: 28380384 RIS Download

Mesh terms: Animals | Cell Line, Tumor | Cells, Cultured | Circadian Clocks | Circadian Rhythm | Creatine | Cryptochromes | Gene Regulatory Networks | Hepatocytes | Humans | Liver | Metabolome | Mice | Nitrogen | Time Factors | Transcription, Genetic

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Associated grants

  • Agency: NIDDK NIH HHS, Id: R01 DK098656
  • Agency: NCI NIH HHS, Id: K99 CA204593
  • Agency: NIGMS NIH HHS, Id: R35 GM118102
  • Agency: NCI NIH HHS, Id: R01 CA057341
  • Agency: NCI NIH HHS, Id: P30 CA016086
  • Agency: NIGMS NIH HHS, Id: R01 GM031082
  • Agency: NCATS NIH HHS, Id: UL1 TR000003
  • Agency: NCI NIH HHS, Id: R01 CA051497
  • Agency: NINDS NIH HHS, Id: R01 NS054794
  • Agency: NCI NIH HHS, Id: F32 CA180370
  • Agency: NIA NIH HHS, Id: R01 AG043483

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