Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing

Ramon C. Sun, Teresa W.M. Fan, Pan Deng, Richard M. Higashi, Andrew N. Lane, Anh Thu Le, Timothy L. Scott, Qiushi Sun, Marc O. Warmoes, Ye Yang

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

Delivering isotopic tracers for metabolic studies in rodents without overt stress is challenging. Current methods achieve low label enrichment in proteins and lipids. Here, we report noninvasive introduction of 13C6-glucose via a stress-free, ad libitum liquid diet. Using NMR and ion chromatography-mass spectrometry, we quantify extensive 13C enrichment in products of glycolysis, the Krebs cycle, the pentose phosphate pathway, nucleobases, UDP-sugars, glycogen, lipids, and proteins in mouse tissues during 12 to 48 h of 13C6-glucose feeding. Applying this approach to patient-derived lung tumor xenografts (PDTX), we show that the liver supplies glucose-derived Gln via the blood to the PDTX to fuel Glu and glutathione synthesis while gluconeogenesis occurs in the PDTX. Comparison of PDTX with ex vivo tumor cultures and arsenic-transformed lung cells versus xenografts reveals differential glucose metabolism that could reflect distinct tumor microenvironment. We further found differences in glucose metabolism between the primary PDTX and distant lymph node metastases.

Original languageEnglish
Article number1646
JournalNature Communications
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2017

Bibliographical note

Funding Information:
This work was supported in part by grants: 1R01ES022191-01 (to T.W.-M.F. and R.M. H.), 1P01CA163223-01A1 (to A.N.L. and T.W.-M.F.), 1U24DK097215-01A1 (to R.M.H., T.W.-M.F., and A.-N.L.), 5R21ES025669-02 (to T.W.M.F.) and the Redox Metabolism Shared Resource(s) of the University of Kentucky Markey Cancer Center (P30CA177558). A.T.L. was supported by T32 5T32CA160003-05 (B.M.E.). R.C.S. was supported by a T32 training grant 5T32ES007266-25 (M.V.). 13C-enriched standards were obtained from NIH Common Fund Metabolite Standards Synthesis Core (http:// www.metabolomicsworkbench.org/standards/index.php). We would also like to thank Ms. Yan Zhang and Teresa Cassel for helping with the mouse necropsy and the BAsT xenograft experiments, Dr Christine Brainson for consulting on mouse pathology and histology, and Dr Piotr Dobrowolski for acquiring the NMR data.

Publisher Copyright:
© 2017 The Author(s).

ASJC Scopus subject areas

  • Chemistry (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Physics and Astronomy (all)

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