β-Hydroxybutyrate Boosts Mitochondrial and Neuronal Metabolism but is not Preferred Over Glucose Under Activated Conditions

Abstract

The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U-C]D-βOHB in conjunction with [1-C]D-glucose under conditions of normo- and hypoglycaemia, as well as under high potassium (40 mmol/L K) depolarization in normo- and hypoglycaemic conditions. The contribution of βOHB to synthesis of GABA was also probed by inhibiting the synthesis of glutamine, a GABA precursor, with methionine sulfoximine (MSO). [U-C]D-βOHB at lower concentrations (0.25 and 1.25 mmol/L) stimulated mitochondrial metabolism, producing greater total incorporation of label into glutamate and GABA but did not have a similar effect in the cytosolic compartment where labelling of glutamine was reduced at 1.25 mmol/L [U-C]D-βOHB. At higher concentrations (2.5 mmol/L) [U-C]D-βOHB inhibited metabolism of [1-C]D-glucose, and reduced total label incorporation and total metabolite pools. When glucose levels were reduced, βOHB was able to partially restore the loss of glutamate and GABA caused by hypoglycaemia, but was not able to supplement levels of lactate, glutamine or alanine or to prevent the increase in aspartate. Under depolarizing conditions glucose was the preferred substrate over βOHB, even in hypoglycaemic conditions where comparatively less βOHB was incorporated except into aspartate isotopomers. Inhibition of glutamine synthesis with MSO had no significant effect on incorporation of label from [U-C]D-βOHB into GABA C2,1 indicating that the majority of this GABA was synthesized in GABAergic neurons from [U-C]D-βOHB rather than from Gln C4,5 imported from astrocytes.

β-Hydroxybutyrate Oxidation Promotes the Accumulation of Immunometabolites in Activated Microglia Cells

“…Unlike most other tissues, the brain cannot utilize fatty acids for energy when blood glucose levels become compromised. However, during periods of low availability, it can be supplemented with the oxidation of alternative substrates like the monocarboxylates pyruvate [ 67 ], lactate [ 68 , 69 ], acetate [ 70 ], and ketone bodies [ 71 , 72 ]. Most of the current knowledge about the utilisation of alternative nutrients by brain cells has been obtained in neurons and astrocytes or in whole-brain experiments either in vivo or using cortical slices.…”

β-Hydroxybutyrate Ameliorates Aβ-Induced Downregulation of TrkA Expression by Inhibiting HDAC1/3 in SH-SY5Y Cells

“…Cell culture media were from American Hyclone Inc. (USA). Ab [25][26][27][28][29][30][31][32][33][34][35] (toxic effect fragment of an Ab peptide) was from American Peptide Inc. (USA), which was solubilized in sterile water at 1 mmol/L concentration and aggregated by in vitro incubation at 37 C for 7 days.…”

“…Cells in BHB group and Ab þ BHB group were pretreated with BHB (at a final concentration of 5 mmol/L); cells in other groups were incubated in BHB-free medium. Three hours later, 40 mL Ab [25][26][27][28][29][30][31][32][33][34][35] (1 mmol/L) was mixed quickly into the 2 mL medium in Ab group and Ab þ BHB group, which Ab [25][26][27][28][29][30][31][32][33][34][35] at a final concentration of 20 mmol/ L (no effect on cell viability), continuing to incubate cells for 24 hours. The cells were collected and used for quantitative real-time-polymerase chain reaction (qRT-PCR) and Western blot analyses.…”

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

“…KBs and MCFAs (produced from MCT supplementation in some versions of the KD, as discussed above) transverse the blood-brain barrier (BBB) into the brain via the assistance of monocarboxylate 1 and 2 transporters expressed on brain microvascular endothelial cells [91,92]. The expression of these transporters increases over 10-fold following a protracted period of ketosis [93]. Polyunsaturated fatty acids (PUFAs) can also cross the BBB although the enabling mechanisms are a matter of debate and the assistance of calveolin-1, FA transporters, phospholipidbound FA translocase, and lipoprotein packaging have all been posited (reviewed by [75]).…”