Metabolic pathways for glucose in astrocytes

Wiesinger, Heinrich; Hamprecht, Bernd; Dringen, Ralf

doi:10.1002/(sici)1098-1136(199709)21:1<22::aid-glia3>3.0.co;2-3

Cited by 167 publications

(121 citation statements)

References 126 publications

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“…Brown, and B. Ransom, unpublished observations) but does not lead to glycogen formation in vitro (Wiesinger et al, 1997). As expected, nerves equilibrated for 60 min in 25 mM fructose had no change in glycogen content as compared with control (3.23 Ϯ 0.29 pmol of glycogen/ g of protein; n ϭ 6; p Ͼ 0.05 vs control); the significance of this observation is discussed later.…”

Section: Glycogen Content Of Ronsupporting

confidence: 63%

“…Fructose, like glucose, sustains the CAP, but it does not induce glycogen synthesis (Wiesinger et al, 1997) (see Fig. 3B).…”

Section: Glycogen Content and Axon Functionmentioning

confidence: 95%

“…Because lactate served as an effective energy source for axon function and appears in the extracellular space with glycogen breakdown (Dringen et al, 1993;Wiesinger et al, 1997), we attempted to interfere with lactate transport to test the theory that lactate was transferred from astrocytes to axons during glucose deprivation. We first tested the bioflavonoid quercetin, which preferentially blocks extrusion of lactate (Belt et al, 1979; Volk et al, Figure 4.…”

Section: Blockade Of Lactate Transport and Axon Function During Glucomentioning

confidence: 99%

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Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Wender

Brown²,

Fern³

et al. 2000

J. Neurosci.

343

339

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We tested the hypothesis that astrocytic glycogen sustains axon function during and enhances axon survival after 60 min of glucose deprivation. Axon function in the rat optic nerve (RON), a CNS white matter tract, was monitored by measuring the area of the stimulus-evoked compound action potential (CAP). Switching to glucose-free artificial CSF (aCSF) had no effect on the CAP area for ϳ30 min, after which the CAP rapidly failed. Exposure to glucose-free aCSF for 60 min caused irreversible injury, which was measured as incomplete recovery of the CAP. Glycogen content of the RON fell to a low stable level 30 min after glucose withdrawal, compatible with rapid use in the absence of glucose. An increase of glycogen content induced by high-glucose pretreatment increased the latency to CAP failure and improved CAP recovery. Conversely, a decrease of glycogen content induced by norepinephrine pretreatment decreased the latency to CAP failure and reduced CAP recovery. To determine whether lactate represented the fuel derived from glycogen and shuttled to axons, we used the lactate transport blockers quercetin, ␣-cyano-4-hydroxycinnamic acid (4-CIN), and p-chloromercuribenzene sulfonic acid ( pCMBS). All transport blockers, when applied during glucose withdrawal, decreased latency to CAP failure and decreased CAP recovery. The inhibitors 4-CIN and pCMBS, but not quercetin, blocked lactate uptake by axons. These results indicated that, in the absence of glucose, astrocytic glycogen was broken down to lactate, which was transferred to axons for fuel. Key words: astrocytes; ␣-cyano-4-hydroxycinnamate; glucose; hypoglycemia; lactate; p-chloromercuribenzene sulfonic acid; quercetin; rat optic nerveThe function of brain glycogen is not well understood. Glycogen turns over rapidly in the brain, however, and turnover is enhanced when adjacent neural activity is increased (Orkand et al., 1973;Pentreath and Kai-Kai, 1982;Swanson et al., 1992). It is appealing to imagine that glycogen might serve to provide fuel to the brain when glucose is in short supply. Indeed, astrocytic glycogen in vitro is degraded rapidly when glucose is withdrawn (Dringen et al., 1993), and glycogen falls rapidly in vivo during ischemia, with a time course that is closely related to the depletion of ATP and the accumulation of lactate (Swanson et al., 1989a). These observations are consistent with the action of glycogen as a fuel source during glucose shortage, but they do not prove this hypothesis. Glycogen content varies by a factor of two or more between brain regions [it is highest in the brainstem and cerebellum and lowest in the striatum and white matter (Swanson et al., 1989a)]. Energy metabolism also varies significantly between different brain regions (Sokoloff et al., 1977). Therefore, glycogen could be more protective against glucose depletion in some areas than in others.Given all of the above, it is natural to wonder whether glycogen can enhance the survival and function of brain tissue in the absence of glucose. Surprisingly, only a single st...

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Section: Glycogen Content Of Ronsupporting

confidence: 63%

“…Fructose, like glucose, sustains the CAP, but it does not induce glycogen synthesis (Wiesinger et al, 1997) (see Fig. 3B).…”

Section: Glycogen Content and Axon Functionmentioning

confidence: 95%

Section: Blockade Of Lactate Transport and Axon Function During Glucomentioning

confidence: 99%

See 1 more Smart Citation

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Wender

Brown²,

Fern³

et al. 2000

J. Neurosci.

343

339

View full text Add to dashboard Cite

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“…Albeit at much lower concentrations, the brain also contains glycogen, which is primarily located in astrocytes (Wiesinger et al, 1997). Although accepted as the principal energy reserve in the CNS by many (Dringen et al, 1993;Swanson, 1992;Watanabe and Passonneau, 1973), the role of glycogen in the brain is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies suggested the involvement of brain glycogen in sleep cycle regulation (Kong et al, 2002;Petit et al, 2002). These changes in glycogen content may be brought about by a number of factors (Wiesinger et al, 1997) including hormones (Dringen and Hamprecht, 1992) and neurotransmitters (Hamai et al, 1999;Sorg and Magistretti, 1992;Swanson et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

Direct, noninvasive measurement of brain glycogen metabolism in humans

Öz

Henry

Seaquist

et al. 2003

Neurochemistry International

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The concentration and metabolism of the primary carbohydrate store in the brain, glycogen, is unknown in the conscious human brain. This study reports the first direct detection and measurement of glycogen metabolism in the human brain, which was achieved using localized 13 C NMR spectroscopy. To enhance the NMR signal, the isotopic enrichment of the glucosyl moieties was increased by administration of 80 g of 99% enriched [1-13 C]glucose in four subjects. 3 h after the start of the label administration, the 13 C NMR signal of brain glycogen C1 was detected (0.36 ± 0.07 mol/g, mean ± S.D., n = 4). Based on the rate of 13 C label incorporation into glycogen and the isotopic enrichment of plasma glucose, the flux through glycogen synthase was estimated at 0.17 ± 0.05 mol/(g h). This study establishes that brain glycogen can be measured in humans and indicates that its metabolism is very slow in the conscious human. The noninvasive detection of human brain glycogen opens the prospect of understanding the role and function of this important energy reserve under various physiological and pathophysiological conditions.

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Astrocytes: Glutamate producers for neurons

et al. 1999

Self Cite

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In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.

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Metabolic pathways for glucose in astrocytes

Cited by 167 publications

References 126 publications

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Astrocytic Glycogen Influences Axon Function and Survival during Glucose Deprivation in Central White Matter

Direct, noninvasive measurement of brain glycogen metabolism in humans

Astrocytes: Glutamate producers for neurons

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