A Cell-Autonomous Mammalian 12 hr Clock Coordinates Metabolic and Stress Rhythms

Bokai Zhu, Qiang Zhang, Yinghong Pan, Emily M. Mace, Brian York, Athanasios C. Antoulas, Clifford Dacso, Bert W. O'Malley

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


Besides circadian rhythms, oscillations cycling with a 12 hr period exist. However, the prevalence, origin, regulation, and function of mammalian 12 hr rhythms remain elusive. Utilizing an unbiased mathematical approach identifying all superimposed oscillations, we uncovered prevalent 12 hr gene expression and metabolic rhythms in mouse liver, coupled with a physiological 12 hr unfolded protein response oscillation. The mammalian 12 hr rhythm is cell autonomous, driven by a dedicated 12 hr pacemaker distinct from the circadian clock, and can be entrained in vitro by metabolic and ER stress cues. Mechanistically, we identified XBP1s as a transcriptional regulator of the mammalian 12 hr clock. Downregulation of the 12 hr gene expression strongly correlates with human hepatic steatosis and steatohepatitis, implying its importance in maintaining metabolic homeostasis. The mammalian 12 hr rhythm of gene expression also is conserved in nematodes and crustaceans, indicating an ancient origin of the 12 hr clock. Our work sheds new light on how perturbed biological rhythms contribute to human disease.

Original languageEnglish (US)
Pages (from-to)1305-1319.e9
JournalCell Metabolism
Issue number6
StatePublished - Jun 6 2017


  • 12 hr clock
  • C. elegans
  • ER stress
  • UPR
  • XBP1s
  • circatidal clock
  • crustaceans
  • metabolic stress
  • mitochondria
  • nonalcoholic fatty liver diseases

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology


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