Clock Regulation of Metabolites Reveals Coupling between Transcription and Metabolism

Saikumari Y. Krishnaiah, Gang Wu, Brian J. Altman, Jacqueline Growe, Seth D. Rhoades, Faith Coldren, Anand Venkataraman, Anthony O. Olarerin-George, Lauren J. Francey, Sarmistha Mukherjee, Saiveda Girish, Christopher P. Selby, Sibel Cal, Ubeydullah ER, Bahareh Sianati, Arjun Sengupta, Ron C. Anafi, I. Halil Kavakli, Aziz Sancar, Joseph A. BaurChi V. Dang, John B. Hogenesch, Aalim M. Weljie

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)961-974.e4
JournalCell Metabolism
Volume25
Issue number4
DOIs
StatePublished - Apr 4 2017

Keywords

  • LCMS
  • chronometabolism
  • chronopharmacology
  • circadian clock
  • circadian metabolism
  • mass spectrometry
  • metabolomics
  • translational transcription feedback loop

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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