Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Medical Sciences, Uppsala University, Uppsala SE-75124, Sweden.
Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Cell Metab. 2019 May 7;29(5):1078-1091.e5. doi: 10.1016/j.cmet.2019.01.023. Epub 2019 Feb 28.
The alignment of fasting and feeding with the sleep/wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here, we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole-cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole-cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with the sleep/wake state.
尽管睡眠/觉醒周期与禁食和进食的同步化由下丘脑神经元协调，但潜在的分子程序仍不完全清楚。在这里，我们证明，通过对 NPY/AgRP 神经元进行自主的昼夜节律调节，时钟转录途径在觉醒时最大限度地促进进食，并在睡眠时促进葡萄糖产生。在动态禁食和进食条件下，对整个细胞和核糖体结合的 mRNA 进行串联分析，确定了 AgRP 神经元中与突触发生、生物能学以及神经递质和肽信号传导有关的活性依赖性基因库的时间控制。突触和昼夜节律途径是整个细胞 RNA 分析所特有的，而生物能学途径则选择性地富集在核糖体结合的转录组中。最后，我们证明 AgRP 时钟介导了对瘦素的转录反应。我们的结果表明，能量感应神经元转录控制的时间限制是饥饿和食物获取与睡眠/觉醒状态同步的基础。
