β-Hydroxybutyrate and Medium-Chain Fatty Acids are Metabolized by Different Cell Types in Mouse Cerebral Cortex...

Ketogenic diets and medium-chain triglycerides are gaining attention as treatment of neurological disorders. Their major metabolites, β-hydroxybutyrate (βHB) and the medium-chain fatty acids (MCFAs) octanoic acid (C8) and decanoic acid (C10), are auxiliary brain fuels. To which extent these fuels compete for metabolism in different brain cell types is unknown. Here, we used acutely isolated mouse cerebral cortical slices to (1) compare metabolism of 200 µM [U-¹³C]C8, [U-¹³C]C10 and [U-¹³C]βHB and (2) assess potential competition between metabolism of βHB and MCFAs by quantifying metabolite ¹³C enrichment using gas chromatography-mass spectrometry (GC-MS) analysis. The ¹³C enrichment in most metabolites was similar with [U-¹³C]C8 and [U-¹³C]C10 as substrates, but several fold lower with [U-¹³C]βHB. The ¹³C enrichment in glutamate was in a similar range for all three substrates, whereas the ¹³C enrichments in citrate and glutamine were markedly higher with both [U-¹³C]C8 and [U-¹³C]C10 compared with [U-¹³C]βHB. As citrate and glutamine are indicators of astrocytic metabolism, the results indicate active MCFA metabolism in astrocytes, while βHB is metabolized in a different cellular compartment. In competition experiments, ¹²C-βHB altered ¹³C incorporation from [U-¹³C]C8 and [U-¹³C]C10 in only a few instances, while ¹²C-C8 and ¹²C-C10 only further decreased the low [U-¹³C]βHB-derived ¹³C incorporation into citrate and glutamine, signifying little competition for oxidative metabolism between βHB and the MCFAs. Overall, the data demonstrate that βHB and MCFAs are supplementary fuels in different cellular compartments in the brain without notable competition. Thus, the use of medium-chain triglycerides in ketogenic diets is likely to be beneficial in conditions with carbon and energy shortages in both astrocytes and neurons, such as GLUT1 deficiency.