{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T11:29:34Z","timestamp":1790508574346,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T00:00:00Z","timestamp":1609977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The role of ketone bodies in the cerebral energy homeostasis of neurological diseases has begun to attract recent attention particularly in acute neurological diseases. In ketogenic therapies, ketosis is achieved by either a ketogenic diet or by the administration of exogenous ketone bodies. The oral ingestion of the ketone ester (KE), (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, is a new method to generate rapid and significant ketosis (i.e., above 6 mmol\/L) in humans. KE is hydrolyzed into \u03b2-hydroxybutyrate (\u03b2HB) and its precursor 1,3-butanediol. Here, we investigate the effect of oral KE administration (3 mg KE\/g of body weight) on brain metabolism of non-fasted mice using liquid chromatography in tandem with mass spectrometry. Ketosis (Cmax = 6.83 \u00b1 0.19 mmol\/L) was obtained at Tmax = 30 min after oral KE-gavage. We found that \u03b2HB uptake into the brain strongly correlated with the plasma \u03b2HB concentration and was preferentially distributed in the neocortex. We showed for the first time that oral KE led to an increase of acetyl-CoA and citric cycle intermediates in the brain of non-fasted mice. Furthermore, we found that the increased level of acetyl-CoA inhibited glycolysis by a feedback mechanism and thus competed with glucose under physiological conditions. The brain pharmacodynamics of this oral KE strongly suggest that this agent should be considered for acute neurological diseases.<\/jats:p>","DOI":"10.3390\/ijms22020524","type":"journal-article","created":{"date-parts":[[2021,1,7]],"date-time":"2021-01-07T02:02:06Z","timestamp":1609984926000},"page":"524","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Ingested Ketone Ester Leads to a Rapid Rise of Acetyl-CoA and Competes with Glucose Metabolism in the Brain of Non-Fasted Mice"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-8711","authenticated-orcid":false,"given":"Laurent","family":"Suissa","sequence":"first","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux \u00c9nergies Alternatives (CEA), University C\u00f4te d\u2019Azur, F-06107 Nice, France"},{"name":"Stroke Unit, University Hospital, F-13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2908-7755","authenticated-orcid":false,"given":"Pavel","family":"Kotchetkov","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux \u00c9nergies Alternatives (CEA), University C\u00f4te d\u2019Azur, F-06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marie","family":"Guigonis","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux \u00c9nergies Alternatives (CEA), University C\u00f4te d\u2019Azur, F-06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Doche","sequence":"additional","affiliation":[{"name":"Stroke Unit, University Hospital, F-13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-5255","authenticated-orcid":false,"given":"Oph\u00e9lie","family":"Osman","sequence":"additional","affiliation":[{"name":"Stroke Unit, University Hospital, F-13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2839-4622","authenticated-orcid":false,"given":"Thierry","family":"Pourcher","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux \u00c9nergies Alternatives (CEA), University C\u00f4te d\u2019Azur, F-06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Lindenthal","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux \u00c9nergies Alternatives (CEA), University C\u00f4te d\u2019Azur, F-06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","article-title":"Physiological roles of ketone bodies as substrates and signals in mammalian tissues","volume":"60","author":"Robinson","year":"1980","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s10545-005-5518-0","article-title":"Cerebral ketone body metabolism","volume":"28","author":"Morris","year":"2005","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1159\/000499563","article-title":"Exogenous ketone bodies as promising neuroprotective agents for developmental brain injury","volume":"40","author":"Wood","year":"2018","journal-title":"Dev. Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"585","DOI":"10.3389\/fneur.2019.00585","article-title":"Ketone bodies in neurological diseases: Focus on neuroprotection and underlying mechanisms","volume":"10","author":"Yang","year":"2019","journal-title":"Front Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2","DOI":"10.21767\/2171-6625.1000188","article-title":"Systematic review of the use of ketones in the management of acute and chronic neurological disorders","volume":"8","author":"White","year":"2017","journal-title":"J. Neurol. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1186\/cc10020","article-title":"Clinical review: Ketones and brain injury","volume":"15","author":"White","year":"2011","journal-title":"Crit. Care."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/978-1-4614-1566-4_15","article-title":"Neuroprotective properties of ketone bodies","volume":"737","author":"Xu","year":"2012","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1254\/jjp.89.36","article-title":"Beta-hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia","volume":"89","author":"Suzuki","year":"2002","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1254\/jjp.87.143","article-title":"Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats","volume":"87","author":"Suzuki","year":"2001","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1038\/jcbfm.2008.79","article-title":"Neuroprotection in diet-induced ketotic rat brain after focal ischemia","volume":"28","author":"Puchowicz","year":"2008","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/978-3-319-55231-6_28","article-title":"Diet-induced ketosis protects against focal cerebral ischemia in mouse","volume":"977","author":"Xu","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1038\/jcbfm.2015.123","article-title":"Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke","volume":"35","author":"Yin","year":"2015","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1159\/000486411","article-title":"Exogenous \u03b2-hydroxybutyrate treatment and neuroprotection in a suckling rat mdel of hypoxic-ischemic encephalopathy","volume":"40","author":"Lee","year":"2018","journal-title":"Dev. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.plefa.2003.09.007","article-title":"The therapeutic implications of ketone bodies: The effects of ketone bodies in pathological conditions: Ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism","volume":"70","author":"Veech","year":"2004","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.yrtph.2012.04.008","article-title":"Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects","volume":"63","author":"Clarke","year":"2012","journal-title":"Regul. Toxicol. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"924","DOI":"10.1016\/j.lfs.2007.07.026","article-title":"Carboxylesterase in the liver and small intestine of experimental animals and human","volume":"81","author":"Taketani","year":"2007","journal-title":"Life Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1093\/jn\/101.12.1719","article-title":"Metabolie fate of 1,3-butanediol in the rat: Conversion to \u03b2-hydroxybutyrate","volume":"101","author":"Tate","year":"1971","journal-title":"J. Nutr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0955-2863(94)00011-A","article-title":"R,S-1,3-butanediol acetoacetate esters, potential alternates to lipid emulsions for total parenteral nutrition","volume":"6","author":"Desrochers","year":"1995","journal-title":"J. Nutr. Biochem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12986-016-0069-y","article-title":"Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague\u2013Dawley rats","volume":"13","author":"Kesl","year":"2016","journal-title":"Nutr. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1042\/cs0810189","article-title":"Ketone infusion lowers hormonal responses to hypoglycaemia: Evidence for acute cerebral utilization of a non-glucose fuel","volume":"81","author":"Amiel","year":"1991","journal-title":"Clin. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1096\/fasebj.9.8.7768357","article-title":"Insulin, ketone bodies, and mitochondrial energy transduction","volume":"9","author":"Sato","year":"1995","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.pneurobio.2006.12.003","article-title":"N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology","volume":"81","author":"Moffett","year":"2007","journal-title":"Prog. Neurobiol."},{"key":"ref_23","first-page":"E746","article-title":"Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia","volume":"270","author":"Hasselbalch","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2485","DOI":"10.1177\/0271678X16669366","article-title":"Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: A dual tracer quantitative positron emission tomography study","volume":"37","author":"Croteau","year":"2017","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1111\/jnc.13958","article-title":"Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer\u2019s disease","volume":"141","author":"Pawlosky","year":"2017","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1002\/nbm.3355","article-title":"Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices: Ketone body oxidation in brain slices","volume":"28","author":"Lemos","year":"2015","journal-title":"NMR Biomed."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1016\/0024-3205(67)90071-9","article-title":"Inhibition of pyruvate kinase and glucokinase by acetyl-CoA and inhibition of glucokinase by phosphoenolpyruvate","volume":"6","author":"Weber","year":"1967","journal-title":"Life Sci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1096\/fj.201600773R","article-title":"Novel ketone diet enhances physical and cognitive performance","volume":"30","author":"Murray","year":"2016","journal-title":"FASEB J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1208\/s12248-016-9879-0","article-title":"The population pharmacokinetics of D-\u03b2-hydroxybutyrate following administration of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate","volume":"18","author":"Shivva","year":"2016","journal-title":"AAPS J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cmet.2016.07.010","article-title":"Nutritional ketosis alters fuel preference and thereby endurance performance in athletes","volume":"24","author":"Cox","year":"2016","journal-title":"Cell Metab."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1042\/bj3430281","article-title":"The proton-linked monocarboxylate transporter (MCT) family: Structure, function and regulation","volume":"2","author":"Halestrap","year":"1999","journal-title":"Biochem. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E1161","DOI":"10.1152\/ajpendo.1995.268.6.E1161","article-title":"Blood-brain barrier permeability of glucose and ketone bodies during short-term starvation in humans","volume":"268","author":"Hasselbalch","year":"1995","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1111\/j.1471-4159.1970.tb11392.x","article-title":"Alcohol dehydrogenase activity in rat brain and liver","volume":"17","author":"Raskin","year":"1970","journal-title":"J. Neurochem."},{"key":"ref_34","first-page":"E169","article-title":"Regional ketone body utilization by rat brain in starvation and diabetes","volume":"250","author":"Hawkins","year":"1986","journal-title":"Am. J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1126\/science.451608","article-title":"Ketone bodies are selectively used by individual brain regions","volume":"205","author":"Hawkins","year":"1979","journal-title":"Science"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E516","DOI":"10.1152\/ajpendo.1998.275.3.E516","article-title":"Monocarboxylate transporter expression in mouse brain","volume":"275","author":"Simpson","year":"1998","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1002\/jnr.20307","article-title":"Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain","volume":"79","author":"Pellerin","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1111\/j.1471-4159.1975.tb04428.x","article-title":"The metabolism of ketone bodies in developing human brain: Development of ketone-body-utilizing enzymes and ketone bodies as precursors for lipid synthesis","volume":"25","author":"Patel","year":"1975","journal-title":"J. Neurochem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1016\/j.metabol.2011.11.009","article-title":"Characterization of D-3-hydroxybutyrylcarnitine (ketocarnitine): An identified ketosis-induced metabolite","volume":"61","author":"Soeters","year":"2012","journal-title":"Metabolism"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"105750","DOI":"10.1016\/j.clineuro.2020.105750","article-title":"Effect of hyperglycemia on stroke outcome is not homogeneous to all patients treated with mechanical thrombectomy","volume":"194","author":"Suissa","year":"2020","journal-title":"Clin. Neurol. Neurosurg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/STROKEAHA.118.023769","article-title":"Glucose modifies the effect of endovascular thrombectomy in patients with acute stroke","volume":"50","author":"Chamorro","year":"2019","journal-title":"Stroke"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1002\/ana.10241","article-title":"Acute hyperglycemia adversely affects stroke outcome: A magnetic resonance imaging and spectroscopy study","volume":"52","author":"Parsons","year":"2002","journal-title":"Ann. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1385\/NCC:5:2:153","article-title":"The role of hyperglycemia in acute ischemic stroke","volume":"5","author":"Gilmore","year":"2006","journal-title":"Neurocrit. Care"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1177\/0271678X19873662","article-title":"Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice","volume":"40","author":"Suissa","year":"2020","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Ore\u0161i\u010d, M. (2010). MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC, 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D608","DOI":"10.1093\/nar\/gkx1089","article-title":"HMDB 4.0: The human metabolome database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic. Acids. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/524\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:07:57Z","timestamp":1760159277000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/524"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,7]]},"references-count":46,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020524"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020524","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,7]]}}}