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

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 (CMR glc ) 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 CMR O2 /CMR glc ) fell during activation in human brain, and the small rise in CMR O2 could not fully support oxidation of lactate produced by disproportionate increases in CMR glc . (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 CMR glc -CMR O2 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 b-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. V C 2017 Wiley Periodicals, Inc.

Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake

“…The ANLS hypothesis continues to generate controversy in the literature (Hertz, 2004; Chuquet et al, 2010; Patel et al, 2014; Lundgaard et al, 2015). Although there are strong arguments against the logic of the ANLS on its face (Dienel, 2017), there has been little conclusive evidence at the cellular level.…”

Glycogen distribution in mouse hippocampus

“…For instance, multiple optical and functional imaging studies have provided experimental support for neuronal glycolysis (Díaz‐García et al, ; Lundgaard et al, ; Patel et al, ), supporting earlier observations by autoradiography (Ryan & Sharp, ; Sharp, ). Interestingly, stoichiometric assessment of oxygen and glucose consumption indicates that a significant portion of released lactate in the extracellular space may not be utilized as substrates of oxidative metabolism (Dienel, ; Dienel & Cruz, ). Considering that lactate signaling may be concentration‐dependent and that local lactate levels can be relatively high in the diffusion‐limiting extracellular space, the interdependent relationship of glucose, glycogen, and lactate should be evaluated with physiologically relevant conditions (Dienel, ).…”

Neuroprotective potential of astroglia

“…The greatest controversy involves why neurons would even need lactate if there is glucose present. There is no immediately obvious answer to this question (Dienel, ). At least one important recent study performed using state‐of‐the‐art in vivo imaging in mouse cortex provided evidence that there is a gradient of lactate from astrocytes to neurons, which makes such transfer physically possible (Machler et al, ).…”