The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome

Cell Metab. 2016 Apr 12;23(4):610-21. doi: 10.1016/j.cmet.2016.03.007.


Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.

Keywords: Nobiletin; circadian clock; clock amplitude-enhancing small molecule; metabolic syndrome; natural flavonoid; retinoid acid receptor-related orphan receptors (RORs).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Circadian Rhythm / drug effects*
  • Flavones / pharmacology
  • Flavones / therapeutic use*
  • Gene Expression Regulation / drug effects
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology
  • Metabolic Syndrome / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism


  • Flavones
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • Rora protein, mouse
  • nobiletin