Nobiletin protects against metabolic syndrome by enhancing circadian rhythms  

作　　者：HE Bao-kun 

机构地区：[1]Department of Gastroenterology,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine [2]Shanghai Key Laboratory of Pancreatic disease,Shanghai General Hospital,Shanghai Jiao Tong University School of Medicine

出　　处：《中国药理学与毒理学杂志》2019年第9期686-687,共2页Chinese Journal of Pharmacology and Toxicology

摘　　要：OBJECTIVE Dysregulation of circadian rhythms is associated with metabolic dysfunction,yet it is unclear whether enhancing clock function by small molecules can ameliorate metabolic disorders.METHODS We used an unbiased chemical screen in fibroblasts expressing PER2::Luc to identify the Clock amplitude-Enhancing Small Mole⁃cule.In diet-induced obese mice and DB/DB mutant mice,we evaluated the effects of the Clock amplitude-Enhancing small Molecule on metabolic syndrome and locomotor activity.RESULTS We identified Nobiletin(NOB),a natural poly⁃methoxylated flavone,as a Clock amplitude-Enhancing Small Molecule by an unbiased chemical screen.In diet-induced obese mice,NOB strongly improved metabolic syndrome and enhanced locomotor activity in a Clock gene-dependent manner.Moreover,the clock is also required for the beneficial effects of NOB on metabolic disorders in DB/DB mutant mice.Notably,NOB enhanced clock protein levels and reprogramed metabolic gene expressions in the liver.Finally,we revealed retinoid acid receptor-related orphan receptors(RORα/γ)as direct targets of NOB.CONCLUSION Altogether,our results demonstrate that a pharmacological intervention that enhances circadian rhythms by small molecule may be as a novel strategy for combating metabolic disease.OBJECTIVE Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function by small molecules can ameliorate metabolic disorders. METHODS We used an unbiased chemical screen in fibroblasts expressing PER2:: Luc to identify the Clock amplitude-Enhancing Small Molecule. In diet-induced obese mice and DB/DB mutant mice, we evaluated the effects of the Clock amplitude-Enhancing small Molecule on metabolic syndrome and locomotor activity. RESULTS We identified Nobiletin(NOB), a natural polymethoxylated flavone, as a Clock amplitude-Enhancing Small Molecule by an unbiased chemical screen. In diet-induced obese mice, NOB strongly improved metabolic syndrome and enhanced locomotor activity in a Clock gene-dependent manner. Moreover, the clock is also required for the beneficial effects of NOB on metabolic disorders in DB/DB mutant mice. Notably, NOB enhanced clock protein levels and reprogramed metabolic gene expressions in the liver. Finally, we revealed retinoid acid receptor-related orphan receptors(RORα/γ) as direct targets of NOB. CONCLUSION Altogether,our results demonstrate that a pharmacological intervention that enhances circadian rhythms by small molecule may be as a novel strategy for combating metabolic disease.

关 键 词：NOBILETIN circadian rhythms metabolic syndrome RORα/γreceptors 

分 类 号：X70[环境科学与工程—环境工程]