Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 76100, Israel.
Institute of Biochemistry, Food Science and Nutrition, Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, 76100, Israel.
Mol Cell Endocrinol. 2021 Feb 5;521:111108. doi: 10.1016/j.mce.2020.111108. Epub 2020 Dec 5.
REV-ERBα is a nuclear receptor that inhibits Bmal1 transcription as part of the circadian clock molecular mechanism. Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) is a master regulator of cell and whole-body energy homeostasis, that serves as an important link between metabolism and circadian clock, in part, by regulating BMAL1 activity. While the connection of REV-ERBα to the circadian clock molecular mechanism is well characterized, the interaction between mTORC1, REV-ERBα and the circadian clock machinery is not very clear. We used leucine and rapamycin to modulate mTORC1 activation and evaluate this effect on circadian rhythms. In the liver, mTORC1 was inhibited by leucine. REV-ERBα overexpression activated the mTORC1 signaling pathway via transcription inhibition of mTORC1 inhibitor, Tsc1, antagonizing the effect of leucine, while its silencing downregulated mTORC1 signaling. Activation of mTORC1 led to increased BMAL1 phosphorylation. Activation as well as inhibition of mTORC1 led to altered circadian rhythms in mouse muscle. Inhibition of liver mTORC1 by leucine or rapamycin led to low-amplitude circadian rhythms. In summary, our study shows that leucine inhibits liver mTORC1 pathway leading to dampened circadian rhythms. REV-ERBα activates the mTORC1 pathway, leading to phosphorylation of the clock protein BMAL1.
REV-ERBα 是一种核受体，作为昼夜节律分子机制的一部分，它抑制 Bmal1 转录。雷帕霉素靶蛋白（mTOR）复合物 1（mTORC1）是细胞和全身能量稳态的主要调节剂，部分通过调节 BMAL1 活性，作为代谢和昼夜节律之间的重要联系。虽然 REV-ERBα 与昼夜节律分子机制的联系已经得到很好的描述，但 mTORC1、REV-ERBα 和昼夜节律机制之间的相互作用还不是很清楚。我们使用亮氨酸和雷帕霉素来调节 mTORC1 的激活，并评估其对昼夜节律的影响。在肝脏中，亮氨酸抑制 mTORC1。REV-ERBα 通过转录抑制 mTORC1 抑制剂 Tsc1 来激活 mTORC1 信号通路，拮抗亮氨酸的作用，而其沉默则下调 mTORC1 信号。mTORC1 的激活导致 BMAL1 磷酸化增加。mTORC1 的激活和抑制导致小鼠肌肉中的昼夜节律发生变化。亮氨酸或雷帕霉素抑制肝脏 mTORC1 导致昼夜节律振幅降低。总之，我们的研究表明，亮氨酸抑制肝脏 mTORC1 途径，导致昼夜节律减弱。REV-ERBα 激活 mTORC1 途径，导致时钟蛋白 BMAL1 磷酸化。
