Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

Gerald A. Dienel

doi:10.1002/jnr.24015

journal article Feb 02, 2017

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

Gerald A. Dienel

Journal of Neuroscience Research Vol. 95 No. 11 pp. 2103-2125 · Wiley

View at Publisher Save 10.1002/jnr.24015

Abstract

Glutamate‐stimulated aerobic glycolysis in astrocytes coupled with lactate shuttling to neurons where it can be oxidized was proposed as a mechanism to couple excitatory neuronal activity with glucose utilization (CMRglc) during brain activation. From the outset, this model was not viable because it did not fulfill critical stoichiometric requirements: (i) Calculated glycolytic rates and measured lactate release rates were discordant in cultured astrocytes. (ii) Lactate oxidation requires oxygen consumption, but the oxygen–glucose index (OGI, calculated as CMRO2/CMRglc) fell during activation in human brain, and the small rise in CMRO2 could not fully support oxidation of lactate produced by disproportionate increases in CMRglc. (iii) Labeled products of glucose metabolism are not retained in activated rat brain, indicating rapid release of a highly labeled, diffusible metabolite identified as lactate, thereby explaining the CMRglc–CMRO2 mismatch. Additional independent lines of evidence against lactate shuttling include the following: astrocytic oxidation of glutamate after its uptake can help “pay” for its uptake without stimulating glycolysis; blockade of glutamate receptors during activation in vivo prevents upregulation of metabolism and lactate release without impairing glutamate uptake; blockade of β‐adrenergic receptors prevents the fall in OGI in activated human and rat brain while allowing glutamate uptake; and neurons upregulate glucose utilization in vivo and in vitro under many stimulatory conditions. Studies in immature cultured cells are not appropriate models for lactate shuttling in adult brain because of their incomplete development of metabolic capability and astrocyte–neuron interactions. Astrocyte–neuron lactate shuttling does not make large, metabolically significant contributions to energetics of brain activation. © 2017 Wiley Periodicals, Inc.

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Details

Published: Feb 02, 2017
Vol/Issue: 95(11)
Pages: 2103-2125
License: View

Authors

G

Gerald A. Dienel

Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, and Department of Cell Biology and Physiology University of New Mexico Albuquerque New Mexico

Cite This Article

Gerald A. Dienel (2017). Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain. Journal of Neuroscience Research, 95(11), 2103-2125. https://doi.org/10.1002/jnr.24015

Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain

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