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Cited by 381Neuroscience and Neuropharmacology ResearchAdvanced MRI Techniques and ApplicationsNeurogenesis and neuroplasticity mechanisms

Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism

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Lundgaard, Iben, Li, Baoman, Xie, Lulu, Kang, Hongyi, Sanggaard, Simon, Haswell, John D. R., Sun, Wei, Goldman, Siri +5 more·2015·Nature Communications
DOI 10.1038/ncomms7807PMC PMC4410436
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Abstract

Metabolically, the brain is a highly active organ that relies almost exclusively on glucose as its energy source. According to the astrocyte-to-neuron lactate shuttle hypothesis, glucose is taken up by astrocytes and converted to lactate, which is then oxidized by neurons. Here we show, using two-photon imaging of a near-infrared 2-deoxyglucose analogue (2DG-IR), that glucose is taken up preferentially by neurons in awake behaving mice. Anaesthesia suppressed neuronal 2DG-IR uptake and sensory stimulation was associated with a sharp increase in neuronal, but not astrocytic, 2DG-IR uptake. Moreover, hexokinase, which catalyses the first enzymatic steps in glycolysis, was highly enriched in neurons compared with astrocytes, in mouse as well as in human cortex. These observations suggest that brain activity and neuronal glucose metabolism are directly linked, and identiy the neuron as the principal locus of glucose uptake as visualized by functional brain imaging. The brain is a highly active organ that relies almost exclusively on glucose as its energy source, but whether glucose is directly taken up by neurons or whether it is converted to lactate by astrocytes before neuronal uptake is still unclear. Here the authors perform in vivoimaging in awake mice and show evidence in support of the direct uptake of glucose by neurons.

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  • Neurons directly take up more than half of blood-borne glucose.

    “In fact, neurons have been shown to directly take up more than half of blood-borne glucose11.”

    From Energy paradox in REM sleep: balancing supply and consumption in brain metabolism (2026) · cites this paper as [11]

    The Discussion (page not specified) reports that neurons took up more glucose analogue than astrocytes in awake mice. It does not establish that neurons take up more than half of blood-borne glucose: the in vivo tracer was delivered into cerebrospinal fluid, and no blood-derived fraction is quantified. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Two recent in vivo studies monitoring glucose analogue accumulation in somatosensory cortex during whisker stimulation used two different glucose analogues and obtained opposite results.

    “Two recent in vivo studies monitored glucose analogue accumulation in somatosensory cortex during whisker stimulation; they used two different glucose analogues and obtained opposite results.”

    From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Lundgaard et al., 2015

  • Using a phosphorylatable glucose analogue (2DG-IR) in nonanesthetized mice, better labeling was seen in neurons than astrocytes, particularly with whisker stimulation.

    “Using a different, phosphorylatable glucose analogue (2DG-IR) in nonanesthetized mice, better labeling was seen in neurons than astrocytes, particularly with whisker stimulation (Lundgaard et al., 2015).”

    From Fueling thought: Management of glycolysis and oxidative phosphorylation in neuronal metabolism (2018) · cites this paper as Lundgaard et al., 2015

  • In vivo measurements of stimulated glucose analog uptake have given conflicting results.

    “In vivo measurements to learn which cell type shows greater stimulated uptake of glucose analogs have given conflicting results (Chuquet et al., 2010; Lundgaard et al., 2015)”

    From Neuronal Stimulation Triggers Neuronal Glycolysis and Not Lactate Uptake (2017) · cites this paper as Lundgaard et al., 2015

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Research works printed but not linked: 2

  1. [42]Siesjo BK Brain Energy Metabolism A Wiley-Interscience publication 1978 New York John Wiley & Sons
  2. [53]Clarke D Lajitha A Maker H Basic Neurochemistry 1989 fourth edn New York Raven Press 542 550 vol.

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Authors
Lundgaard, I., Li, B., Xie, L., Kang, H., Sanggaard, S., Haswell, J. D. R., Sun, W., Goldman, S., Blekot, S., Nielsen, M., Takano, T., Deane, R., & Nedergaard, M.
Affiliations
  • University of Copenhagen (DK)
  • University of Rochester Medicine (US)
Corresponding author
  • Lundgaard, Iben
  • Nedergaard, Maiken
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2015-04-23
Volume
6
Issue
1
Pages
6807-6807
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms7807
PMC
PMC4410436
OpenAlex
W2053405269
Cited by
381
References
66
Citations by year
2026: 31 · 2025: 38 · 2024: 32 · 2023: 38 · 2022: 27 · 2021: 33 · 2020: 34 · 2019: 30 · 2018: 39 · 2017: 34 · 2016: 32 · 2015: 11
FWCI
17.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Lundbeckfonden
  • Novo Nordisk
  • Novo Nordisk Fonden (NNF13OC0004258)
  • H. Lundbeck A/S
  • National Institutes of Health
  • National Institute on Aging (R01AG048769)
  • National Institute of Neurological Disorders and Stroke (R01NS078304, R01NS078167, R01NS075177)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD076892)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords
neuronal glucose uptake, brain glucose metabolism, 2-deoxyglucose, hexokinase, astrocytes, sensory stimulation, anesthesia, brain energy metabolism, functional neuroimaging, awake behaving mice
MeSH terms
Anesthetics, Dissociative, Animals, Antimetabolites, Astrocytes, Brain, Cells, Cultured, Cerebral Cortex, Deoxyglucose, Glucose, Hexokinase, Humans, Hypnotics and Sedatives, Immunohistochemistry, Ketamine, Neurons, Physical Stimulation, RNA, Messenger, Wakefulness, Xylazine, Spectroscopy, Near-Infrared, Reverse Transcriptase Polymerase Chain Reaction, Mice, Functional Neuroimaging

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