Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation
Open accessAbstract
Abstract [13C]Acetate is known to label metabolites preferentially in astrocytes rather than neurons and it has consequently been used as a marker for astrocytic activity. Recent discoveries suggest that control of acetate metabolism and its contributions to the synthesis of metabolites in brain is not as simple as first thought. Here, using a Guinea pig brain cortical tissue slice model metabolizing [1‐13C]D‐glucose and [1,2‐13C]acetate, we investigated control of acetate metabolism and the degree to which it reflects astrocytic activity. Using a range of [1,2‐13C]acetate concentrations, we found that acetate is a poor substrate for metabolism and will inhibit metabolism of itself and of glucose at concentrations in excess of 2 mmol/L. By activating astrocytes using potassium depolarization, we found that use of [1,2‐13C]acetate to synthesize glutamine decreases significantly under these conditions showing that acetate metabolism does not necessarily reflect astrocytic activity. By blocking synthesis of glutamine using methionine sulfoximine, we found that significant amount of [1,2‐13C]acetate are still incorporated into GABA and its metabolic precursors in neurons, with around 30% of the GABA synthesized from [1,2‐13C]acetate likely to be made directly in neurons rather than from glutamine supplied by astrocytes. Finally, to test whether activity of the acetate metabolizing enzyme acetyl‐CoA synthetase is under acetylation control in the brain, we incubated slices with the AceCS1 deacetylase silent information regulator 1 (SIRT1) activator SRT 1720 and showed consequential increased incorporation of [1,2‐13C]acetate into metabolites. Taken together, these data show that acetate metabolism is not directly nor exclusively related to astrocytic metabolic activity, that use of acetate is related to enzyme acetylation and that acetate is directly metabolized to a significant degree in GABAergic neurons. Changes in acetate metabolism should be interpreted as modulation of metabolism through changes in cellular energetic status via altered enzyme acetylation levels rather than simply as an adjustment of glial–neuronal metabolic activity. image
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A recent study of acetate metabolism in brain slices showed a substantial ability of neurons to metabolize acetate directly.
“However, this conclusion depends on the assumption that acetate is metabolized only in glia; a recent study of acetate metabolism in brain slices showed a substantial ability of neurons to metabolize acetate directly, which calls the compartment-specific modeling into question (Rowlands et al., 2017).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Rowlands et al., 2017
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism
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“…this conclusion depends on the assumption that acetate is metabolized only in glia; a recent study of acetate metabolism in brain slices showed a substantial ability of neurons to metabolize acetate directly, which calls the compartment-specific modeling into question (Rowlands et al., 2017).”
Background
- Authors
- Rowlands, B. D., Klugmann, M., & Rae, C. D.
- Affiliations
- UNSW Sydney (AU)
- Corresponding author
- Rae, Caroline D.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2017-01-23
- Volume
- 140
- Issue
- 6
- Pages
- 903-918
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- OpenAlex
- W2560153775
- Cited by
- 38
- References
- 71
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 7 · 2023: 9 · 2022: 4 · 2021: 4 · 2020: 6 · 2018: 3 · 2017: 1
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Australian Research Council
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- acetate metabolism, astrocytes, GABA synthesis, glutamine synthesis, acetyl-CoA synthetase, SIRT1, neuronal metabolism, potassium depolarization, methionine sulfoximine, cortical slices, 13C labeling
- MeSH terms
- Animals, Astrocytes, Cerebral Cortex, Female, gamma-Aminobutyric Acid, Guinea Pigs, Organ Culture Techniques, Acetic Acid, Sirtuin 1, GABAergic Neurons
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