A ketogenic diet increases transport and oxidation of ketone bodies in RG2 and 9L gliomas without affecting tumor growth

Henk M. De Feyter, Kevin L. Behar, Jyotsna U. Rao, Kirby Madden-Hennessey, Kevan L. Ip, Fahmeed Hyder, Lester R. Drewes, Jean François Geschwind, Robin A. De Graaf, Douglas L. Rothman

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Background The dependence of tumor cells, particularly those originating in the brain, on glucose is the target of the ketogenic diet, which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of ketogenic diets has been of particular interest for therapy in brain tumors, which reportedly lack the ability to oxidize ketone bodies and therefore would be starved during ketosis. Because studies assessing the tumors' ability to oxidize ketone bodies are lacking, we investigated in vivo the extent of ketone body oxidation in 2 rodent glioma models. Methods Ketone body oxidation was studied using 13C MR spectroscopy in combination with infusion of a 13C-labeled ketone body (beta-hydroxybutyrate) in RG2 and 9L glioma models. The level of ketone body oxidation was compared with nontumorous cortical brain tissue. Results The level of 13C-beta-hydroxybutyrate oxidation in 2 rat glioma models was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a ketogenic diet, the ketone body monocarboxylate transporter was upregulated, facilitating uptake and oxidation of ketone bodies in the gliomas. Conclusions These results demonstrate that rat gliomas can oxidize ketone bodies and indicate upregulation of ketone body transport when fed a ketogenic diet. Our findings contradict the hypothesis that brain tumors are metabolically inflexible and show the need for additional research on the use of ketogenic diets as therapy targeting brain tumor metabolism.

Original languageEnglish (US)
Pages (from-to)1079-1087
Number of pages9
JournalNeuro-Oncology
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2016

Bibliographical note

Funding Information:
H. M.D.F was supported by fellowship 10A087 from the American Institute for Cancer Research and a 2013 Discovery Award from the American Brain Tumor Association. F.H. was supported by NIH grants P30-NS052519, R01 EB-011968, and R01 CA-140102. As members of the Yale Cancer Center, H.M.D.F. and F.H. are supported by NIH grant CA-16359 from the National Cancer Institute

Publisher Copyright:
© 2016 The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Keywords

  • C MRS
  • Glioma
  • Ketogenic diet
  • MCT1
  • Metabolism

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