mTOR signaling regulates central and peripheral circadian clock function.
mTOR signaling regulates central and peripheral circadian clock function.
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DOI：
10.1371/journal.pgen.1007369
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发表时间：
2018-05
期刊：
影响因子：
4.5
通讯作者：
Liu AC
中科院分区：
文献类型：
--
作者：
Ramanathan C;Kathale ND;Liu D;Lee C;Freeman DA;Hogenesch JB;Cao R;Liu AC
生物钟协调生理和新陈代谢。mTOR（mammalian/mechanistic target of rapamycin）是一种主要的细胞内传感器，其整合营养和能量状态以调节蛋白质合成、代谢和细胞生长。先前的研究已经确定了mTOR在调节视交叉上核（SCN）中的光夹带和中央昼夜节律钟的同步中的关键作用。鉴于mTOR活性在包括SCN在内的各种组织和细胞中表现出强大的昼夜节律振荡，在此我们继续研究mTOR在中枢和外周昼夜节律振荡器中协调自主时钟功能的作用。使用遗传和药理学方法的组合，我们表明，mTOR调节内在的时钟特性，包括周期和幅度。在肝细胞和脂肪细胞的外周时钟模型中，mTOR抑制延长周期并抑制振幅，而mTOR激活缩短周期并增加振幅。Tsc 2-/-成纤维细胞中mTOR的组成性激活提高了核心时钟蛋白的水平，包括CLOCK 1，BMAL 1和CLOCK。血清刺激以mTOR依赖性但Bmal 1和Period独立的方式诱导成纤维细胞中的Bmal 1上调。与细胞时钟模型的结果一致，mTOR扰动还调节离体SCN和肝脏时钟的周期和幅度。此外，mTOR杂合小鼠在恒定黑暗和恒定光照下均显示出运动活动的昼夜节律周期延长。总之，这些结果支持mTOR在昼夜节律计时和将代谢状态与昼夜节律钟功能联系起来方面的重要作用。生物钟协调动物的日常生理和代谢。人们对确定将代谢信号与昼夜节律时间保持联系起来的机制产生了相当大的兴趣。mTOR（mammalian/mechanistic target of rapamycin）是一种主要的细胞内传感器，其将营养和能量状态整合到基本细胞过程中。先前的研究已经确定了mTOR在调节视交叉上核（SCN）中的光夹带和中央昼夜节律钟的同步中的关键作用。鉴于mTOR活动在包括SCN在内的各种细胞和组织中表现出强大的昼夜节律，在这里我们研究了mTOR在协调中枢和外周昼夜节律钟中的自主功能中的作用。使用遗传和药理学方法的组合，我们表明mTOR抑制减慢了生物钟并抑制了时钟振荡，而mTOR激活则加速了细胞，组织以及小鼠中的时钟并增强了时钟振荡。总之，这些结果支持mTOR在将代谢状态与昼夜节律时间保持联系起来方面的重要作用。
The circadian clock coordinates physiology and metabolism. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to regulate protein synthesis, metabolism, and cell growth. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian oscillations in a variety of tissues and cells including the SCN, here we continued to investigate the role of mTOR in orchestrating autonomous clock functions in central and peripheral circadian oscillators. Using a combination of genetic and pharmacological approaches we show that mTOR regulates intrinsic clock properties including period and amplitude. In peripheral clock models of hepatocytes and adipocytes, mTOR inhibition lengthens period and dampens amplitude, whereas mTOR activation shortens period and augments amplitude. Constitutive activation of mTOR in Tsc2–/–fibroblasts elevates levels of core clock proteins, including CRY1, BMAL1 and CLOCK. Serum stimulation induces CRY1 upregulation in fibroblasts in an mTOR-dependent but Bmal1- and Period-independent manner. Consistent with results from cellular clock models, mTOR perturbation also regulates period and amplitude in the ex vivo SCN and liver clocks. Further, mTOR heterozygous mice show lengthened circadian period of locomotor activity in both constant darkness and constant light. Together, these results support a significant role for mTOR in circadian timekeeping and in linking metabolic states to circadian clock functions. The circadian clock coordinates daily physiology and metabolism in animals. There has been considerable interest in identifying mechanisms that link metabolic signals to circadian time keeping. mTOR (mammalian/mechanistic target of rapamycin) is a major intracellular sensor that integrates nutrient and energy status to fundamental cellular processes. Previous studies have identified a key role for mTOR in regulating photic entrainment and synchrony of the central circadian clock in the suprachiasmatic nucleus (SCN). Given that mTOR activities exhibit robust circadian rhythms in a variety of cells and tissues including the SCN, here we investigated the role of mTOR in orchestrating autonomous functions in central and peripheral circadian clocks. Using a combination of genetic and pharmacological approaches we show that mTOR inhibition slows down the circadian clock and dampens clock oscillations, whereas mTOR activation accelerates the clock and enhances clock oscillations in cells, tissues as well as in mice. Together, these results support a significant role for mTOR in linking metabolic states to circadian time keeping.
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影响因子：
16.2
作者：
Cao R;Robinson B;Xu H;Gkogkas C;Khoutorsky A;Alain T;Yanagiya A;Nevarko T;Liu AC;Amir S;Sonenberg N
通讯作者：
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影响因子：
4.8
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影响因子：
64.5
作者：
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通讯作者：
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