Cited by 252Neuroscience and Neuropharmacology ResearchCancer, Hypoxia, and MetabolismNeurogenesis and neuroplasticity mechanisms

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Do active cerebral neurons really use lactate rather than glucose?

Chih, Ching-Ping, Lipton, Peter, Roberts, Eugene L·2001·Trends in Neurosciences

DOI 10.1016/s0166-2236(00)01920-2

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Abstract

Glucose has long been considered the substrate for neuronal energy metabolism in the brain. Recently, an alternative explanation of energy metabolism in the active brain, the astrocyte-neuron lactate shuttle hypothesis, has received attention. It suggests that during neural activity energy needs in glia are met by anaerobic glycolysis, whereas neuronal metabolism is fueled by lactate released from glia. In this article, we critically examine the evidence supporting this hypothesis and explain, from the perspective of enzyme kinetics and substrate availability, why neurons probably use ambient glucose, and not glial-derived lactate, as the major substrate during activity.

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A Bird's‐Eye View of Glycolytic Upregulation in Activated Brain: The Major Fate of Lactate Is Release From Activated Tissue, Not Shuttling to Nearby Neurons
Dienel, G. A., Rothman, D. L., & Mangia, S. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70111 · Cited by 21
“…ANLS model has been a controversial, debated topic for decades, and many investigators have challenged its validity (e.g., Chih and Roberts 2003; Chih et al. 2001; Hertz et al. 1998, 2007; Hertz and Dienel 2005; Hertz 2004; Dienel and Hertz 2001; Dienel 2017, 2019a, 2019b, 2012a, 2012b; Mangia…”
Training-induced elevations in extracellular lactate in hippocampus and striatum: Dissociations by cognitive strategy and type of reward
Newman, L. A., Scavuzzo, C. J., Gold, P. E., & Korol, D. L. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.12.001 · Cited by 21
2.1 The Support of Energy Metabolism in the Central Nervous System with Substrates Other than Glucose
Roberts, E. L. (2007) · Springer eBooks · doi:10.1007/978-0-387-30411-3_7 · Cited by 21
Feasibility of direct mapping of cerebral fluorodeoxy‐D‐glucose metabolism in situ at subcellular resolution using soft X‐ray fluorescence
Poitry‐Yamate, C., Gianoncelli, A., Kaulich, B., Kourousias, G., Magill, A. W., Lepore, M. G., Gajdosik, V., & Rolf Gruetter, A. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23171 · Cited by 20
“…well as glial processes (Smith, 2010), the physiological mechanisms underlying in vivo 18FDG PET neuroimages (Frackowiak et al., 2002), and the cell specificity of glucose metabolism, which has not yet been completely established (Chih et al., 2001), requires measurements at micrometer resolution.”
Background
Mammalian cerebral metabolism and amino acid neurotransmission during hibernation
Osborne, P. G., & Hashimoto, M. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05543.x · Cited by 20
1.2 Glucose, Oxidative Energy Metabolism, and Neural Function in Brain Slices—Glycolysis Plays a Key Role in Neural Activity
Okada, Y., & Lipton, P. (2007) · Springer eBooks · doi:10.1007/978-0-387-30411-3_2 · Cited by 20
Astrogliopathy as a loss of astroglial protective function against glycoxidative stress under hyperglycemia
Takahashi, S., Izawa, Y., & Suzuki, N. (2012) · Rinsho Shinkeigaku · doi:10.5692/clinicalneurol.52.41 · Cited by 19
Role of Brain Glycogen During Ischemia, Aging and Cell-to-Cell Interactions
Bastian, C., Quinn, J. P., Doherty, C. M., Franke, C., Faris, A. E. R., Brunet, S., & Baltan, S. (2019) · Advances in neurobiology · doi:10.1007/978-3-030-27480-1_12 · Cited by 18
Energy and Amino Acid Neurotransmitter Metabolism in Astrocytes
Waagepetersen, H. S., Sonnewald, U., & Schousboe, A. (2008) · Springer eBooks · doi:10.1007/978-0-387-79492-1_7 · Cited by 17
How the ‘Aerobic/Anaerobic Glycolysis’ Meme Formed a ‘Habit of Mind’ Which Impedes Progress in the Field of Brain Energy Metabolism
Schurr, A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031433 · Cited by 16
“The second prong questioned the ability of a waste product (lactate) to replace glucose, the universal obligatory substrate of energy metabolism, and even if it could be a substrate for ATP production, it should not be more than a minor contributor, never to replace glucose [37,38].”
Background
Energetic substrate availability regulates synchronous activity in an excitatory neural network
Tourigny, D. S., Karim, M. K. A., Echeveste, R., Kotter, M., & O'Neill, J. S. (2019) · PLoS ONE · doi:10.1371/journal.pone.0220937 · Cited by 17
“The nature of this neuronastrocyte relationship remains controversial however, with conflicting theories concerning the primary substrate of resting versus active neural metabolism as well as the relative fluxes through metabolic pathways in the two cell types (12-14).”
Background
From antioxidant to neuromodulator: The role of ascorbate in the management of major depression disorder
Ferreira, N. R., Vitorino, C., & Fortuna, A. C. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115300 · Cited by 16
Energy Metabolism in the Brain
Dienel, G. A. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-397179-1.00003-8 · Cited by 18
Development of a Model to Test Whether Glycogenolysis Can Support Astrocytic Energy Demands of Na+, K+-ATPase and Glutamate-Glutamine Cycling, Sparing an Equivalent Amount of Glucose for Neurons
Rothman, D. L., & Dienel, G. A. (2019) · Advances in neurobiology · doi:10.1007/978-3-030-27480-1_14 · Cited by 14
A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies
Dienel, G. A., Schousboe, A., McKenna, M. C., & Rothman, D. L. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15812 · Cited by 14
“…2001 ; Hertz, 2004a; Hertz & Dienel, 2005 ; Hertz, Gibbs, & Dienel, 2014 ; Hertz, Swanson, et al., 1998 ) and other groups (Bak et al., 2009 ; Chih et al., 2001 ; Chih & Roberts Jr, 2003; Dienel, 2012a, 2012c ; Dienel & Cruz, 2004 ; DiNuzzo et al., 2010a ; Lange et al., 2015 ; Mangia et al.,…”
Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a
Nguyen, N. T. Q., Ooi, L., Piller, S. C., & Münch, G. W. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201300145 · Cited by 13
“Resveratrol induces pronounced decreases in glucose consumption by Neuro2a cells Because glucose is the major energy source for living cells to produce ATP and GTP [38], we investigated whether the mechanism behind these resveratrol-induced increases in highenergy phosphates was due to an increase in glucose uptake.”
Background
d-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick
Baker, K., & Edwards, T. M. (2007) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2007.06.004 · Cited by 13
Lactate transportation is required for lymphocyte activation
Bröer, S. (2005) · Nature Chemical Biology · doi:10.1038/nchembio1205-356 · Cited by 12
Basic Principles of Functional MRI
Tang, C. Y. (2018) · Oxford University Press eBooks · doi:10.1093/med/9780190297763.003.0002 · Cited by 12
Redox Shuttles in the Brain
Pardo, B., & Contreras, L. (2011) · Advances in neurobiology · doi:10.1007/978-1-4614-1788-0_29 · Cited by 11
Autoimmune Modulation of Astrocyte-Mediated Homeostasis
Korn, T., Rao, M. S., & Magnus, T. (2006) · NeuroMolecular Medicine · doi:10.1385/nmm:9:1:1 · Cited by 12
“But still, there is an ongoing debate regarding whether this substrate shuttle hypothesis reflects reality in vivo ( Chih et al., 2001 ).”
Effect of temperature on FAD and NADH-derived signals and neurometabolic coupling in the mouse auditory and motor cortex
Ibrahim, B. A., Wang, H., Lesicko, A. M. H., Bucci, B., Paul, K., & Llano, D. A. (2017) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-017-2037-4 · Cited by 10
“The correlation between the higher blood flow carrying oxygen, uptake, and utilization of glucose and lactate upon neuronal activity is called neurometabolic coupling which has been reported by numerous in vitro [48, 61, 76, 102] and in vivo [9, 77, 94] studies.”
Background
Astroglia in Leukodystrophies
Jorge, M. S., & Bugiani, M. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-9913-8_9 · Cited by 11
Impact of Astrocytes on the Injury Induced by In Vitro Ischemia
Roque, C., & Baltazar, G. (2017) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-017-0483-3 · Cited by 10
Lactate is an alternative energy fuel to glucose in neurons under anesthesia
Yamada, A., Yamamoto, K., Imamoto, N., Momosaki, S., Hosoi, R., Yamaguchi, M., & Inoue, O. (2009) · Neuroreport · doi:10.1097/wnr.0b013e32833244f0 · Cited by 9
Effects of creatine and β-guanidinopropionic acid and alterations in creatine transporter and creatine kinases expression in acute seizure and chronic epilepsy models
Kim, D. W., Yeo, S., Ryu, H. J., Kim, J., Song, H., Kwon, O., Choi, S. Y., & Kang, T. (2010) · BMC Neuroscience · doi:10.1186/1471-2202-11-141 · Cited by 9
“ATP production by glycolysis in glia [4] and neurons has been recognized as an alternative source of energy [5,6].”
Background
The Feud over Lactate and Its Role in Brain Energy Metabolism: An Unnecessary Burden on Research and the Scientists Who Practice It
Schurr, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26094429 · Cited by 12
“This study was followed by an opinion article that essentially debunked the ANLS hypothesis [29].”
In vivo calibration of genetically encoded metabolite biosensors must account for metabolite metabolism during calibration and cellular volume
Dienel, G. A., & Rothman, D. L. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15775 · Cited by 9
“The notion of neuronal oxidation of astrocyte-derived lactate as preferred fuel during activation has been a controversial topic for decades (e.g., Chih et al., 2001 ; Chih & Roberts Jr, 2003 ; Dienel, 2012 ; Dienel, 2019a ; Dienel, 2019b; Hertz, 2004 ) in large part because data claimed to support…”
Background
Multifactorial Distress, the Warburg Effect, and Respiratory and pH Imbalance in Cancer Development
Drochioiu, G. (2023) · Stresses · doi:10.3390/stresses3020036 · Cited by 10
“Even working brain tissues partly oxidize glucose and produce some lactic acid [100,144–147].”
Background
Aldehydes and disturbance of carbohydrate metabolism: Some consequences and possible approaches to its normalization
Dmitriev, L. F., & Дугин, С. Ф. (2007) · Archives of Physiology and Biochemistry · doi:10.1080/13813450701384783 · Cited by 8
“Finally, anaerobic glycolysis is activated and L-lactate is produced (Chin et al., 2001).”
Background
Lactate-starved neurons in ALS
Martinez, B. (2012) · Disease Models & Mechanisms · doi:10.1242/dmm.010892 · Cited by 7
“Glia have important roles in sustaining neuronal function, including glutamate cycling and transport of glycolytic substrates to axons during periods of intense activity (Chih et al., 2001).”
Background
Extracellular levels of glucose in the hippocampus and striatum during maze training for food or water reward in male rats
Scavuzzo, C. J., Newman, L. A., Gold, P. E., & Korol, D. L. (2020) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113385 · Cited by 7
Impaired active avoidance learning in infant rats appears to be related to insufficient metabolic recruitment of the lateral septum
Riedel, A., Gruß, M., Bock, J., & Braun, K. (2009) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2009.11.001 · Cited by 7
Functional brain network controllability dysfunction in Alzheimer’s disease and its relationship with cognition and gene expression profiling
Zheng, C., Xiao, X., Zhao, W. D., Yang, Z., Guo, S., & Initiative, A. D. N. (2024) · Journal of Neural Engineering · doi:10.1088/1741-2552/ad357e · Cited by 8
“Although glucose was thought to be the primary fuel for the energy needed by neurons to maintain their activity, lactic acid produced by glial cells also provided fuel for neuronal activity in response to long-term stimulation [77].”
Metabolic response of SH-SY5Y cells to gold nanoparticles by NMR-based metabolomics analyses
Paris, D., Melck, D. J., Longo, A., Napoletano, S., Carotenuto, G., Nicolais, L., Motta, A., & Vitale, E. (2016) · Biomedical Physics & Engineering Express · doi:10.1088/2057-1976/2/4/045003 · Cited by 6
“Lactate might play useful roles in the adult CNS, since it is thought to be an important source of energy fuel for neurons (Pellerin and Magistretti 1994, Chih et al 2001).”
Background
Glial-neuronal interactions and brain energy metabolism
Brown, A. M., Tekkök, S., & Ransom, B. (2004) · Springer eBooks · doi:10.1007/978-1-4020-7937-5_11 · Cited by 6

Authors: Chih, C.-P., Lipton, P., & Roberts, E. L.
Affiliations: Miami VA Healthcare System (US)
University of Wisconsin–Madison (US)
University of Miami (US)
Corresponding author: Roberts, Eugene L
Venue: Trends in Neurosciences
Publisher: Elsevier BV
Published: 2001-10
Volume: 24
Issue: 10
Pages: 573-578
ISSN: 0166-2236 (ISSN-L)
DOI: 10.1016/s0166-2236(00)01920-2
OpenAlex: W1966886729
Cited by: 252
References: 67
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 6 · 2021: 3 · 2020: 8 · 2019: 5 · 2018: 6 · 2017: 12 · 2016: 3 · 2015: 6 · 2014: 8 · 2013: 5 · 2012: 13
FWCI: 1.78
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Trends in Neurosciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
Keywords: astrocyte-neuron lactate shuttle, neuronal energy metabolism, glucose utilization, lactate, anaerobic glycolysis, brain energy metabolism, substrate availability, enzyme kinetics
MeSH terms: Animals, Astrocytes, Cerebral Cortex, Glucose, Humans, Neurons, Lactic Acid

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Do active cerebral neurons really use lactate rather than glucose?

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