Response to ‘comment on recent modeling studies of astrocyte-neuron metabolic interactions’: much ado about nothing

Mangia, Silvia; DiNuzzo, Mauro; Giove, Federico; Carruthers, Anthony; Simpson, Ian A; Vannucci, Susan J

doi:10.1038/jcbfm.2011.29

Cited by 92Neuroscience and Neuropharmacology ResearchAmino Acid Enzymes and MetabolismCancer, Hypoxia, and Metabolism

Response to ‘comment on recent modeling studies of astrocyte-neuron metabolic interactions’: much ado about nothing

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Mangia, Silvia, DiNuzzo, Mauro, Giove, Federico, Carruthers, Anthony, Simpson, Ian A, Vannucci, Susan J·2011·Journal of Cerebral Blood Flow & Metabolism

DOI 10.1038/jcbfm.2011.29PMC PMC3130323

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Abstract

For many years, a tenet of cerebral metabolism held that glucose was the obligate energy substrate of the mammalian brain and that neuronal oxidative metabolism represented the majority of this glucose utilization. In 1994, Pellerin and Magistretti formulated the astrocyte-neuron lactate shuttle (ANLS) hypothesis, in which astrocytes, not neurons, metabolized glucose, with subsequent transport of the glycolytically derived lactate to fuel the energy needs of the neuron during neurotransmission. By considering the concentrations and kinetic characteristics of the nutrient transporter proteins, Simpson et al later supported the opposite view, in which lactate flows from neurons to astrocytes, thus leading to the neuron-astrocyte lactate shuttle (NALS). Most recently, a commentary was published in this journal attempting to discredit the NALS. This challenge has stimulated the present response in which we detail the inaccuracies of the commentary and further model several different possibilities. Although our simulations continue to support the predominance of neuronal glucose utilization during activation and neuronal to astrocytic lactate flow, the most important result is that, regardless of the direction of the flow, the overall contribution of lactate to cerebral glucose metabolism is found to be so small as to make this ongoing debate 'much ado about nothing'.

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MCT and lactate transport contribute to neuronal health and function.
“If an ANLS operates at rest, it could also explain why chronic disruption of MCT, LDH, or glycogenolysis in astrocytes can affect neuronal function (Suzuki et al., 2011; Zhang et al., 2016; Mazuel et al., 2017); these and similar results showing that MCT and lactate transport contribute to neuronal health and function provide evidence for some critical biological role for lactate uptake, but do”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Mangia et al., 2011

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Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization.
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“One is based on the astrocyte–neuron lactate shuttle (ANLS) hypothesis as originally proposed by Pellerin and Magistretti (1994) and subsequently modeled by Aubert and colleagues (Aubert and Costalat, 2005; Aubert et al, 2007).”
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“The ANLS hypothesis has been quite controversial for a long time (Chih et al., 2001; Gjedde and Marrett, 2001; Hertz, 2004; Mangia et al., 2011; Dienel, 2012, 2017; Bak and Walls, 2018; Barros and Weber, 2018; see also Dienel [2017] for strong arguments against ANLS at the tissue level).”
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Authors: Mangia, S., DiNuzzo, M., Giove, F., Carruthers, A., Simpson, I. A., & Vannucci, S. J.
Affiliations: University of Minnesota (US)
Fondazione Santa Lucia (IT)
Centro Ricerche Enrico Fermi (IT)
University of Massachusetts Chan Medical School (US)
Pennsylvania State University (US)
Weill Cornell Medicine (US)
Corresponding author: Mangia, Silvia
ORCID: Mangia, Silvia
DiNuzzo, Mauro
Giove, Federico
Simpson, Ian A
Vannucci, Susan J
Venue: Journal of Cerebral Blood Flow & Metabolism
Publisher: SAGE Publications
Published: 2011-03-23
Volume: 31
Issue: 6
Pages: 1346-1353
ISSN: 0271-678X (ISSN-L)
1559-7016
DOI: 10.1038/jcbfm.2011.29
PMC: PMC3130323
OpenAlex: W2020125871
Cited by: 92
References: 50
Citations by year: 2026: 3 · 2025: 4 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 4 · 2019: 5 · 2018: 6 · 2017: 12 · 2016: 7 · 2015: 5 · 2014: 7 · 2013: 15 · 2012: 14
FWCI: 5.17
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK36081, R01DK044888, DK44888, R01DK075130, DK075130, R01DK036081, R56DK036081)
National Institute of Neurological Disorders and Stroke (P30NS057091)
National Center for Research Resources (P41RR008079, P41RR08079)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: astrocyte-neuron lactate shuttle, brain glucose metabolism, lactate transport, nutrient transporters, brain energy metabolism
MeSH terms: Animals, Astrocytes, Brain, Energy Metabolism, Glucose, Humans, Models, Neurological, Neurons, Lactic Acid

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Response to ‘comment on recent modeling studies of astrocyte-neuron metabolic interactions’: much ado about nothing

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