The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome.
The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome.
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DOI：
10.1016/j.cmet.2016.03.007
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发表时间：
2016-04-12
期刊：
影响因子：
29
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
He B;Nohara K;Park N;Park YS;Guillory B;Zhao Z;Garcia JM;Koike N;Lee CC;Takahashi JS;Yoo SH;Chen Z
昼夜节律失调与代谢功能障碍有关，但尚不清楚增强生物钟功能是否可以改善代谢紊乱。在使用表达PER 2：：Luc的成纤维细胞的无偏化学筛选中，我们鉴定了Nobiletin（NOB），一种天然多甲氧基化黄酮，作为时钟振幅增强小分子（CEM）。当给予饮食诱导的肥胖（DIO）小鼠时，NOB强烈抵消代谢综合征，并以时钟基因依赖的方式增加能量消耗和运动活动。在db/db突变小鼠中，NOB对代谢紊乱的缓解作用也需要时钟。在DIO小鼠肝脏中，NOB增强了时钟蛋白水平，并引起了明显的基因表达重塑。我们将维甲酸受体相关孤儿受体（ROR）确定为NOB的直接靶点，揭示了通过昼夜节律基因网络增强昼夜节律以对抗代谢疾病的药理学干预。
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 (CEM). 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 (RORs) as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.