Supply and demand in cerebral energy metabolism: the role of nutrient transporters

Simpson, Ian A; Carruthers, Anthony; Vannucci, Susan J

doi:10.1038/sj.jcbfm.9600521

Cited by 812Barrier Structure and Function StudiesNeuroscience and Neuropharmacology ResearchAmino Acid Enzymes and Metabolism

Supply and demand in cerebral energy metabolism: the role of nutrient transporters

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Simpson, Ian A, Carruthers, Anthony, Vannucci, Susan J·2007·Journal of Cerebral Blood Flow & Metabolism

DOI 10.1038/sj.jcbfm.9600521PMC PMC2094104

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Abstract

Glucose is the obligate energetic fuel for the mammalian brain, and most studies of cerebral energy metabolism assume that the majority of cerebral glucose utilization fuels neuronal activity via oxidative metabolism, both in the basal and activated state. Glucose transporter (GLUT) proteins deliver glucose from the circulation to the brain: GLUT1 in the microvascular endothelial cells of the blood-brain barrier (BBB) and glia; GLUT3 in neurons. Lactate, the glycolytic product of glucose metabolism, is transported into and out of neural cells by the monocarboxylate transporters (MCT): MCT1 in the BBB and astrocytes and MCT2 in neurons. The proposal of the astrocyte-neuron lactate shuttle hypothesis suggested that astrocytes play the primary role in cerebral glucose utilization and generate lactate for neuronal energetics, especially during activation. Since the identification of the GLUTs and MCTs in brain, much has been learned about their transport properties, that is capacity and affinity for substrate, which must be considered in any model of cerebral glucose uptake and utilization. Using concentrations and kinetic parameters of GLUT1 and -3 in BBB endothelial cells, astrocytes, and neurons, along with the corresponding kinetic properties of the MCTs, we have successfully modeled brain glucose and lactate levels as well as lactate transients in response to neuronal stimulation. Simulations based on these parameters suggest that glucose readily diffuses through the basal lamina and interstitium to neurons, which are primarily responsible for glucose uptake, metabolism, and the generation of the lactate transients observed on neuronal activation.

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Lactate released from skeletal muscles during exercise and ketone bodies derived from liver from metabolism of fatty acids are transported from blood into the brain across the blood-brain barrier by monocarboxylate transporter-1 (MCT1).
“Lactate released from skeletal muscles during exercise, and ketone bodies derived from liver from metabolism of fatty acids are transported from blood into the brain across the BBB by monocarboxylate transporter-1 (MCT1) (540), and then utilized as alternative energy metabolites by the brain (487).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [540]
Detailed transport modeling shows that MCT2 is capable of ample lactate export from neurons at physiological concentrations.
“Moreover, detailed transport modeling shows that MCT2 is capable of ample lactate export from neurons at physiological concentrations (Simpson et al., 2007).”
From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Simpson et al., 2007

THE [ 14 C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1
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The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders
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Blood lactate is an important energy source for the human brain.
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Role of Monocarboxylate Transporters in Drug Delivery to the Brain
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The role of astroglia in neuroprotection
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Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism
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“Moreover, detailed transport modeling shows that MCT2 is capable of ample lactate export from neurons at physiological concentrations (Simpson et al., 2007).”
Background
Morphological, cellular and molecular basis of brain infection in COVID-19 patients
Crunfli, F., Carregari, V. C., Veras, F. P., Vendramini, P. H., Valença, A. G. F., Antunes, A. S. L. M., Brandão-Teles, C., da Silva Zuccoli, G., Reis-de-Oliveira, G., Silva-Costa, L. C., et al. (2020) · doi:10.1101/2020.10.09.20207464 · Cited by 331 · see citing works
The role of glucose transporters in brain disease: Diabetes and Alzheimer’s disease
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13 C MRS studies of neuroenergetics and neurotransmitter cycling in humans
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The Role of APOE4 in Disrupting the Homeostatic Functions of Astrocytes and Microglia in Aging and Alzheimer’s Disease
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Lactate fuels the human brain during exercise.
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The biochemistry of ketogenesis and its role in weight management, neurological disease and oxidative stress
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APOE alters glucose flux through central carbon pathways in astrocytes
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Cognitive cost as dynamic allocation of energetic resources
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Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma
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Chronic social stress-induced hyperglycemia in mice couples individual stress susceptibility to impaired spatial memory
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Authors: Simpson, I. A., Carruthers, A., & Vannucci, S. J.
Affiliations: Pennsylvania State University (US)
University of Massachusetts Chan Medical School (US)
Morgan Stanley Children's Hospital (US)
ORCID: Simpson, Ian A
Vannucci, Susan J
Venue: Journal of Cerebral Blood Flow & Metabolism
Publisher: SAGE Publications
Published: 2007-11
Volume: 27
Issue: 11
Pages: 1766-1791
ISSN: 0271-678X (ISSN-L)
1559-7016
DOI: 10.1038/sj.jcbfm.9600521
PMC: PMC2094104
OpenAlex: W2055908419
Cited by: 812
References: 152
Citations by year: 2026: 29 · 2025: 36 · 2024: 39 · 2023: 35 · 2022: 36 · 2021: 46 · 2020: 62 · 2019: 39 · 2018: 49 · 2017: 42 · 2016: 44 · 2015: 49 · 2014: 45 · 2013: 57 · 2012: 47
FWCI: 3.01
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
Funders: National Institutes of Health (5p01hd030704-10)
National Institute of Diabetes and Digestive and Kidney Diseases (DK36081, R01DK044888, DK44888, R01DK075130, R01DK036081, R56DK036081)
National Institute of Neurological Disorders and Stroke (R01NS041405, NS41405-01)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01 HD30704)
Topics: Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: brain glucose metabolism, glucose transporters, GLUT1, GLUT3, monocarboxylate transporters, MCT1, MCT2, blood-brain barrier, astrocyte-neuron lactate shuttle, lactate transport, astrocytes, neuronal activation, glucose diffusion, transport kinetics
MeSH terms: Animals, Brain Chemistry, Carrier Proteins, Energy Metabolism, Glucose, Humans, Kinetics, Lactic Acid

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