Temporal control of metabolic amplitude by Nocturnin

The timing of food intake and nutrient utilization is critical to health and regulated in part by the circadian clock. Recently, increased amplitude of circadian oscillations and metabolic output was found to improve health in diabetic and obesity mouse models. Here, we report a novel function for the circadian deadenylase Nocturnin as a regulator of metabolic amplitude across the day/night cycle and in response to nutrient challenge. We show that mice lacking Nocturnin (Noct-/-) display significantly increased amplitudes of mRNA expression of hepatic genes encoding key metabolic enzymes regulating lipid and cholesterol synthesis, both over the daily circadian cycle and in response to fasting and refeeding. Noct-/- mice have increased plasma triglyceride throughout the night and increased amplitude of hepatic cholesterol levels. Therefore, posttranscriptional control by Nocturnin regulates the amplitude of these critical metabolic pathways and loss of this activity results in increased metabolic flux and reduced obesity. Total RNA was isolated from liver samples of Wildtype (WT) mice and mice lacking Nocturnin (Noct-/-) and the hepatic transcriptome analyzed by mRNA-seq. WT and Noct-/- mice were on a light:dark LD 12:12 cycle and fed standard chow Ad Libitum.进食时机与营养利用对健康至关重要，其调控过程部分由生物钟（circadian clock）介导。近期研究表明，增强生物钟振荡与代谢输出的振幅，可改善糖尿病及肥胖小鼠模型的健康状态。本研究首次揭示了昼夜节律脱腺苷酶诺特林（Nocturnin）的全新功能：其可调控昼夜周期及营养应激下的代谢振幅。 研究表明，缺失诺特林的小鼠（Noct-/-），其肝脏中编码调控脂质与胆固醇合成关键代谢酶的基因的mRNA表达振幅，在昼夜节律周期及禁食-复食应激下均显著升高。Noct-/-小鼠夜间血浆甘油三酯水平持续升高，且肝脏胆固醇水平的振荡振幅显著增强。由此可见，诺特林介导的转录后调控可维持上述关键代谢通路的振幅，而该功能缺失会导致代谢流增加并缓解肥胖。 本研究从野生型（Wildtype, WT）小鼠及诺特林缺失型（Noct-/-）小鼠的肝脏样本中提取总RNA，并通过mRNA测序（mRNA-seq）分析肝脏转录组。所有WT及Noct-/-小鼠均饲养于12小时光照/12小时黑暗（LD 12:12）的光周期环境中，并自由采食标准啮齿类饲料。