Potent Effects of Flavonoid Nobiletin on Amplitude, Period, and Phase of the Circadian Clock Rhythm in PER2::LUCIFERASE Mouse Embryonic Fibroblasts

PLoS One. 2017 Feb 2;12(2):e0170904. doi: 10.1371/journal.pone.0170904. eCollection 2017.


Flavonoids are natural polyphenols that are widely found in plants. The effects of flavonoids on obesity and numerous diseases such as cancer, diabetes, and Alzheimer's have been well studied. However, little is known about the relationships between flavonoids and the circadian clock. In this study, we show that continuous or transient application of flavonoids to the culture medium of embryonic fibroblasts from PER2::LUCIFERASE (PER2::LUC) mice induced various modifications in the circadian clock amplitude, period, and phase. Transient application of some of the tested flavonoids to cultured cells induced a phase delay of the PER2::LUC rhythm at the down slope phase. In addition, continuous application of the polymethoxy flavonoids nobiletin and tangeretin increased the amplitude and lengthened the period of the PER2::LUC rhythm. The nobiletin-induced phase delay was blocked by co-treatment with U0126, an ERK inhibitor. In summary, among the tested flavonoids, polymethoxy flavones increased the amplitude, lengthened the period, and delayed the phase of the PER2::LUC circadian rhythm. Therefore, foods that contain polymethoxy flavones may have beneficial effects on circadian rhythm disorders and jet lag.

MeSH terms

  • Animals
  • Cells, Cultured
  • Circadian Rhythm / drug effects*
  • Circadian Rhythm / physiology
  • Fibroblasts / drug effects
  • Fibroblasts / physiology
  • Flavones / administration & dosage
  • Flavones / pharmacology*
  • Flavonoids / administration & dosage
  • Flavonoids / pharmacology
  • Gene Knock-In Techniques
  • Jet Lag Syndrome / drug therapy
  • Jet Lag Syndrome / physiopathology
  • Liver / drug effects
  • Liver / physiology
  • Luciferases / genetics
  • Luciferases / metabolism
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Transgenic
  • Period Circadian Proteins / genetics
  • Period Circadian Proteins / metabolism


  • Flavones
  • Flavonoids
  • Per2 protein, mouse
  • Period Circadian Proteins
  • nobiletin
  • Luciferases

Grant support

This work was partially supported by the Council for Science, Technology, and Innovation; Cross-ministerial Strategic Innovation Promotion Program (SIP); and Technologies for Creating Next-generation Agriculture, Forestry, and Fisheries (funding agency: Bio-oriented Technology Research Advancement Institution, NARO).