Lack of appropriate stoichiometry: Strong evidence against an energetically important astrocyte–neuron lactate shuttle in brain. Issue 11 (2nd February 2017)

• Record Type: Journal Article
• Authors: Dienel, Gerald A.
• Other Names: Schousboe Arne guestEditor.; Yu Albert C. H. guestEditor.; McKenna Mary C. guestEditor.
• Is Part Of: Journal of neuroscience research. Volume 95:Issue 11(2017)
• Page Start: 2103
• Page End: 2125
• Publication Date: 2017-02-02
• Subjects: brain activation -- glucose -- lactate -- metabolism -- oxygen–glucose index; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24015
• Languages: English
• ISSNs: 0360-4012

Abstract

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. Abstract : Lactate shuttling in activated brain is not substantial because total CMRglc > oxidative CMRglc, CMRO2 /CMRglc falls, small CMRO2 increases cannot support necessary lactate oxidation, labeled metabolites of glucose are not quantitatively retained, lactate is rapidly dispersed and released, and regulation of aerobic glycolysis involves β2 ‐adrenergic receptors, not glutamate uptake.