@article{17aabe66b6de4664a414abaebbec6fcf,
title = "The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome",
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.",
keywords = "Nobiletin, circadian clock, clock amplitude-enhancing small molecule, metabolic syndrome, natural flavonoid, retinoid acid receptor-related orphan receptors (RORs)",
author = "Baokun He and Kazunari Nohara and Noheon Park and Park, {Yong Sung} and Bobby Guillory and Zhaoyang Zhao and Garcia, {Jose M.} and Nobuya Koike and Lee, {Cheng Chi} and Takahashi, {Joseph S.} and Yoo, {Seung Hee} and Zheng Chen",
note = "Funding Information: We thank C. Lee for reagent; C. Stephan, E. Song, C. Ayoub, and T.M. Tran for technical support; and S. McKnight, C. Green, M. Bogdanov, G. Lee, D. Marshak, C. Wu, P. Griffin, R. Garcia-Ordonez, and G. Gloston for helpful advice and/or critical reading of the manuscript. This work is supported in part by The Welch Foundation (AU-1731), the American Heart Association (11SDG7600045), and the NIH/National Institute on Aging (R01AG045828) to Z.C., NIH/National Institute of General Medical Sciences (R01 GM114424) to S.-H.Y., Texas Medical Center Digestive Disease Center P/F Awards (National Institute of Diabetes and Digestive and Kidney Diseases Center Grant P30-DK056338) to S.-H.Y. and Z.C., U.S.A. Department of Veterans Affairs, BX000507 and CX000174; and NIH AG040583 to J.M.G., T32AG000183 to B.G., NIH/DP1 OD000895 to C.C.L., and JSPS KAKENHI (26293048) and the Uehara Memorial Foundation to N.K. J.S.T. is an Investigator in the Howard Hughes Medical Institute. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",
year = "2016",
month = apr,
day = "12",
doi = "10.1016/j.cmet.2016.03.007",
language = "English (US)",
volume = "23",
pages = "610--621",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}