Unraveling the complex metabolic nature of astrocytes

Bouzier‐Sore, Anne‐Karine; Pellerin, Luc

doi:10.3389/fncel.2013.00179

Cited by 113 publications

(79 citation statements)

References 123 publications

(147 reference statements)

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“…6C). For the interpretation of our results, it is important to consider the glial cell content of the cultures, because the ability of neurons to up-regulate glycolysis has been highly controversial (13,14). Moreover, some authors claim that MCT1, which we found robustly induced upon stimulation of synaptic activity (Fig.…”

Section: Activity-mediated Changes In Metabolic Gene Expression Occurmentioning

confidence: 79%

“…Several studies suggested that aerobic glycolysis and L-lactate production are a predominant feature of astrocytes. According to the so-called astrocyte-neuron-lactate shuttle (ANLS) hypothesis, astrocytederived L-lactate is taken up by neurons, which convert it back to pyruvate to fuel mitochondrial respiration (14,37). The ANLS hypothesis apparently argues against the existence of a neuronal Warburg effect that involves increased neuronal glucose uptake and L-lactate release.…”

Section: Discussionmentioning

confidence: 99%

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Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Bas‐Orth

Tan²,

Lau

et al. 2017

Journal of Biological Chemistry

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Edited by F. Anne StephensonSynaptic activity drives changes in gene expression to promote long lasting adaptations of neuronal structure and function. One example of such an adaptive response is the buildup of acquired neuroprotection, a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions. A hallmark of acquired neuroprotection is the stabilization of mitochondrial structure and function. We therefore re-examined previously identified sets of synaptic activity-regulated genes to identify genes that are directly linked to mitochondrial function. In mouse and rat primary hippocampal cultures, synaptic activity caused an up-regulation of glycolytic genes and a concomitant down-regulation of genes required for oxidative phosphorylation, mitochondrial biogenesis, and maintenance. Changes in metabolic gene expression were induced by action potential bursting, but not by glutamate bath application activating extrasynaptic NMDA receptors. The specific and coordinate pattern of gene expression changes suggested that synaptic activity promotes a shift of neuronal energy metabolism from oxidative phosphorylation toward aerobic glycolysis, also known as the Warburg effect. The ability of neurons to up-regulate glycolysis has, however, been debated. We therefore used FACS sorting to show that, in mixed neuron glia co-cultures, activity-dependent regulation of metabolic gene expression occurred in neurons. Changes in gene expression were accompanied by changes in the phosphorylation-dependent regulation of the key metabolic enzyme, pyruvate dehydrogenase. Finally, increased synaptic activity caused an increase in the ratio of L-lactate production to oxygen consumption in primary hippocampal cultures. Based on these data we suggest the existence of a synaptic activity-mediated neuronal Warburg effect that may promote mitochondrial homeostasis and neuroprotection.Synaptic activity can drive changes in gene expression to promote long lasting adaptations of neuronal structure and function (1, 2). Examples of such gene transcription-dependent adaptive responses are the formation of long term memories, activity-dependent dendritic remodeling, and the buildup of acquired neuroprotection. The latter is defined as a synaptic activity-and gene transcription-mediated increase in the resistance of neurons against harmful conditions (3). We have previously identified a number of so-called activity-regulated inhibitor of death genes that are able to confer such neuroprotection (4, 5). Although the exact mechanisms through which those genes confer neuroprotection are not yet fully understood, the functional changes mediated by activity-regulated inhibitor of death genes all seem to result in the protection of mitochondria (5-7). In the present study, we re-examined the synaptic activity-regulated gene pool to search for additional genes that are more directly linked to mitochondrial function. We found activity-dependent changes in the expression of several genes that encode for...

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Section: Activity-mediated Changes In Metabolic Gene Expression Occurmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Bas‐Orth

Tan²,

Lau

et al. 2017

Journal of Biological Chemistry

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“…Unlike neurons, astrocytes favor the production of lactate by aerobic glycolysis even in the absence of oxygen restriction (called the Warburg effect), while also efficiently producing ATP by mitochondrial respiration (called the Pasteur effect) (5). The metabolic capacity of astrocytes to produce lactate provides critical metabolic support to neurons (6).…”

Section: Introductionmentioning

confidence: 99%

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Kim

Han

Jang

et al. 2015

International Journal of Oncology

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Abstract. Among the primary brain tumors, glioblastoma multiforme (GBM) has a radical proliferation ability that complicates the therapeutic modulation of cancer progression. The majority of GBM patients have a low survival rate (<1 year) due to radical tumor growth and late cancer diagnosis. Previous reports have shown that astrocytes have a specific metabolic organization that includes the production of lactate, the storage of glycogen, and use of lactate to support neurons which possess higher capacity of metabolism compared to neurons. We hypothesized that these characteristics of astrocytes could contribute to enhanced proliferation of GBM compared to neuroblastoma (NB). Here, we show that U87MG cells (a model of GBM) proliferate more rapidly than SH-SY5Y cells (a model of NB). A higher extracellular acidification rate and maximal mitochondrial oxygen consumption rate were observed in U87MG cells compared to SH-SY5Y cells. The expression levels of lactate dehydrogenase (LDH)-A and LDH-B were higher in U87MG cells and primary cultured astrocytes than in SH-SY5Y cells and neurons. Furthermore, the mRNA levels of succinate dehydrogenase and peroxisome proliferator-activated receptor-γ were high in U87MG cells, suggesting that these cells have high capacity for mitochondrial metabolism and uptake of fatty acids related to synthesis of the cell membrane, respectively. Taken together, we demonstrate that GBM cells are characterized by activation of the LDH-expression-related glycolytic pathway and mitochondrial metabolic capacity, suggesting two innate properties of astrocytes that could provide a driving force for the growth ability of GBM. Based on these findings, we propose that therapeutic approaches aimed at treating GBM could target LDH for modulating the metabolic properties of GBM cells.

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“…Meanwhile, we do not know the specific response of each cell type in the PET studies. Given that the native context of the brain includes other cells that have a critical role in regulating neuronal metabolism (77)(78)(79), such as astrocytes, we tested 2-DG uptake in the more complex system of hippocampal slices. Here, we observed results that were similar to the in vitro studies, thereby suggesting that the effects of Wnt3a are mainly localized in neurons; however, further studies are required to confirm this hypothesis.…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Unraveling the complex metabolic nature of astrocytes

Cited by 113 publications

References 123 publications

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

Synaptic Activity Drives a Genomic Program That Promotes a Neuronal Warburg Effect

High-capacity glycolytic and mitochondrial oxidative metabolisms mediate the growth ability of glioblastoma

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

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