Activity-Dependent Regulation of Surface Glucose Transporter-3

Ferreira, José Luiz P.; Burnett, Arthur L.; Rameau, Gerald A.

doi:10.1523/jneurosci.1850-09.2011

Cited by 108 publications

(99 citation statements)

References 25 publications

(26 reference statements)

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“…Glutamate, a key excitatory neurotransmitter, increases protein levels of surface glucose transporter 3 (GLUT3) in neurons (32) and enhances glucose uptake and glycogen synthesis in cultured cortical astrocytes (33). In the present study, brain glutamate was maintained even during exhaustive exercise (Fig.…”

Section: Discussionsupporting

confidence: 50%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

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Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters (MCTs) to maintain neuronal functions such as hippocampus-regulated memory formation. Although prolonged exhaustive exercise decreases brain glycogen, the role of this decrease and lactate transport in the exercising brain remains less clear. Because muscle glycogen fuels exercising muscles, we hypothesized that astrocytic glycogen plays an energetic role in the prolonged-exercising brain to maintain endurance capacity through lactate transport. To test this hypothesis, we used a rat model of exhaustive exercise and capillary electrophoresismass spectrometry-based metabolomics to observe comprehensive energetics of the brain (cortex and hippocampus) and muscle (plantaris). At exhaustion, muscle glycogen was depleted but brain glycogen was only decreased. The levels of MCT2, which takes up lactate in neurons, increased in the brain, as did muscle MCTs. Metabolomics revealed that brain, but not muscle, ATP was maintained with lactate and other glycogenolytic/glycolytic sources. Intracerebroventricular injection of the glycogen phosphorylase inhibitor 1,4-dideoxy-1,4-imino-D-arabinitol did not affect peripheral glycemic conditions but suppressed brain lactate production and decreased hippocampal ATP levels at exhaustion. An MCT2 inhibitor, α-cyano-4-hydroxycinnamate, triggered a similar response that resulted in lower endurance capacity. These findings provide direct evidence for the energetic role of astrocytic glycogen-derived lactate in the exhaustive-exercising brain, implicating the significance of brain glycogen level in endurance capacity. Glycogen-maintained ATP in the brain is a possible defense mechanism for neurons in the exhausted brain.brain glycogen | lactate transport | ATP | endurance capacity | metabolomics G lucose derived from blood is the primary energy source for generating ATP in the brain, but an important energy reserve is brain glycogen synthesized from glucose in astrocytes (1). Astrocytic glycogen is broken down through glycogenolysis/glycolysis to produce lactate as a neuronal energy substrate transported by monocarboxylate transporters (MCTs) (2). Indeed, brain glycogen decreases during memory tasks (3) and in some physiologically exhaustive conditions such as sleep deprivation (4) and hypoglycemia (5). The genetic/pharmacologic inhibitions of glycogenolysis and/or lactate transport impair neuronal survival under severe hypoglycemia, as well as axon transmission and hippocampus-related memory formation (6-8). Therefore, astrocytic glycogen-derived lactate is a critical energy source for meeting brain energy demands for neuronal functions and/or survival.Although less than for exercising muscles, physical exercise activates brain neurons and increases brain energy demand (9). Blood glucose and lactate contribute to brain energetics during moderate or intense exercise (10, 11). Muscle glycogen is an important energy for maintaining muscle contraction during endurance ex...

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Section: Discussionsupporting

confidence: 50%

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Matsui

Omuro

Liu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Moreover, synaptic activity causes an increase in neuronal surface expression of the glucose transporter GLUT3, which has been shown to protect neurons from excitotoxicity (42,43).…”

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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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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“…Cultured neurons mobilize glucose transporter GLUT3 in response to glutamate (Ferreira et al, 2011). We therefore asked whether GLUT1, the predominant transporter of oligodendrocytes and astrocytes (Zhang et al, 2014), behaves similarly.…”

Section: Nmda Receptor Activation Triggers Glut1 Surface Expression Amentioning

confidence: 99%

Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism

Saab

Tzvetavona

Trevisiol

et al. 2016

Neuron

428

389

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Oligodendrocytes make myelin and support axons metabolically with lactate. However, it is unknown how glucose utilization and glycolysis are adapted to the different axonal energy demands. Spiking axons release glutamate and oligodendrocytes express NMDA receptors of unknown function. Here we show that the stimulation of oligodendroglial NMDA receptors mobilizes glucose transporter GLUT1, leading to its incorporation into the myelin compartment in vivo. When myelinated optic nerves from conditional NMDA receptor mutants are challenged with transient oxygen-glucose deprivation, they show a reduced functional recovery when returned to oxygen-glucose but are indistinguishable from wild-type when provided with oxygen-lactate. Moreover, the functional integrity of isolated optic nerves, which are electrically silent, is extended by preincubation with NMDA, mimicking axonal activity, and shortened by NMDA receptor blockers. This reveals a novel aspect of neuronal energy metabolism in which activity-dependent glutamate release enhances oligodendroglial glucose uptake and glycolytic support of fast spiking axons.

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Activity-Dependent Regulation of Surface Glucose Transporter-3

Cited by 108 publications

References 25 publications

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

Astrocytic glycogen-derived lactate fuels the brain during exhaustive exercise to maintain endurance capacity

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

Oligodendroglial NMDA Receptors Regulate Glucose Import and Axonal Energy Metabolism

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