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 and Ye Yang
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Ramon C. Sun: University of Kentucky
Teresa W.-M. Fan: University of Kentucky
Pan Deng: University of Kentucky
Richard M. Higashi: University of Kentucky
Andrew N. Lane: University of Kentucky
Anh-Thu Le: University of Kentucky
Timothy L. Scott: University of Kentucky
Qiushi Sun: University of Kentucky
Marc O. Warmoes: University of Kentucky
Ye Yang: University of Kentucky

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01518-z

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