Reevaluation of Astrocyte-Neuron Energy Metabolism with Astrocyte Volume Fraction Correction: Impact on Cellular Glucose
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REVIEW
Reevaluation of Astrocyte‑Neuron Energy Metabolism with Astrocyte Volume Fraction Correction: Impact on Cellular Glucose Oxidation Rates, Glutamate–Glutamine Cycle Energetics, Glycogen Levels and Utilization Rates vs. Exercising Muscle, and Na+/K+ Pumping Rates Gerald A. Dienel1,2 · Douglas L. Rothman3 Received: 4 July 2020 / Revised: 31 August 2020 / Accepted: 3 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Accurate quantification of cellular contributions to rates of substrate utilization in resting, activated, and diseased brain is essential for interpretation of data from studies using [18F]fluorodeoxyglucose-positron-emission tomography (FDG-PET) and [13C]glucose/magnetic resonance spectroscopy (MRS). A generally-accepted dogma is that neurons have the highest energy demands of all brain cells, and calculated neuronal rates of glucose oxidation in awake, resting brain accounts for 70–80%, with astrocytes 20–30%. However, these proportions do not take cell type volume fractions into account. To evaluate the conclusion that neuron-astrocyte glucose oxidation rates are similar when adjusted for astrocytic volume fraction (Hertz, Magn Reson Imaging 2011; 29, 1319), the present study analyzed data from 31 studies. On average, astrocytes occupy 6.1, 9.6, and 15% of tissue volume in hippocampus, cerebral cortex, and cerebellum, respectively, and regional astrocytic metabolic rates are adjusted for volume fraction by multiplying by 17.6, 11.4, and 6.8, respectively. After adjustment, astrocytic glucose oxidation rates in resting awake rat brain are 4–10 fold higher than neuronal oxidation rates. Volume-fraction adjustment also increases brain glycogen concentrations and utilization rates to be similar to or exceed exercising muscle. Ion flux calculations to evaluate sodium/potassium homeostasis during neurotransmission are not correct if astrocyte-neuron volume fractions are assumed to be equal. High rates of glucose and glycogen utilization after adjustment for volume fraction indicate that astrocytic energy demands are much greater than recognized, with most of the ATP being used for functions other than glutamate processing in the glutamate-glutamine cycle, challenging the notion that astrocytes ’feed hungry neurons’. Keywords Astrocyte · Glucose oxidation · Glycogen metabolism · Neuron · Volume fraction · Surface-to-volume ratio Abbreviations ECF Extracellular fluid EM Electron microscopy Glc Glucose * Gerald A. Dienel [email protected] Douglas L. Rothman [email protected] 1
Department of Neurology, Mail Slot 500, University of Arkansas for Medical Sciences, 4301 W. Markham St., Little Rock, AR 72205, USA
2
Department of Cell Biology and Physiology, University of New Mexico School of Medicine, Albuquerque, NM 87131, USA
3
Magnetic Resonance Research Center and Department of Radiology, Yale University, New Haven, CT 06520, USA
Glc-6-P Glucose-6-phosphate Glu Glutamate Gln Glutamine Glu-Gln cycle Glutamate-glutamine cycle GLUT
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