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

Andersen, Jens V.; Westi, Emil W.; Neal, Elliott S.; Aldana, Blanca I.; Borges, Karin

doi:10.1007/s11064-022-03726-6

Cited by 11 publications

(15 citation statements)

References 42 publications

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“… 109,110 The same is true for medium chain triglycerides that are often used in conjunction with ketogenic diets and are also being tested by themselves 75,76,111,112 . Medium chain triglycerides provide medium chain fatty acids that can be metabolized directly by astrocytes and are also turned into “ketone bodies” by the liver, which are used by neurons as fuel 113,114 . Pyruvate, which is predominantly metabolized by neurons, 115 has also been shown to be protective against epilepsy 37,99,115–117 .…”

Section: Glycogen and Seizure Generation: Glycogenolysis Maintains K+...mentioning

confidence: 99%

Potential new roles for glycogen in epilepsy

et al. 2022

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Seizures often originate in epileptogenic foci. Between seizures (interictally), these foci and some of the surrounding tissue often show low signals with 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in many epileptic patients, even when there are no radiologically detectable structural abnormalities. Low FDG-PET signals are thought to reflect glucose hypometabolism. Here, we review knowledge about metabolism of glucose and glycogen and oxidative stress in people with epilepsy and in acute and chronic rodent seizure models.

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Section: Glycogen and Seizure Generation: Glycogenolysis Maintains K+...mentioning

confidence: 99%

Potential new roles for glycogen in epilepsy

et al. 2022

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“…However, even if plausible, this remains highly speculative, the measurements in urine do not let one conclude that the same changes can be found in the brain or reflect brain metabolism of MCFA being connected to neurotransmitter recycling in astrocytes. Based on our and previous in-vitro findings, we hypothesise that MCT may enhance anti-seizure drug-induced GABAgeric properties and thus leads to further seizure frequency reduction ( 65 , 69 – 73 ). Future studies are necessary to directly measure metabolic processes within the brain tissue.…”

Section: Discussionmentioning

confidence: 60%

“…The measured anaplerotic influx in the brain into the TCA cycle was found to be significantly associated with glutamine production ( 72 ), which would also support our previous hypothesis about the linkage to astrocytic metabolism ADDIN EN.CITE ( 72 , 99 ). Most recent research showed as well, indication of active MCFA metabolism in astrocytes, while βHB is metabolised in a different cellular compartment ( 73 ).…”

Section: Discussionmentioning

confidence: 99%

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil

Berk

Ottka²,

Law³

et al. 2022

Front. Vet. Sci.

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Consumption of medium-chain triglycerides (MCT) has been shown to improve seizure control, reduce behavioural comorbidities and improve cognitive function in epileptic dogs. However, the exact metabolic pathways affected by dietary MCT remain poorly understood. In this study, we aimed to identify changes in the metabolome and neurotransmitters levels relevant to epilepsy and behavioural comorbidities associated with the consuming of an MCT supplement (MCT-DS) in dogs with idiopathic epilepsy (IE). Metabolic alterations induced by a commercial MCT-DS in a population of 28 dogs with IE were evaluated in a 6-month multi-centre, prospective, randomised, double-blinded, controlled cross-over trial design. A metabolic energy requirement-based amount of 9% MCT or control oil was supplemented to the dogs' stable base diet for 3 months, followed by the alternative oil for another 3 months. A validated, quantitative nuclear magnetic resonance (NMR) spectroscopy platform was applied to pre- and postprandially collected serum samples to compare the metabolic profile between both DS and baseline. Furthermore, alterations in urinary neurotransmitter levels were explored. Five dogs (30%) had an overall reduction in seizure frequency of ≥50%, and were classified as MCT-responders, while 23 dogs showed a ≤50% reduction, and were defined as MCT non-responders. Amino-acid metabolism was significantly influenced by MCT consumption compared to the control oil. While the serum concentrations of total fatty acids appeared similar during both supplements, the relative concentrations of individual fatty acids differed. During MCT supplementation, the concentrations of polyunsaturated fatty acids and arachidonic acid were significantly higher than under the control oil. β-Hydroxybutyric acid levels were significantly higher under MCT supplementation. In total, four out of nine neurotransmitters were significantly altered: a significantly increased γ-aminobutyric acid (GABA) concentration was detected during the MCT-phase accompanied by a significant shift of the GABA-glutamate balance. MCT-Responders had significantly lowered urinary concentrations of histamine, glutamate, and serotonin under MCT consumption. In conclusion, these novel data highlight metabolic changes in lipid, amino-acid and ketone metabolism due to MCT supplementation. Understanding the metabolic response to MCT provides new avenues to develop better nutritional management with improved anti-seizure and neuroprotective effects for dogs with epilepsy, and other behavioural disorders.

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“…Octanoic acid stimulates astrocyte ketone synthesis and release (Auestad et al, 1991; Blázquez et al, 1999; Thevenet et al, 2016), which has been proposed to be shuttled to neurons (Guzmán & Blázquez, 2001), whereas decanoic acid induces astrocyte lactate synthesis and release (Damiano et al, 2020; Lee et al, 2018; Thevenet et al, 2016). Supplementation with medium‐chain fatty acids hereby supports both astrocytic and neuronal energy metabolism, via oxidation of fatty acids and ketones, respectively (Figure 5) (Andersen, Westi, et al, 2021, 2023). Induction of fatty acid metabolism in astrocytes have been shown to be protective during ischemia (Sayre et al, 2017), whereas supplementation with octanoic acid was able to correct Aβ‐induced memory impairments in chicks (Gibbs et al, 2009), which may be mediated by elevated astrocytic metabolic support.…”

Section: Excitotoxicity and Dysfunctional Glutamate And Gaba Homeostasismentioning

confidence: 84%

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

Andersen

Schousboe

2023

Journal of Neurochemistry

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Since it was first generally accepted that the two amino acids glutamate and GABA act as principal neurotransmitters, several landmark discoveries relating to this function have been uncovered. Synaptic homeostasis of these two transmitters involves several cell types working in close collaboration and is facilitated by specialized cellular processes. Notably, glutamate and GABA are extensively recycled between neurons and astrocytes in a process known as the glutamate/GABA-glutamine cycle, which is essential to maintain synaptic transmission. The glutamate/GABAglutamine cycle is intimately coupled to cellular energy metabolism and relies on the metabolic function of both neurons and astrocytes. Importantly, astrocytes display unique metabolic features allowing extensive metabolite release, hereby providing metabolic support for neurons. Furthermore, astrocytes undergo complex metabolic adaptations in response to injury and pathology, which may greatly affect the glutamate/GABA-glutamine cycle and synaptic transmission during disease. In this Milestone Review we outline major discoveries in relation to synaptic balancing of glutamate and GABA signaling, including cellular uptake, metabolism, and recycling.We provide a special focus on how astrocyte function and metabolism contribute to sustain neuronal transmission through metabolite transfer. Recent advances on cellular glutamate and GABA homeostasis are reviewed in the context of brain pathology, including glutamate toxicity and neurodegeneration. Finally, we consider how pathological astrocyte metabolism may serve as a potential target of metabolic intervention. Integrating the multitude of fine-tuned cellular processes supporting neurotransmitter recycling, will aid the next generation of major discoveries on brain glutamate and GABA homeostasis.

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

Cited by 11 publications

References 42 publications

Potential new roles for glycogen in epilepsy

Potential new roles for glycogen in epilepsy

Metabolic fingerprinting of dogs with idiopathic epilepsy receiving a ketogenic medium-chain triglyceride (MCT) oil

Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytes

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