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

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

Author information

1
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
2
Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
3
Division of Endocrinology, Diabetes and Metabolism, MCL, Center for Translational Research in Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, and Department of Medicine, and Molecular and Cell Biology, Dan L. Duncan Cancer Center, Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA.
4
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
5
Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA; Howard Hughes Medical Institute, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
6
Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA. Electronic address: zheng.chen.1@uth.tmc.edu.

Abstract

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)

Comment in

PMID:
27076076
PMCID:
PMC4832569
DOI:
10.1016/j.cmet.2016.03.007
[Indexed for MEDLINE]
Free PMC Article

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