Abstract
The dependence of brain tumor cells on glucose is the target of the ketogenic diet (KD), which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of KDs as therapy has been of particular interest for brain tumors because they reportedly cannot oxidize ketone bodies and therefore would be starved. However, in vivo studies assessing the ability of tumors to oxidize ketone bodies are lacking. We investigated ketone body oxidation in vitro and vivo using 13C magnetic resonance spectroscopy in combination with infusion of the 13C-labeled ketone body, beta-hydroxybutyrate (BHB) in two rodent glioma models (9L & RG2). The detection of 13C in glutamate following the infusion of [2,4-13C]-BHB was the primary outcome parameter and proof of oxidative 13C-BHB metabolism in the rat gliomas. Steady-state metabolic modeling was applied to further characterize the 13C-BHB metabolism. The level of glutamate 13C-labeling and 13C-BHB oxidation in 9L and RG2 rat gliomas was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a KD, immunohistochemistry showed that the ketone body transporter MCT1 was upregulated, facilitating uptake and doubling oxidation of ketone bodies in gliomas. These results demonstrate that rat gliomas can easily oxidize ketone bodies and indicate an adaptation through upregulation of ketone body transport when fed a KD. These data are not supporting the hypothesis that brain tumors are metabolically inflexible. Furthermore, there are indications that KDs in humans could also induce an increase in MCT1. MCT1 is a drug target for which an inhibitor is currently investigated in a clinical trial. Overall, these results indicate that the use of KDs as therapy targeting brain tumor metabolism and the effect of such diets on MCT1 needs further investigation, particularly in patients.
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