mTOR 信號調節中樞和外周生物鐘

 ॐ↑ HACS ↑ ॐ

|文章標題：

mTOR signaling regulates central and peripheral circadian clock function.

|核心內容：

生物鐘協調生理和新陳代謝的各項平衡。mTOR (哺乳動物/機械性雷帕黴素靶標)是一種主要的細胞內傳感器，它整合了營養和能量狀態來調節蛋白質合成、代謝和細胞生長。以前的研究已經證實 mTOR 在調節視交叉上核中樞生物鐘的感光卷吸和同步化過程中起著關鍵作用。鑑於 mTOR 活動在包括 SCN 在內的各種組織和細胞中表現出強大的晝夜節律振蕩，我們在這裡繼續研究 mTOR 在協調中樞和外周晝夜振蕩器的自主生物鐘功能中的作用。

抑制mTOR會延長周期，降低振幅

結合遺傳學和藥理學的方法，我們發現 mTOR 調節內在的時鐘特性，包括周期和振幅。在肝細胞和脂肪細胞周圍生物鐘模型中，mTOR 抑制延長周期和抑制振幅，而 mTOR 活化縮短周期和增加振幅。Tsc2-/-成纖維細胞中 mTOR 的組成性激活提高了包括 CRY1、 BMAL1和 CLOCK 在內的核心鍾蛋白水平。血清刺激誘導成纖維細胞 CRY1上調，呈 mTOR 依賴但 Bmal1-和周期無關的方式。與細胞生物鐘模型的結果一致，mTOR 擾動也調節體外 SCN 和肝臟生物鐘的周期和振幅。此外，mTOR 雜合子小鼠在恆定的黑暗和恆定的光照條件下都表現出運動活動的晝夜節律時間延長。綜上所述，這些結果支持了 mTOR 在晝夜節律計時和連接代謝狀態和晝夜節律生物鐘功能方面的重要作用。

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.

參考文獻：https://dx.doi.org/10.1371/journal.pgen.1007369

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