Liu Zhiwei, Huang Moli, Wu Xi, Shi Guangsen, Xing Lijuan, Dong Zhen, Qu Zhipeng, Yan Jie, Yang Ling, Panda Satchidananda, Xu Ying
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing 210061, China.
Cambridge Suda Genome Resource Center, Soochow University, Suzhou 215006, China.
Cell Rep. 2014 Jun 12;7(5):1509-1520. doi: 10.1016/j.celrep.2014.04.032. Epub 2014 May 22.
Organization of circadian behavior, physiology, and metabolism is important for human health. An S662G mutation in hPER2 has been linked to familial advanced sleep-phase syndrome (FASPS). Although the paralogous phosphorylation site S714 in PER1 is conserved in mice, its specific function in circadian organization remains unknown. Here, we find that the PER1S714G mutation accelerates the molecular feedback loop. Furthermore, hPER1S714G mice, but not hPER2S662G mice, exhibit peak time of food intake that is several hours before daily energy expenditure peaks. Both the advanced feeding behavior and the accelerated clock disrupt the phase of expression of several key metabolic regulators in the liver and adipose tissue. Consequently, hPER1S714G mice rapidly develop obesity on a high-fat diet. Our studies demonstrate that PER1 and PER2 are linked to different downstream pathways and that PER1 maintains coherence between the circadian clock and energy metabolism.
昼夜节律行为、生理和新陈代谢的组织对人类健康很重要。hPER2中的S662G突变与家族性早睡综合征（FASPS）有关。尽管PER1中同源的磷酸化位点S714在小鼠中是保守的，但其在昼夜节律组织中的具体功能仍不清楚。在这里，我们发现PER1S714G突变加速了分子反馈回路。此外，hPER1S714G小鼠，而非hPER2S662G小鼠，表现出食物摄入高峰时间比每日能量消耗高峰提前数小时。提前的进食行为和加速的生物钟都会扰乱肝脏和脂肪组织中几种关键代谢调节因子的表达相位。因此，hPER1S714G小鼠在高脂饮食下会迅速肥胖。我们的研究表明，PER1和PER2与不同的下游途径相关联，并且PER1维持昼夜节律钟与能量代谢之间的一致性。
