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 can cross the blood-brain barrier and provides energy to the brain.
“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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“Lactate uptake and subsequent utilization by consumer 422 tissues (especially active oxidative muscle fibers, liver, kidney, heart, lungs and brain) have been 423 reported to be directly dependent on lactate delivery to these tissues as determined from blood 424 lactate concentration and regional blood flow (1, 2, 5,…”
BackgroundEnergy Metabolism of the Brain
McKenna, M. C., Dienel, G. A., Sonnewald, U., Waagepetersen, H. S., & Schousboe, A. (2012) · Elsevier eBooks · doi:10.1016/b978-0-12-374947-5.00011-0 · Cited by 161 · see citing works
Maintained exercise‐enhanced brain executive function related to cerebral lactate metabolism in men
Hashimoto, T., Tsukamoto, H., Takenaka, S., Olesen, N. D., Petersen, L. G., Sørensen, H., Nielsen, H. B., Secher, N. H., & Ogoh, S. (2018) · The FASEB Journal · doi:10.1096/fj.201700381rr · Cited by 156 · see citing works
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L-Lactate Promotes Adult Hippocampal Neurogenesis
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“It is well established that there are differences in the functionality and connectivity between the ventral and dorsal hippocampus (Sahay and Hen, 2007; Huckleberry et al., 2018).”
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A metabolic switch in brain: glucose and lactate metabolism modulation by ascorbic acid
Castro, M. A., Beltrán, F. A., Brauchi, S. E., & Concha, I. I. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06151.x · Cited by 147 · see citing works
“Only under extreme conditions, like starvation or prolonged exercise, could these compounds be important exogenous sources of metabolic fuel for the brain (Hasselbalch et al. 1995; Dalsgaard 2006; Quirstoff et al. 2008).”
BackgroundZimmer, P., Bloch, W., Schenk, A., Oberste, M., Riedel, S., Kool, J., Langdon, D. W., Dalgas, U., Kesselring, J., & Bansi, J. (2017) · Multiple Sclerosis Journal · doi:10.1177/1352458517728342 · Cited by 146 · see citing works
Lactate oxidation at the mitochondria: a lactate-malate-aspartate shuttle at work
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“In the brain, however, increasing the concentration of lactate in circulation (e.g., as during exercise) results in an increase in lactate disposal in the brain (Quistorff et al., 2008; van Hall et al., 2009; Boumezbeur et al., 2010; Dienel, 2012).”
BackgroundMultiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin
Farshbaf, M. J., & Alviña, K. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.649929 · Cited by 143 · see citing works
“In addition, lactate could be used as energy source by neurons (Quistorff et al., 2008).”
BackgroundBDNF Impact on Biological Markers of Depression—Role of Physical Exercise and Training
Murawska‐Ciałowicz, E., Wiatr, M., Ciałowicz, M., de Assis, G. G., Borowicz, W., Rocha‐Rodrigues, S., Paprocka‐Borowicz, M., & Marques, A. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18147553 · Cited by 140 · see citing works
“It is also one of the important metabolites produced during exercise, and assists as a fuel for the brain [119].”
BackgroundOrgan-Specific Physiological Responses to Acute Physical Exercise and Long-Term Training in Humans
HEINONEN, I. H. A., Kalliokoski, K. K., Hannukainen, J. C., Duncker, D. J., Nuutila, P., & Knuuti, J. M. (2014) · Physiology · doi:10.1152/physiol.00067.2013 · Cited by 127 · see citing works
“However, with increasing exercise intensity, brain glucose uptake decreases (75) as the uptake and utilization of lactate is enhanced (65, 139, 182).”
BackgroundLactate Dehydrogenase B: A Metabolic Marker of Response to Neoadjuvant Chemotherapy in Breast Cancer
Dennison, J. B., Molina, J. R., Mitra, S., Gonzalez-Angulo, A. M., Balko, J. M., Kuba, M. G., Sanders, M. E., Pinto, J. A., Gómez, H., Arteaga, C. L., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0623 · Cited by 115 · see citing works
“In tissues like the brain that use lactate as energy source, LDHB promotes lactate uptake during exercise; other cells like erythrocytes use LDHB for glycolysis to synthesize lactate (37).”
Takimoto, M., & Hamada, T. (2014) · Journal of Applied Physiology · doi:10.1152/japplphysiol.01288.2013 · Cited by 115 · see citing works
“In addition, GLUT1, the well-characterized transport system for D-glucose, is also abundantly expressed in astrocytic and endothelial cells (33, 47).”
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“Lactate is a major exercise-induced products [69, 70].”
Lactate administration reproduces specific brain and liver exercise‐related changes
Lezi, E., Lu, J., Selfridge, J. E., Burns, J. M., & Swerdlow, R. H. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12394 · Cited by 110 · see citing works
“Lactate imported from the blood to the brain is used to generate energy (Quistorff et al. 2008; Gallagher et al. 2009; van Hall et al. 2009; Boumezbeur et al. 2010; Wyss et al. 2011), protects ischemic neurons (Berthet et al. 2009), and facilitates memory formation (Newman et al. 2011; Suzuki et…”
BackgroundXue, X., Liu, B., Hu, J., Bian, X., & Lou, S. (2022) · Nutrition & Metabolism · doi:10.1186/s12986-022-00687-z · Cited by 109 · see citing works
“the concentration of lactate is between 1 and 15 mM, there is no indication that cerebral lactate uptake will be saturated [67], indicating that the brain is with the highcapacity lactate transport system.”
BackgroundHypoxia and exercise provoke both lactate release and lactate oxidation by the human brain
Overgaard, M., Rasmussen, P. V., Bohm, A. M., Seifert, T., Brassard, P., Zaar, M., Homann, P. H., Evans, K. A., Nielsen, H. B., & Secher, N. H. (2012) · The FASEB Journal · doi:10.1096/fj.11-191999 · Cited by 102 · see citing works
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Cerebral glucose and lactate consumption during cerebral activation by physical activity in humans
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“40–50% of total carbohydrate uptake (10).”
BackgroundLactate is an energy substrate for rodent cortical neurons and enhances their firing activity
Karagiannis, A., Gallopin, T., Lacroix, A., Plaisier, F., Piquet, J., Geoffroy, H., Hepp, R., Naudé, J., Gac, B. L., Egger, R., et al. (2021) · eLife · doi:10.7554/elife.71424 · Cited by 102 · see citing works
“Peripheral lactate released by skeletal muscles, which can reach 15 mM in plasma following an intense physical exercise (Quistorff et al., 2008), could also facilitate this effect.”
BackgroundCerebral perfusion, oxygenation and metabolism during exercise in young and elderly individuals
Fisher, J. P., Hartwich, D., Seifert, T., Olesen, N. D., McNulty, C. L., Nielsen, H. B., LIESHOUT, J. J. V., & Secher, N. H. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2012.244905 · Cited by 102 · see citing works
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“[129] B.”
Sympathetic influence on cerebral blood flow and metabolism during exercise in humans
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“As mentioned, the ratio of lactate to pyruvate indicates the cytosolic ratio of NAD to NADH and, thus, the cytosolic L/P ratio reflects the combined flux of these reactions and cannot, a priori, be taken as an indication of hypoxia (Quistorff et al., 2008).”
BackgroundInfluentialSelf-citationCerebral Lactate Metabolism After Traumatic Brain Injury
Patet, C., Suys, T., Carteron, L., & Oddo, M. (2016) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-016-0638-5 · Cited by 98 · see citing works
The lactate sensor GPR81 regulates glycolysis and tumor growth of breast cancer
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The tortuous path of lactate shuttle discovery: From cinders and boards to the lab and ICU
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“This is compatible with the experimental findings showing during activation a disproportionate increase in glucose compared with oxygen consumption that is not explained by the quantity of lactate accumulation in the brain (Madsen et al, 1999) or total carbohydrate use (Quistorff et al, 2008).”
BackgroundHemichannel-mediated release of lactate
Karagiannis, A., Sylantyev, S., Hadjihambi, A., Hosford, P. S., Kasparov, S., & Gourine, A. V. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15611912 · Cited by 93 · see citing works
“lactate concentration in the venous blood is higher than in the arterial blood supplying the brain.(31,32) For decades it has been thought that MCTs are the only pathway of lactate transport from the cells which produce it.”
Effect of Exercise on Brain Health: The Potential Role of Lactate as a Myokine
Hashimoto, T., Tsukamoto, H., Ando, S., & Ogoh, S. (2021) · Metabolites · doi:10.3390/metabo11120813 · Cited by 92 · see citing works
“Regarding metabolism, although the brain relies mainly on glucose at rest, during high-intensity exercise, the brain becomes dependent on lactate delivery [53,54] and repeated HIIE, which attenuates the increase in systemic blood lactate, resulting in impaired maintenance of HIIE-enhanced cognitive performance (i.”
BackgroundQuintard, H., Patet, C., Zerlauth, J.-B., Suys, T., Bouzat, P., Pellerin, L., Meuli, R. A., Magistretti, P. J., & Oddo, M. (2015) · Journal of Neurotrauma · doi:10.1089/neu.2015.4057 · Cited by 88 · see citing works
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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).”
Lactate Shuttling and Lactate use as Fuel after Traumatic Brain Injury: Metabolic Considerations
Dienel, G. A. (2014) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2014.153 · Cited by 85 · see citing works
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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).”
BackgroundThe interactive effects of acute exercise and hypoxia on cognitive performance: A narrative review
Ando, S., Komiyama, T., Sudo, M., Higaki, Y., Ishida, K., Costello, J. T., & Katayama, K. (2019) · Scandinavian Journal of Medicine and Science in Sports · doi:10.1111/sms.13573 · Cited by 78 · see citing works
Hypoxia and Its Acid–Base Consequences: From Mountains to Malignancy
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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 ].”
BackgroundJalloh, I., Helmy, A. E., Shannon, R. J., Gallagher, C., Menon, D. K., Carpenter, K. L. H., & Hutchinson, P. J. (2013) · Journal of Neurotrauma · doi:10.1089/neu.2013.2947 · Cited by 67 · see citing works
“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 66 · see citing works
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“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).”
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“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 61 · see citing works
“In response to exercise the associated increase in CBF enhances cerebral oxygenation whereas, in contrast, muscle oxygenation declines with increasing work rate (83).”
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“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…”
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Quistorff, B., & Grunnet, N. (2011) · Aging · doi:10.18632/aging.100329 · Cited by 56 · see citing works
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Why does the brain (not) have glycogen?
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Nutritional Care for Aging Cats and Dogs
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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 · see citing works
“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 · see citing works
“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 55 · see citing works
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“, 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 48 · see citing works
“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 47 · see citing works
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 · see citing works
“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 · see citing works
“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 · see citing works
“…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 47 · see citing works
“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
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“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
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“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).”
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“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].”
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Lactic acidosis: implications for human exercise performance
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Aspects on the Physiological and Biochemical Foundations of Neurocritical Care
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Glucocorticoids, metabolism and brain activity
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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 · see citing works
Self-citation
- 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 › Complementary and alternative medicine › 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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