Influence of a ketogenic diet on glial metabolism in vivo - Oligodendrocytes
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE206576 | GEO | 2022/06/24
REPOSITORIES: GEO
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Project description:To maintain homeostasis, the body including the brain reprograms its metabolism in response to altered nutrition or disease. However, the consequences of these challenges for the energy metabolism of the different brain cell types remain unknown. Here, we generated a proteome atlas of the major CNS cell types from young and adult mice, after feeding the therapeutically relevant low-carbohydrate, high-fat ketogenic diet (KD) and during neuroinflammation. Under steady-state conditions, CNS cell types prefer distinct modes of energy metabolism. Surprisingly, the comparison with KD revealed distinct cell type-specific strategies to manage the altered availability of energy metabolites. Astrocytes and neurons but not oligodendrocytes demonstrated metabolic plasticity. Unexpectedly, inflammatory demyelinating disease changed the neuronal metabolic signature in a similar direction as KD. Together, these findings highlight the importance of the metabolic crosstalk between CNS cells and between the periphery and the brain to manage altered nutrition and neurological disease.
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Project description:It is largely unknown how cells in the central nervous system (CNS) adapt their energy metabolism to nutritional challenges or disease. To unravel the molecular basis of these adaptations, we generated a comprehensive proteome dataset of all major CNS cell types. Magnetic bead sorting was used to acutely isolate neurons, astrocytes, oligodendrocytes, microglia, and endothelial cells from the cortex of individual young and adult mice challenged by feeding ketogenic diet or by neuroinflammatory disease. Label-free quantification of cell type-specific proteomes was performed by using an ion mobility-enhanced data-independent acquisition (DIA) workflow with alternating low and elevated energy (referred to as UDMSE). The combination of tissue metabolomic and expression analyses with cellular proteomic and transcriptomic analyses revealed that the strategies to manage the altered availability of energy metabolites differed between CNS cell types. Our data provide insights into key mechanisms of cell type-specific metabolic remodeling and a framework for the crosstalk between CNS cells in response to CNS challenges, which may have implications for the management of neurological diseases.
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Project description:Epilepsy affects between 1-2% of people worldwide and is defined symptomatically by the appearance of spontaneous, recurrent seizures. The ketogenic diet (KD) is an anticonvulsant treatment that has been used to manage medically-intractable epilepsies. Both clinical and experimental reports show that the KD can be used to treat a variety of seizure types. During KD treatment, ketone bodies, rather than glucose, become the major energy substrate for the brain; somehow, metabolic conversion confers a potent anticonvulsant effect. The KD requires 10-12 days to become maximally effective, suggesting that changes in gene expression are involved in its anticonvulsant action. Despite its use for over 80 years, the mechanism of the diet remains unknown. It is expected that this work will help elucidate the underlying anticonvulsant action of the KD and contribute to future, rationale-based drug development. We propose to identify sets of genes activated/repressed within hippocampus after treatment with a KD. We hypothesize that gene expression patterns induced by alterations in metabolic pathways are critically involved with the anticonvulsant effects of the KD in mice. Mice (n=44, 129svJ) will be used for these experiments. Animals will be fed either a KD (n=22) or control diet (n=22) for 14 days. After this time, ten animals from each group will be subjected to flurothyl seizure testing to confirm seizure threshold elevation. Of the remaining KD- (n=12) or control-fed (n=12) animals, two left hippocampi will be pooled together such that six arrays from each treatment group can be tested. This is expected to reduce biological variability. Right hippocampi (n=12/group) will be maintained in our lab for corroborative analysis via RT-PCR and immunohistochemistry. All tissue samples will be rapidly dissected, frozen in liquid nitrogen, and stored at -80C until shipping/corroborative testing. Data analysis will be completed with Significance of Array Measurement (SAM) program using ANOVA from protection for multiple comparisons. Please use the Affy chip with known genes in lieu of the chip containing mostly EST's.
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