title: The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Baokun
authors.initials: B
authors.lastname: He
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Kazunari
authors.initials: K
authors.lastname: Nohara
authors.affiliation: Department of Neuroscience, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
authors.forename: Noheon
authors.initials: N
authors.lastname: Park
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Yong-Sung
authors.initials: YS
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Bobby
authors.initials: B
authors.lastname: Guillory
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Garcia
authors.affiliation: Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Koike
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Cheng Chi
authors.initials: CC
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Takahashi
authors.affiliation: Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA.
authors.forename: Seung-Hee
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: 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.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
mesh_terms: D000818:Animals; D002940:Circadian Rhythm / Q000187:drug effects*; D047309:Flavones / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D024821:Metabolic Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D047309:Flavones; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539739:Rora protein, mouse; C008661:nobiletin
keywords: Nobiletin; circadian clock; clock amplitude-enhancing small molecule; metabolic syndrome; natural flavonoid; retinoid acid receptor-related orphan receptors (RORs)