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 language | English (US) |
|---|---|
| Pages (from-to) | 610-621 |
| Number of pages | 12 |
| Journal | Cell Metabolism |
| Volume | 23 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 12 2016 |
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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
Cite this
The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome. / He, Baokun; Nohara, Kazunari; Park, Noheon; Park, Yong Sung; Guillory, Bobby; Zhao, Zhaoyang; Garcia, Jose M.; Koike, Nobuya; Lee, Cheng Chi; Takahashi, Joseph S.; Yoo, Seung Hee; Chen, Zheng.
In: Cell Metabolism, Vol. 23, No. 4, 12.04.2016, p. 610-621.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome
AU - He, Baokun
AU - Nohara, Kazunari
AU - Park, Noheon
AU - Park, Yong Sung
AU - Guillory, Bobby
AU - Zhao, Zhaoyang
AU - Garcia, Jose M.
AU - Koike, Nobuya
AU - Lee, Cheng Chi
AU - Takahashi, Joseph S.
AU - Yoo, Seung Hee
AU - Chen, Zheng
PY - 2016/4/12
Y1 - 2016/4/12
N2 - 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.
AB - 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.
KW - circadian clock
KW - clock amplitude-enhancing small molecule
KW - metabolic syndrome
KW - natural flavonoid
KW - Nobiletin
KW - retinoid acid receptor-related orphan receptors (RORs)
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U2 - 10.1016/j.cmet.2016.03.007
DO - 10.1016/j.cmet.2016.03.007
M3 - Article
VL - 23
SP - 610
EP - 621
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 4
ER -