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Lactate fuels the human brain during exercise.
Abstract
The human brain releases a small amount of lactate at rest, and even an increase in arterial blood lactate during anesthesia does not provoke a net cerebral lactate uptake. However, during cerebral activation associated with exercise involving a marked increase in plasma lactate, the brain takes up lactate in proportion to the arterial concentration. Cerebral lactate uptake, together with glucose uptake, is larger than the uptake accounted for by the concomitant O 2 uptake, as reflected by the decrease in cerebral metabolic ratio (CMR) [the cerebral molar uptake ratio O 2 /(glucose+½ lactate)] from a resting value of 6 to <2. The CMR also decreases when plasma lactate is not increased, as during prolonged exercise, cerebral activation associated with mental activity, or exposure to a stressful situation. The CMR decrease is prevented with combined β 1 ‐ and β 2 ‐adrenergic receptor blockade but not with β 1 ‐adrenergic blockade alone. Also, CMR decreases in response to epinephrine, suggesting that a β 2 ‐adrenergic receptor mechanism enhances glucose and perhaps lactate transport across the blood‐brain barrier. The pattern of CMR decrease under various forms of brain activation suggests that lactate may partially replace glucose as a substrate for oxidation. Thus, the notion of the human brain as an obligatory glucose consumer is not without exceptions.—Quistorff, B., Secher, N. H., and Van Lieshout, J. J. Lactate fuels the human brain during exercise. FASEB J. 22, 3443–3449 (2008)
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“peripheral blood lactate (e.g., from muscles) can cross the blood–brain barrier and provides energy to the brain”
From Dose-Response Matters! - A Perspective on the Exercise Prescription in Exercise-Cognition Research (2019) · cites this paper as Quistorff et al., 2008
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“However, with reference to the first point, an increase of arterial lactate by anesthesia or lactate infusion did not significantly increase the lactate uptake into the brain (Kuhr et al., 1988; Quistorff et al., 2008; Rose, 2010).”
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“In contrast, blood lactate substantially increases during/after high-intensity exercise, and it is taken up by the brain (Ide et al., 2000; GonzalezAlonso et al., 2004; Quistorff et al., 2008; Siebenmann et al., 2021).”
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“Lastly, akin to the situation of heavy exercise and high metabolic demand, in critical illness with compromised perfusion and oxygen delivery, lactate produced in large amounts in skeletal muscle [ 85 ] may be a preferred fuel for neuronal and cardiac mitochondrial oxidation [ 17 , 117 ].”
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“9,19,27,28 Exercise-induced arterial lactate elevation to 2.5–3.5 mmol/L re-sults in lactate uptake by the brain as measured using AV concentration differences.”
InfluentialPark, J.-H., Kim, J., & Mikami, T. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.736905 · Cited by 68
Schroeder, U., Himpe, B., Pries, R., Vonthein, R., Nitsch, S., & Wollenberg, B. (2013) · Nutrition and Cancer · doi:10.1080/01635581.2013.804579 · Cited by 65
“It was shown that the human brain and the heart belongs to those organs in which lactate can replace glucose as energetic substrate during intensive exercise with elevated blood lactate level (14,15).”
BackgroundCoco, M., Caggia, S., Musumeci, G., Perciavalle, V., Graziano, A. C. E., Pannuzzo, G., & Cardile, V. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23154 · Cited by 64
“The muscular lactate is released into the blood, and it has been observed that O2, glucose, and lactate extractions by the CNS increase during maximal exercise, supporting the hypothesis that brain activation is enhanced during intense exercise (Dalsgaard et al., 2002, 2004; Quistorff et al., 2008).”
BackgroundHyperventilation, cerebral perfusion, and syncope
Immink, R. V., Pott, F. C., Secher, N. H., & LIESHOUT, J. J. V. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00637.2013 · Cited by 62
“In response to exercise the associated increase in CBF enhances cerebral oxygenation whereas, in contrast, muscle oxygenation declines with increasing work rate (83).”
BackgroundSelf-citationHertz, L., Gibbs, M. E., & Dienel, G. A. (2014) · Frontiers in Neuroscience · doi:10.3389/fnins.2014.00261 · Cited by 58
“Small amounts of lactate, equivalent to ∼5% of the glucose entering brain, are released to blood under resting conditions (Quistorff et al., 2008; Dienel, 2012), whereas during activation considerable quantities of lactate are released from brain to blood, both directly (22% during spreading…”
BackgroundInfluentialBerndt, N., Kann, O., & Holzhütter, H.-G. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2015.70 · Cited by 56
Quistorff, B., & Grunnet, N. (2011) · Aging · doi:10.18632/aging.100329 · Cited by 56
Self-citationPetit, J.-M., Gyger, J., Burlet-Godinot, S., Fiumelli, H., Martin, J., & Magistretti, P. J. (2013) · SLEEP · doi:10.5665/sleep.3034 · Cited by 56
Herold, F., Aye, N., Lehmann, N., Taubert, M., & Müller, N. G. (2020) · Brain Sciences · doi:10.3390/brainsci10030175 · Cited by 56
Why does the brain (not) have glycogen?
DiNuzzo, M., Maraviglia, B., & Giove, F. (2011) · BioEssays · doi:10.1002/bies.201000151 · Cited by 53
Huang, Z., Zhang, Y., Zhou, R., Yang, L., & Pan, H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.656455 · Cited by 58
Nutritional Care for Aging Cats and Dogs
Laflamme, D. P. (2012) · Veterinary Clinics of North America Small Animal Practice · doi:10.1016/j.cvsm.2012.04.002 · Cited by 57
Wang, R., He, M., Ou, X., Xie, X., & Kang, Y. (2022) · Frontiers in Neurology · doi:10.3389/fneur.2022.662385 · Cited by 54
Regulation of cerebral metabolism during cortical spreading depression
Feuerstein, D., Backes, H., Gramer, M., Takagaki, M., Gabel, P., Kumagai, T., & Graf, R. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15612779 · Cited by 52
“Quistorff et al.30 reviewed studies that measured arterio-venous differences of lactate concentrations during physical exercise and accordingly, during periods of elevated arterial lactate concentrations.”
BackgroundTwisk, F. (2014) · Frontiers in Physiology · doi:10.3389/fphys.2014.00109 · Cited by 51
“The distinction between patients with ME/CFS with post-exertional malaise and patients without post-exertional malaise is reflected by particular clinical and immunological differences (Maes et al., 2012a; Brenu et al., 2013).”
BackgroundTheriault, J. E., Shaffer, C., Dienel, G. A., Sander, C. Y. M., Hooker, J. M., Dickerson, B. C., Barrett, L. F., & Quigley, K. S. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105373 · Cited by 60
Rowing, the ultimate challenge to the human body – implications for physiological variables
Volianitis, S., & Secher, N. H. (2009) · Clinical Physiology and Functional Imaging · doi:10.1111/j.1475-097x.2009.00867.x · Cited by 50
“, 2002) and it serves as a substrate for tissues including muscle, and the brain (Quistorff et al., 2008; Secher et al., 2008).”
BackgroundSelf-citationExecutive function after exhaustive exercise
Sudo, M., Komiyama, T., Aoyagi, R., Nagamatsu, T., Higaki, Y., & Ando, S. (2017) · European Journal of Applied Physiology · doi:10.1007/s00421-017-3692-z · Cited by 50
“Rather, lactate is well known to be taken up in the brain, which serves as an energy fuel (Quistorff et al. 2008; van Hall 2010).”
Törpel, A., Herold, F., Hamacher, D., Müller, N. G., & Schega, L. (2018) · Journal of Clinical Medicine · doi:10.3390/jcm7100337 · Cited by 49
Seifert, T., Rasmussen, P., Brassard, P., Homann, P. H., Wissenberg, M., Nordby, P., Stallknecht, B. M., Secher, N. H., & Nielsen, H. B. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00277.2009 · Cited by 47
“Cerebral energy metabolism is covered almost exclusively by oxidation of glucose since the molar ratio between the brain oxygen (O2) uptake to that of glucose (the O2-glucose index; OGI) is close to 6 (23).”
BackgroundSelf-citationInterleukin 6-independent metabolic reprogramming as a driver of cancer-related fatigue
Grossberg, A. J., Vichaya, E. G., Gross, P. S., Ford, B. G., Scott, K. A., Estrada, D. J., Vermeer, D. W., Vermeer, P. D., & Dantzer, R. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.05.043 · Cited by 47
“How metabolic exhaustion at the level of the muscle is communicated to the brain and how that influences top-down behavioral control is largely unknown, as peripheral metabolite effectors of exhaustion, such as lactate, do not appear to cause fatigue like behavior when delivered to the brain (Matsui et al., 2017; Quis…”
BackgroundCerebral non‐oxidative carbohydrate consumption in humans driven by adrenaline
Seifert, T. S., Brassard, P., Jørgensen, T. B., Hamada, A. J., Rasmussen, P., Quistorff, B., Secher, N. H., & Nielsen, H. B. (2008) · The Journal of Physiology · doi:10.1113/jphysiol.2008.162073 · Cited by 47
“…OGI and OCI have been observed during intense visual stimulation in the rat (Schmalbruch et al. 2002) and in humans confined in a PET scanner (Fox et al. 1988) and similar decreases have been reported during maximal whole body exercise where the OCI may become as low as 1.7 (Quistorff et al. 2008).”
BackgroundMethodInfluentialSelf-citationRedox Signaling in Widespread Health Benefits of Exercise
Louzada, R. A. N., Bouvière, J., Matta, L., Werneck‐de‐Castro, J. P., Dupuy, C., de Carvalho, D. P., & Fortunato, R. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7949 · Cited by 49
“Serum lactate can be uptaken by a wide range of cells such as contracting skeletal muscles themselves (16), heart (59), brain (132), liver (48), kidney (112), astrocytes, or neurons (126).”
Dietary Energy Partition: The Central Role of Glucose
Remesar, X., & Alemany, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21207729 · Cited by 45
“The brain is an active user of lactate [37] and glycerol [38,39].”
BackgroundA trade-off between cognitive and physical performance, with relative preservation of brain function
Longman, D. P., Stock, J. T., & Wells, J. C. K. (2017) · Scientific Reports · doi:10.1038/s41598-017-14186-2 · Cited by 46
Kann, O. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15867 · Cited by 44
“During exhaustive physical exercise, the brain takes up lactate in amounts that may supersede the uptake of glucose (Ide et al., 2000; Quistorff et al., 2008), and alterations such as moderate hypoglycemia and reduced cerebral oxygenation were reported (Rasmussen et al., 2010; Secher et al., 2008).”
BackgroundBlonz, E. R. (2017) · Journal of Alzheimer s Disease · doi:10.3233/jad-170549 · Cited by 43
Fedotova, E. I., Долгачева, Л. П., Abramov, A. Y., & Berezhnov, A. V. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02583-8 · Cited by 49
Dennis, A., Thomas, A. G., Rawlings, N. B., Near, J., Nichols, T. E., Clare, S., Johansen-Berg, H., & Stagg, C. J. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00351 · Cited by 43
Qiu, L.-L., Tan, X.-X., Yang, J., Ji, M., Zhang, H., Zhao, C., Xia, J., & Sun, J. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03413-9 · Cited by 44
“Notably, lactate is a molecular released after exercise by the muscle, which could cross the blood–brain barrier (BBB) [25] and support neuronal energy demands [26].”
BackgroundColucci, A. C. M., Tassinari, I. D., Loss, E. D. S., & de Fraga, L. S. (2023) · Neuroscience · doi:10.1016/j.neuroscience.2023.06.022 · Cited by 46
Lactic acidosis: implications for human exercise performance
Cairns, S. P., & Lindinger, M. I. (2025) · European Journal of Applied Physiology · doi:10.1007/s00421-025-05750-0 · Cited by 40
Aspects on the Physiological and Biochemical Foundations of Neurocritical Care
Nordström, C., Koskinen, L., & Olivecrona, M. (2017) · Frontiers in Neurology · doi:10.3389/fneur.2017.00274 · Cited by 40
Glucocorticoids, metabolism and brain activity
Jaszczyk, A., & Juszczak, G. R. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.03.007 · Cited by 45
Reduced gluconeogenesis and lactate clearance in Huntington's disease
Josefsen, K. E., Nielsen, S. M. B., Campos, A., Seifert, T., Hasholt, L., Nielsen, J. E., Nørremølle, A., Skotte, N. H., Secher, N. H., & Quistorff, B. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.08.009 · Cited by 38
Self-citation
Metadata
- Authors
- Quistorff, B., Secher, N. H., & Van Lieshout, J. J.
- Affiliations
- University of Copenhagen (DK)
- Department of Internal Medicine, Medium Care Unit University of Amsterdam Amsterdam The Netherlands
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2008-07-24
- Volume
- 22
- Issue
- 10
- Pages
- 3443-3449
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2141894573
- Cited by
- 262
- References
- 54
- Citations by year
- 2026: 17 · 2025: 21 · 2024: 15 · 2023: 23 · 2022: 14 · 2021: 14 · 2020: 12 · 2019: 14 · 2018: 10 · 2017: 13 · 2016: 12 · 2015: 15 · 2014: 19 · 2013: 16 · 2012: 15
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Health Sciences › Medicine › Physiology (medical) › Cardiovascular and exercise physiology
- Keywords
- brain energy metabolism, physical activity, glucose oxidation, beta-adrenergic receptors, epinephrine, blood-brain barrier transport, brain glucose metabolism
- MeSH terms
- Anaerobiosis, Brain, Glucose, Humans, Oxygen, Exercise, Lactic Acid
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