小鼠急性冷应激期间代谢通量的综合量化。

Cell metabolism Pub Date : 2023-11-07 Epub Date: 2023-10-05 DOI:10.1016/j.cmet.2023.09.002
Marc R Bornstein, Michael D Neinast, Xianfeng Zeng, Qingwei Chu, Jessie Axsom, Chelsea Thorsheim, Kristina Li, Megan C Blair, Joshua D Rabinowitz, Zoltan Arany
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引用次数: 0

摘要

冷诱导产热(CIT)作为治疗肥胖的一种潜在途径被广泛研究,但对驱动CIT的代谢变化缺乏全面的了解。在这里,我们对急性冷暴露的代谢反应进行了全面和定量的分析,利用代谢组学分析和未麻醉小鼠的最小干扰同位素追踪研究。在寒冷暴露期间,棕色脂肪组织(BAT)主要通过禁食小鼠的脂肪和喂食小鼠的葡萄糖来促进三羧酸(TCA)循环,这突出了BAT的代谢灵活性。BAT很少使用支链氨基酸或酮,而这些氨基酸或酮在寒冷暴露期间会被肌肉大量消耗。令人惊讶的是,同位素标记分析显示,BAT主要通过丙酮酸羧化作用使用葡萄糖进行TCA再合成。最后,我们发现,在禁食期间,冷诱导的肝脏糖异生对CIT至关重要,这表明了葡萄糖代谢的关键功能作用。总之,这些发现提供了驱动急性CIT的代谢重组的详细地图。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Comprehensive quantification of metabolic flux during acute cold stress in mice.

Cold-induced thermogenesis (CIT) is widely studied as a potential avenue to treat obesity, but a thorough understanding of the metabolic changes driving CIT is lacking. Here, we present a comprehensive and quantitative analysis of the metabolic response to acute cold exposure, leveraging metabolomic profiling and minimally perturbative isotope tracing studies in unanesthetized mice. During cold exposure, brown adipose tissue (BAT) primarily fueled the tricarboxylic acid (TCA) cycle with fat in fasted mice and glucose in fed mice, underscoring BAT's metabolic flexibility. BAT minimally used branched-chain amino acids or ketones, which were instead avidly consumed by muscle during cold exposure. Surprisingly, isotopic labeling analyses revealed that BAT uses glucose largely for TCA anaplerosis via pyruvate carboxylation. Finally, we find that cold-induced hepatic gluconeogenesis is critical for CIT during fasting, demonstrating a key functional role for glucose metabolism. Together, these findings provide a detailed map of the metabolic rewiring driving acute CIT.

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