PT  - JOURNAL ARTICLE
AU  - Sheng Hui
AU  - Alexis J. Cowan
AU  - Xianfeng Zeng
AU  - Lifeng Yang
AU  - Tara TeSlaa
AU  - Xiaoxuan Li
AU  - Caroline Bartman
AU  - Zhaoyue Zhang
AU  - Cholsoon Jang
AU  - Lin Wang
AU  - Wenyun Lu
AU  - Jennifer Rojas
AU  - Joseph Baur
AU  - Joshua D. Rabinowitz
TI  - Quantitative fluxomics of circulating metabolites
AID  - 10.1101/2020.03.02.973669
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.03.02.973669
4099  - http://biorxiv.org/content/early/2020/03/03/2020.03.02.973669.short
4100  - http://biorxiv.org/content/early/2020/03/03/2020.03.02.973669.full
AB  - Mammalian organs are nourished by nutrients carried by the blood circulation. These nutrients originate from diet and internal stores, and can undergo various interconversions before their eventual use as tissue fuel. Here we develop isotope tracing, mass spectrometry, and mathematical analysis methods to determine the direct sources of circulating nutrients, their interconversion rates, and eventual tissue-specific contributions to TCA cycle metabolism. Experiments with fifteen nutrient tracers enabled extensive accounting both for circulatory metabolic cycles and tissue TCA inputs, across fed and fasted mice on either high carbohydrate or ketogenic diet. We find that a majority of circulating carbon flux is carried by two major cycles: glucose-lactate and triglyceride-glycerol-fatty acid. Futile cycling through these pathways is prominent when dietary content of the associated nutrients is low, rendering internal metabolic activity robust to food choice. The presented in vivo flux quantification methods are broadly applicable to different physiological and disease states.