Global determination of reaction rates and lipid turnover kinetics in Mus musculus
Global determination of reaction rates and lipid turnover kinetics in Mus musculus
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DOI：
10.1016/j.cmet.2023.03.007
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发表时间：
2023-04-04
期刊：
影响因子：
29
通讯作者：
Fu，Suneng
中科院分区：
文献类型：
--
作者：
Chen，Qishan;Li，Hu;Fu，Suneng
代谢是生命的基础，但测量代谢反应率仍然具有挑战性。在这里，我们应用C13通量组学在4天的时间内监测12个组织、9个脑区室和1,000多种代谢物同位素的饮食葡萄糖碳代谢。用基本代谢物单元（EMU）模型确定了围绕中心碳代谢的85个反应的速率。乳酸氧化，而不是糖酵解，发生的速度与三羧酸循环（TCA）相当，支持乳酸作为主要燃料。我们扩展了EMU框架，以跟踪和量化代谢物在组织中的流动。具体而言，尿苷代谢的多器官EMU模拟表明，组织-血液交换，而不是合成，控制核苷酸稳态。相比之下，同位素指纹和动力学分析显示棕色脂肪组织（BAT）具有最高的棕榈酸合成活性，但对循环没有明显的贡献，这表明组织自主合成燃烧机制。总之，这项研究证明了膳食通量组学在体内动力学映射中的实用性，并为阐明器官间代谢串扰提供了丰富的资源。
Metabolism is fundamental to life, but measuring metabolic reaction rates remains challenging. Here, we applied C13 fluxomics to monitor the metabolism of dietary glucose carbon in 12 tissues, 9 brain compartments, and over 1,000 metabolite isotopologues over a 4-day period. The rates of 85 reactions surrounding central carbon metabolism are determined with elementary metabolite unit (EMU) modeling. Lactate oxidation, not glycolysis, occurs at a comparable pace with the tricarboxylic acid cycle (TCA), supporting lactate as the primary fuel. We expand the EMU framework to track and quantify metabolite flows across tissues. Specifically, multi-organ EMU simulation of uridine metabolism shows that tissue-blood exchange, not synthesis, controls nucleotide homeostasis. In contrast, isotopologue fingerprinting and kinetic analyses reveal the brown adipose tissue (BAT) having the highest palmitate synthesis activity but no apparent contribution to circulation, suggesting a tissue-autonomous synthesis-to-burn mechanism. Together, this study demonstrates the utility of dietary fluxomics for kinetic mappingin vivoand provides a rich resource for elucidating inter-organ metabolic cross talk.