Physiological Stimulation Increases Nonoxidative Glucose Metabolism in the Brain of the Freely Moving Rat

Fellows, Lesley K.; Boutelle, Martyn G.; Fillenz, Marianne

doi:10.1111/j.1471-4159.1993.tb03285.x

Cited by 173 publications

(100 citation statements)

References 24 publications

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“…Virtually all the metabolic products of [2-3H]glucose in the neuronal cells consisted of tri tiated water, pyruvate, and lactate. This suggests that anaerobic glycolysis predominates in these cells, a conclusion in accord with the results of other studies of brain and neuronal tissue (Par dridge, 1983;Fellows et a!., 1993). Despite the pre dominance of glycolysis in these cells, it was not possible to use the appearance of 3H20 in the me dium as a measure of the total phosphorylation rate, because up to 50% of the tritium was retained in downstream metabolites rather than in 3H20 (Fig.…”

Section: Discussionsupporting

confidence: 82%

Coupled Glucose Transport and Metabolism in Cultured Neuronal Cells: Determination of the Rate-Limiting Step

Whitesell

Ward

McCall

et al. 1995

J Cereb Blood Flow Metab

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Summary: In brain and nerves the phosphorylation of glucose, rather than its transport, is generally considered the major rate-limiting step in metabolism. Since little is known regarding the kinetic coupling between these pro cesses in neuronal tissues, we investigated the transport and phosphorylation of [2-3H)glucose in two neuronal cell models: a stable neuroblastoma cell line (NCB20), and a primary culture of isolated rat dorsal root ganglia cells. When transport and phosphorylation were measured in series, phosphorylation was the limiting step. because in tracellular glucose concentrations were the same as those outside of cells, and because the apparent Km for glucose utilization was lower than expected for the transport step. However, the apparent Km was still severalfold higher than the Km of hexokinase I. When [2-3H)glucose efflux and phosphorylation were measured from the same intra- 814 cellular glucose pool in a parallel assay, rates of glucose efflux were three-to-fivefold greater than rates of phos phorylation. With the parallel assay, we observed that activation of glucose utilization by the sodium channel blocker veratridine caused a selective increase in glucose phosphorylation and was without effect on glucose trans port. In contrast to results with glucose, both cell types accumulated 2-deoxY-D-[1 4 C)glucose to concentrations severalfold greater than extracellular concentrations. We conclude from these studies' that glucose utilization in neuronal cells is phosphorylation-limited, and that the coupling between transport and phosphorylation depends on the type of hexose used.

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Section: Discussionsupporting

confidence: 82%

Coupled Glucose Transport and Metabolism in Cultured Neuronal Cells: Determination of the Rate-Limiting Step

Whitesell

Ward

McCall

et al. 1995

J Cereb Blood Flow Metab

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“…Thus, microdialysis studies in rats indicate a marked increase in the concentration of extracellular lactate in striatum during physiological sensory stimulation (Fellows et al 1993). This activity-linked lactate peak is completely inhibited when glutamate uptake inhibitors such as b-threohydroxyaspartate or pyrrolidine-2,4-dicarboxylate are present in the perfusate, thus providing further support for the existence of glutamate-stimulated glycolysis during activation (Fray et al 1996;Demestre et al 1997).…”

Section: In Vivo Observations Are Consistent With the Proposed Modelmentioning

confidence: 75%

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Magistretti¹,

Pellerin²

1999

Phil. Trans. R. Soc. Lond. B

664

458

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Despite striking advances in functional brain imaging, the cellular and molecular mechanisms that underlie the signals detected by these techniques are still largely unknown. The basic physiological principle of functional imaging is represented by the tight coupling existing between neuronal activity and the associated local increase in both blood £ow and energy metabolism. Positron emission tomography (PET) signals detect blood £ow, oxygen consumption and glucose use associated with neuronal activity; the degree of blood oxygenation is currently thought to contribute to the signal detected with functional magnetic resonance imaging, while magnetic resonance spectroscopy (MRS) identi¢es the spatio-temporal pattern of the activity-dependent appearance of certain metabolic intermediates such as glucose or lactate. Recent studies, including those of neurotransmitter-regulated metabolic £uxes in puri¢ed preparations and analyses of the cellular localization of enzymes and transporters involved in energy metabolism, as well as in vivo microdialysis and MRS approaches have identi¢ed the neurotransmitter glutamate and astrocytes, a speci¢c type of glial cell, as pivotal elements in the coupling of synaptic activity with energy metabolism. Astrocytes are ideally positioned to sense increases in synaptic activity and to couple them with energy metabolism. Indeed they possess specialized processes that cover the surface of intraparenchymal capillaries, suggesting that astrocytes may be a likely site of prevalent glucose uptake. Other astrocyte processes are wrapped around synaptic contacts which possess receptors and reuptake sites for neurotransmitters. Glutamate stimulates glucose uptake into astrocytes. This e¡ect is mediated by speci¢c glutamate transporters present on these cells. The activity of these transporters, which is tightly coupled to the synaptic release of glutamate and operates the clearance of glutamate from the extracellular space, is driven by the electrochemical gradient of Na + . This Na + -dependent uptake of glutamate into astrocytes triggers a cascade of molecular events involving the Na + /K + -ATPase leading to the glycolytic processing of glucose and the release of lactate by astrocytes. The stoichiometry of this process is such that for one glutamate molecule taken up with three Na + ions, one glucose molecule enters an astrocyte, two ATP molecules are produced through aerobic glycolysis and two lactate molecules are released. Within the astrocyte, one ATP molecule fuels one`turn of the pump' while the other provides the energy needed to convert glutamate to glutamine by glutamine synthase. Evidence has been accumulated from structural as well as functional studies indicating that, under aerobic conditions, lactate may be the preferred energy substrate of activated neurons. Indeed, in the presence of oxygen, lactate is converted to pyruvate, which can be processed through the tricarboxylic acid cycle and the associated oxidative phosphorylation, to yield 17 ATP molecules per lactate molecule....

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“…Also, dopamine may affect cerebral carbohydrate turnover (Fellows et al, 1993) and is released in small amounts from the brain during prolonged exercise (Nybo et al, 2003b). Tryptophan, the precursor of the neurotransmitter serotonin (Bequet et al, 2001;Cambray-Deakin et al, 1988), is taken up from blood in small amounts.…”

Section: Noradrenaline and Other Neurotransmittersmentioning

confidence: 99%

Fuelling Cerebral Activity in Exercising Man

Dalsgaard

2005

J Cereb Blood Flow Metab

136

137

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The metabolic response to brain activation in exercise might be expressed as the cerebral metabolic ratio (MR; uptake O 2 /glucose + 1/2 lactate). At rest, brain energy is provided by a balanced oxidation of glucose as MR is close to 6, but activation provokes a 'surplus' uptake of glucose relative to that of O 2 . Whereas MR remains stable during light exercise, it is reduced by 30% to 40% when exercise becomes demanding. The MR integrates metabolism in brain areas stimulated by sensory input from skeletal muscle, the mental effort to exercise and control of exercising limbs. The MR decreases during prolonged exhaustive exercise where blood lactate remains low, but when vigorous exercise raises blood lactate, the brain takes up lactate in an amount similar to that of glucose. This lactate taken up by the brain is oxidised as it does not accumulate within the brain and such pronounced brain uptake of substrate occurs independently of plasma hormones. The 'surplus' of glucose equivalents taken up by the activated brain may reach B10 mmol, that is, an amount compatible with the global glycogen level. It is suggested that a low MR predicts shortage of energy that ultimately limits motor activation and reflects a biologic background for 'central fatigue'.

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Physiological Stimulation Increases Nonoxidative Glucose Metabolism in the Brain of the Freely Moving Rat

Cited by 173 publications

References 24 publications

Coupled Glucose Transport and Metabolism in Cultured Neuronal Cells: Determination of the Rate-Limiting Step

Coupled Glucose Transport and Metabolism in Cultured Neuronal Cells: Determination of the Rate-Limiting Step

Cellular mechanisms of brain energy metabolism and their relevance to functional brain imaging

Fuelling Cerebral Activity in Exercising Man

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