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

Nat Commun. 2017 Nov 21;8(1):1646. doi: 10.1038/s41467-017-01518-z.

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.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carbon Isotopes / chemistry
  • Carbon Isotopes / metabolism*
  • Cell Line, Tumor
  • Citric Acid Cycle
  • Female
  • Glucose / chemistry
  • Glucose / metabolism*
  • Glycogen / chemistry
  • Glycogen / metabolism
  • Glycolysis
  • Heterografts
  • Humans
  • Liver / chemistry
  • Liver / metabolism
  • Lung Neoplasms / chemistry
  • Lung Neoplasms / metabolism*
  • Magnetic Resonance Spectroscopy
  • Male
  • Metabolic Networks and Pathways*
  • Metabolomics / methods*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Pentose Phosphate Pathway

Substances

  • Carbon Isotopes
  • Glycogen
  • Glucose