Journal
CELL METABOLISM
Volume 23, Issue 4, Pages 610-621Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2016.03.007
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Funding
- Welch Foundation [AU-1731]
- American Heart Association [11SDG7600045]
- NIH/National Institute on Aging [R01AG045828]
- NIH/National Institute of General Medical Sciences [R01 GM114424]
- Texas Medical Center Digestive Disease Center P/F Awards (National Institute of Diabetes and Digestive and Kidney Diseases) [P30-DK056338]
- U.S.A. Department of Veterans Affairs [BX000507, CX000174]
- NIH [AG040583, T32AG000183, NIH/DP1 OD000895]
- JSPS [26293048]
- Uehara Memorial Foundation
- Grants-in-Aid for Scientific Research [26293048] Funding Source: KAKEN
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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.
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