Noninvasive liquid diet delivery of stable isotopes into mouse models for deep metabolic network tracing.
Ramon C SunTeresa W-M FanPan DengRichard M HigashiAndrew N LaneAnh-Thu LeTimothy L ScottQiushi SunMarc O WarmoesYe YangPublished in: Nature communications (2017)
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.
Keyphrases
- lymph node
- mass spectrometry
- blood glucose
- liquid chromatography
- weight loss
- physical activity
- high resolution
- induced apoptosis
- mouse model
- magnetic resonance
- high performance liquid chromatography
- gene expression
- ionic liquid
- neoadjuvant chemotherapy
- fatty acid
- blood pressure
- sentinel lymph node
- stress induced
- tandem mass spectrometry
- gas chromatography
- high speed
- skeletal muscle
- endoplasmic reticulum stress
- adipose tissue
- capillary electrophoresis
- radiation therapy
- insulin resistance
- metabolic syndrome
- heat stress