Laboratory of Chronobiology, Charité Universitätsmedizin Berlin, Berlin, Germany.
Institute of Pharmacology, Center for Cardiovascular Research CCR, Charité Universitätsmedizin Berlin, Berlin, Germany.
Nat Struct Mol Biol. 2017 Jan;24(1):15-22. doi: 10.1038/nsmb.3331. Epub 2016 Nov 28.
Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK-BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK-BMAL1-dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.
生物钟是细胞自主振荡器，调节广泛的生理、代谢和行为过程中的日常节律。代谢信号的反馈，如氧化还原状态、NAD/NADH 和 AMP/ADP 比或血红素，调节生物钟节律，从而优化 24 小时周期内的能量利用。我们表明，节律性血红素降解产生信号分子一氧化碳 (CO)，是正常生物钟节律以及生物钟代谢输出所必需的。CO 通过减弱 CLOCK-BMAL1 与靶启动子的结合来抑制生物钟转录。CO 产生血红素加氧酶的药理学抑制或基因耗竭会破坏哺乳动物细胞和果蝇的正常日常周期。在小鼠肝细胞中，抑制 CO 的产生会导致 CLOCK-BMAL1 依赖性生物钟基因表达的全局上调和葡萄糖代谢失调。总之，我们的研究结果表明，CO 代谢是基本生物钟机制、代谢和行为之间的重要联系。
