Global determination of reaction rates and lipid turnover kinetics in Mus musculus

• Published in: Cell metabolism 2023-04, Vol.35 (4), p.711-721.e4
• Main Authors: Chen, Qishan, Li, Hu, Tian, He, Lam, Sin Man, Liao, Yilie, Zhang, Ziyin, Dong, Manyuan, Chen, Shaoru, Yao, Yuxiao, Meng, Jiemiao, Zhang, Yong, Zheng, Lemin, Meng, Zhuo-Xian, Han, Weiping, Shui, Guanghou, Zhu, Dahai, Fu, Suneng
• Format: Article
• Language: English
• Subjects: Animals; Carbon - metabolism; Citric Acid Cycle; dietary fluxomics; elementary metabolite units; Glucose - metabolism; inter-organ metabolite flow; Lactic Acid - metabolism; Lipids; Mice; multi-organ EMU modeling
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2023.03.007

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 mapping in vivo and provides a rich resource for elucidating inter-organ metabolic cross talk. [Display omitted] •Quantification of >1,000 metabolite isotopologues and 85 reaction rates in vivo•Rate calculation identifies lactate as the main pyruvate source entering TCA•Multi-organ EMU model shows blood-tissue exchange dictating uridine homeostasis•Palmitate kinetic analysis posits DNL-driven glucose oxidation in BAT Qishan et al. combine dietary fluxomics with mathematical modeling to reveal the routes and rates of glucose metabolism in vivo and how its synthetic products are either confined locally or delivered to remote sites.