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

Baokun He, Kazunari Nohara, Noheon Park, Yong Sung Park, Bobby Guillory, Zhaoyang Zhao, Jose M. Garcia, Nobuya Koike, Cheng Chi Lee, Joseph S. Takahashi, Seung Hee Yoo, Zheng Chen

Research output: Contribution to journalArticle

135 Scopus citations

Abstract

Summary 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.

Original languageEnglish (US)
Pages (from-to)610-621
Number of pages12
JournalCell Metabolism
Volume23
Issue number4
DOIs
StatePublished - Apr 12 2016

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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    He, B., Nohara, K., Park, N., Park, Y. S., Guillory, B., Zhao, Z., Garcia, J. M., Koike, N., Lee, C. C., Takahashi, J. S., Yoo, S. H., & Chen, Z. (2016). The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. Cell Metabolism, 23(4), 610-621. https://doi.org/10.1016/j.cmet.2016.03.007