2020
DOI: 10.3390/metabo10090346
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β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

Abstract: Metabolic regulation of immune cells has arisen as a critical set of processes required for appropriate response to immunological signals. While our knowledge in this area has rapidly expanded in leukocytes, much less is known about the metabolic regulation of brain-resident microglia. In particular, the role of alternative nutrients to glucose remains poorly understood. Here, we use stable-isotope (13C) tracing strategies and metabolomics to characterize the oxidative metabolism of β-hydroxybutyrate (BHB) in … Show more

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Cited by 16 publications
(9 citation statements)
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“…While the main objectives of this article were to demonstrate a proof‐of‐concept measurement of DNL activity and substrate preference in a typical cell culture setup using a simple 13 C NMR approach with [U‐ 13 C]glucose as the test substrate, we did observe significant effects of LPS on lipid metabolism in this microglial cell line. In microglia, LPS has been shown to reprogram glucose metabolism from oxidative phosphorylation to glycolysis and lactate export 12–14 . This would be expected to reduce acetyl‐CoA production from glucose and is therefore consistent with our observations of a reduced contribution of glucose carbons to fatty acid biosynthesis.…”
Section: Resultssupporting
confidence: 90%
“…While the main objectives of this article were to demonstrate a proof‐of‐concept measurement of DNL activity and substrate preference in a typical cell culture setup using a simple 13 C NMR approach with [U‐ 13 C]glucose as the test substrate, we did observe significant effects of LPS on lipid metabolism in this microglial cell line. In microglia, LPS has been shown to reprogram glucose metabolism from oxidative phosphorylation to glycolysis and lactate export 12–14 . This would be expected to reduce acetyl‐CoA production from glucose and is therefore consistent with our observations of a reduced contribution of glucose carbons to fatty acid biosynthesis.…”
Section: Resultssupporting
confidence: 90%
“…Microglia cell lines would require cancer cell‐like bioenergetics to sustain perpetual growth, appear to require much higher concentrations of BHB for efficacy, and may yield results divergent from differentiated human microglia used here. For example, BHB was shown to upregulate the expression of NOS2 , a key proinflammatory gene in BV2 microglial cells, 50 while our data showed BHB downregulates NOS2 (Figure 1B) and proinflammatory responses in general. Notably, we found significant effects of BHB at concentrations between 0.1 and 2 mM, a range equivalent to physiological blood levels when beneficial effects occur in human studies.…”
Section: Discussioncontrasting
confidence: 46%
“…For example, recent work has highlighted the importance of glutamine as a fuel source for microglia, 59 and detailed stable-isotope tracing experiments in both mouse and human microglial cell lines have shown that supplementation with the ketone body β-hydroxybutyrate enhances the LPS-induced glycolytic switch and synergistically increased lactate and succinate accumulation. 60 Collectively, these findings suggest that E4 microglia are predisposed to a pro-glycolytic, pro-inflammatory phenotype, which they are then unable to resolve via metabolic reprogramming, setting up a situation conducive to chronic neuroinflammation.…”
Section: Discussionmentioning
confidence: 99%