Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling

Darío García-Rodríguez, Alfredo Giménez-Cassina, Darío García-Rodríguez, Alfredo Giménez-Cassina

Abstract

Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called "ketogenic diets," which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.

Keywords: acetoacetate; brain metabolism; epilepsy; ketogenic diet; ketone bodies; metabolic signaling; neuronal excitability; β-hydroxybutyrate.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 García-Rodríguez and Giménez-Cassina.

Figures

Figure 1
Figure 1
Effects of ketone bodies on cell excitability. The proposed mechanisms for ketone bodies’ (KBs) action on neuronal excitability are depicted. GABA levels: KB β-hydroxybutyrate (BHB) and acetoacetate are converted into Acetyl-CoA at a faster rate than with other substrates, which enters the Krebs cycle reducing the levels of oxaloacetate. To replenish the Krebs cycle, aspartate is converted to oxaloacetate, generating high levels of glutamate. Through the glutamate decarboxylase of GABAergic neurons, glutamate is converted into GABA, increasing the intracellular GABA pool. Glutamate signaling: BHB competes with chloride (Cl-) for the allosteric binding site of the vesicular glutamate transporter (VGLUT). The competition reduces the levels of glutamate inside the vesicles and reduces glutamatergic signaling. K-ATP channels: Ketone bodies (KBs) enter directly into the mitochondria, without generating cytosolic ATP. The lack of cytosolic ATP could provoke the activation of potassium ATP-sensitive (K-ATP) channels, causing the hyperpolarization of the cell. K-ATP channels may also be modulated directly by KBs or indirectly through the activation of alternative receptors. ASIC1a channels: KBs generate a local decrease in pH, which activates the acid sensing ion channel (ASIC1a). These channels participate in seizure termination. KBs may also directly modulate the ASIC1a. KCNQ2/3 channels: BHB directly activates KCNQ channels, which generate a potassium current. This potassium current causes the hyperpolarization of the cell. KBs may also regulate neuronal excitability by participating in mitochondrial permeability transition (mPT) and subsequent oscillations in cytosolic calcium levels.
Figure 2
Figure 2
Effects of ketone bodies on gene expression. The proposed mechanisms for the effect of Ketone Bodies (KBs) on gene expression are presented. Glutamate-cysteine ligase (GCL) expression: KBs increase the transcription of the GCL gene, which is the rate-limiting enzyme in the glutathione (GSH) biosynthesis. The incremented expression of GCL increases the levels of GSH, which in turn leads to a rise in antioxidant defenses. HDAC inhibition: KBs are inhibitors of the class I histone deacetylases (HDACs). The inhibition of HDACs provokes a remodeling in the chromatin structure that leads to increased expression of the antioxidant-related genes Foxo3a and Mt2, and to an increased expression of the Bdnf gene mediated by NF-κB and p300. ADK expression: KBs reduce the expression levels of the adenosine kinase (ADK) gene. This transcriptional inhibition favors high levels of adenosine (Ado) that activate the adenosine 1 receptors (A1R). The activation of these receptors have anti-seizure effects on the cell by reducing firing rates.
Figure 3
Figure 3
Effects of ketone bodies on cell signaling. Hypothetical impact of Ketone bodies (KB) on cell signaling. KB may impact cell signaling through their extracellular receptors GPR109a and/or FFAR3, having an impact on intracellular cell signaling. KB may also impact cell signaling by entering cells through the monocarboxylate transporters (MTCs) 1/2. Inside the cell, in combination with reduced or absent glycolysis due to very low levels of glucose, KB may alter the redox balance of the cell, also with potential consequences in cell signaling. In turn, the alterations in the signaling pathways of the cell lead to different downstream effects with biological outcomes.

References

    1. Al-Mudallal A. S., LaManna J. C., Lust W. D., Harik S. I. (1996). Diet-induced ketosis does not cause cerebral acidosis. Epilepsia 37, 258–261. 10.1111/j.1528-1157.1996.tb00022.x
    1. Badman M. K., Koester A., Flier J. S., Kharitonenkov A., Maratos-Flier E. (2009). Fibroblast growth factor 21-deficient mice demonstrate impaired adaptation to ketosis. Endocrinology 150, 4931–4940. 10.1210/en.2009-0532
    1. Badman M. K., Pissios P., Kennedy A. R., Koukos G., Flier J. S., Maratos-Flier E. (2007). Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab. 5, 426–437. 10.1016/j.cmet.2007.05.002
    1. Bernardi P., Rasola A., Forte M., Lippe G. (2015). The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology. Physiol. Rev. 95, 1111–1155. 10.1152/physrev.00001.2015
    1. Blázquez C., Sánchez C., Velasco G., Guzmán M. (1998). Role of carnitine palmitoyltransferase I in the control of ketogenesis in primary cultures of rat astrocytes. J. Neurochem. 71, 1597–1606. 10.1046/j.1471-4159.1998.71041597.x
    1. Blázquez C., Woods A., De Ceballos M. L., Carling D., Guzman M. (1999). The AMP-activated protein kinase is involved in the regulation of ketone body production by astrocytes. J. Neurochem. 73, 1674–1682. 10.1046/j.1471-4159.1999.731674.x
    1. Bozzo L., Puyal J., Chatton J.-Y. (2013). Lactate modulates the activity of primary cortical neurons through a receptor-mediated pathway. PLoS One 8:e71721. 10.1371/journal.pone.0071721
    1. Burkhalter J., Fiumelli H., Allaman I., Chatton J. Y., Martin J. L. (2003). Brain-derived neurotrophic factor stimulates energy metabolism in developing cortical neurons. J. Neurosci. 23, 8212–8220. 10.1523/JNEUROSCI.23-23-08212.2003
    1. Cahill G. F., Jr. (2006). Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22. 10.1146/annurev.nutr.26.061505.111258
    1. Cai Q.-Y., Zhou Z.-J., Luo R., Gan J., Li S.-P., Mu D.-Z., et al. . (2017). Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. World J. Pediatr. 13, 528–536. 10.1007/s12519-017-0053-2
    1. Chavan R., Feillet C., Costa S. S., Delorme J. E., Okabe T., Ripperger J. A., et al. . (2016). Liver-derived ketone bodies are necessary for food anticipation. Nat. Commun. 7:10580. 10.1038/ncomms10580
    1. Corkey B. E., Deeney J. T. (2020). The redox communication network as a regulator of metabolism. Front. Physiol. 11:567796. 10.3389/fphys.2020.567796
    1. Cox P. J., Kirk T., Ashmore T., Willerton K., Evans R., Smith A., et al. . (2016). Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 24, 256–268. 10.1016/j.cmet.2016.07.010
    1. Dahlin M., Elfving A., Ungerstedt U., Amark P. (2005). The ketogenic diet influences the levels of excitatory and inhibitory amino acids in the CSF in children with refractory epilepsy. Epilepsy Res. 64, 115–125. 10.1016/j.eplepsyres.2005.03.008
    1. Dahlin M., Martin D. A., Hedlund Z., Jonsson M., Von Dobeln U., Wedell A. (2015). The ketogenic diet compensates for AGC1 deficiency and improves myelination. Epilepsia 56, e176–181. 10.1111/epi.13193
    1. Dallérac G., Moulard J., Benoist J.-F., Rouach S., Auvin S., Guilbot A., et al. . (2017). Non-ketogenic combination of nutritional strategies provides robust protection against seizures. Sci. Rep. 7:5496. 10.1038/s41598-017-05542-3
    1. Danial N. N., Gramm C. F., Scorrano L., Zhang C.-Y., Krauss S., Ranger A. M., et al. . (2003). BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 424, 952–956. 10.1038/nature01825
    1. Danial N. N., Walensky L. D., Zhang C.-Y., Choi C. S., Fisher J. K., Molina A. J., et al. . (2008). Dual role of proapoptotic BAD in insulin secretion and β cell survival. Nat. Med. 14, 144–153. 10.1038/nm1717
    1. Davidian N. M., Butler T. C., Poole D. T. (1978). The effect of ketosis induced by medium chain triglycerides on intracellular pH of mouse brain. Epilepsia 19, 369–378. 10.1111/j.1528-1157.1978.tb04503.x
    1. De Cabo R., Mattson M. P. (2019). Effects of intermittent fasting on health, aging, and disease. N. Engl. J. Med. 381, 2541–2551. 10.1056/NEJMra1905136
    1. DeVivo D. C., Leckie M. P., Ferrendelli J. S., McDougal D. B., Jr. (1978). Chronic ketosis and cerebral metabolism. Ann. Neurol. 3, 331–337. 10.1002/ana.410030410
    1. Díaz-García C. M., Mongeon R., Lahmann C., Koveal D., Zucker H., Yellen G. (2017). Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab. 26, 361.e4–374.e4. 10.1016/j.cmet.2017.06.021
    1. Digby J. E., Martinez F., Jefferson A., Ruparelia N., Chai J., Wamil M., et al. . (2012). Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler. Thromb. Vasc. Biol. 32, 669–676. 10.1161/ATVBAHA.111.241836
    1. Dittenhafer-Reed K. E., Richards A. L., Fan J., Smallegan M. J., Fotuhi Siahpirani A., Kemmerer Z. A., et al. . (2015). SIRT3 mediates multi-tissue coupling for metabolic fuel switching. Cell Metab. 21, 637–646. 10.1016/j.cmet.2015.03.007
    1. Dunwiddie T. V., Worth T. (1982). Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J. Pharmacol. Exp. Ther. 220, 70–76.
    1. Edson N. L., Leloir L. F. (1936). Ketogenesis-antiketogenesis: metabolism of ketone bodies. Biochem. J. 30, 2319–2332. 10.1042/bj0302319
    1. Elizondo-Vega R., Cortés-Campos C., Barahona M. J., Carril C., Ordenes P., Salgado M., et al. . (2016). Inhibition of hypothalamic MCT1 expression increases food intake and alters orexigenic and anorexigenic neuropeptide expression. Sci. Rep. 6:33606. 10.1038/srep33606
    1. Erecińska M., Nelson D., Daikhin Y., Yudkoff M. (1996). Regulation of GABA level in rat brain synaptosomes: fluxes through enzymes of the GABA shunt and effects of glutamate, calcium, and ketone bodies. J. Neurochem. 67, 2325–2334. 10.1046/j.1471-4159.1996.67062325.x
    1. Etherington L.-A. V., Frenguelli B. G. (2004). Endogenous adenosine modulates epileptiform activity in rat hippocampus in a receptor subtype-dependent manner. Eur. J. Neurosci. 19, 2539–2550. 10.1111/j.0953-816X.2004.03355.x
    1. Fan J., Lin R., Xia S., Chen D., Elf S. E., Liu S., et al. . (2016). Tetrameric acetyl-CoA acetyltransferase 1 is important for tumor growth. Mol. Cell 64, 859–874. 10.1016/j.molcel.2016.10.014
    1. Fernandez-Fernandez S., Almeida A., Bolanos J. P. (2012). Antioxidant and bioenergetic coupling between neurons and astrocytes. Biochem. J. 443, 3–11. 10.1042/BJ20111943
    1. Fisher F. M., Maratos-Flier E. (2016). Understanding the physiology of FGF21. Annu. Rev. Physiol. 78, 223–241. 10.1146/annurev-physiol-021115-105339
    1. Fu S.-P., Liu B.-R., Wang J.-F., Xue W.-J., Liu H.-M., Zeng Y.-L., et al. . (2015a). β-Hydroxybutyric acid inhibits growth hormone-releasing hormone synthesis and secretion through the GPR109A/extracellular signal-regulated 1/2 signalling pathway in the hypothalamus. J. Neuroendocrinol. 27, 212–222. 10.1111/jne.12256
    1. Fu S.-P., Wang J.-F., Xue W.-J., Liu H.-M., Liu B.-R., Zeng Y.-L., et al. . (2015b). Anti-inflammatory effects of BHBA in both in vivo and in vitro Parkinson’s disease models are mediated by GPR109A-dependent mechanisms. J. Neuroinflammation 12:9. 10.1186/s12974-014-0230-3
    1. Garber A. J., Menzel P. H., Boden G., Owen O. E. (1974). Hepatic ketogenesis and gluconeogenesis in humans. J. Clin. Invest. 54, 981–989. 10.1172/JCI107839
    1. Garriga-Canut M., Schoenike B., Qazi R., Bergendahl K., Daley T. J., Pfender R. M., et al. . (2006). 2-Deoxy-D-glucose reduces epilepsy progression by NRSF-CtBP-dependent metabolic regulation of chromatin structure. Nat. Neurosci. 9, 1382–1387. 10.1038/nn1791
    1. Giménez-Cassina A., Danial N. N. (2015). Regulation of mitochondrial nutrient and energy metabolism by BCL-2 family proteins. Trends Endocrinol. Metab. 26, 165–175. 10.1016/j.tem.2015.02.004
    1. Giménez-Cassina A., Garcia-Haro L., Choi C. S., Osundiji M. A., Lane E., Huang H., et al. . (2014). Regulation of hepatic energy metabolism and gluconeogenesis by BAD. Cell Metab. 19, 272–284. 10.1016/j.cmet.2013.12.001
    1. Giménez-Cassina A., Lim F., Díaz-Nido J. (2012a). Chronic inhibition of glycogen synthase kinase-3 protects against rotenone-induced cell death in human neuron-like cells by increasing BDNF secretion. Neurosci. Lett. 531, 182–187. 10.1016/j.neulet.2012.10.046
    1. Giménez-Cassina A., Martínez-François J. R., Fisher J. K., Szlyk B., Polak K., Wiwczar J., et al. . (2012b). BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. Neuron 74, 719–730. 10.1016/j.neuron.2012.03.032
    1. Giorgio V., Guo L., Bassot C., Petronilli V., Bernardi P. (2018). Calcium and regulation of the mitochondrial permeability transition. Cell Calcium 70, 56–63. 10.1016/j.ceca.2017.05.004
    1. Goldberg E. L., Shchukina I., Asher J. L., Sidorov S., Artyomov M. N., Dixit V. D. (2020). Ketogenesis activates metabolically protective γdelta T cells in visceral adipose tissue. Nat. Metab. 2, 50–61. 10.1038/s42255-019-0160-6
    1. González A., Hall M. N., Lin S.-C., Hardie D. G. (2020). AMPK and TOR: the yin and yang of cellular nutrient sensing and growth control. Cell Metab. 31, 472–492. 10.1016/j.cmet.2020.01.015
    1. Grimsrud P. A., Carson J. J., Hebert A. S., Hubler S. L., Niemi N. M., Bailey D. J., et al. . (2012). A quantitative map of the liver mitochondrial phosphoproteome reveals posttranslational control of ketogenesis. Cell Metab. 16, 672–683. 10.1016/j.cmet.2012.10.004
    1. He W., Miao F.-J., Lin D.-C., Schwandner R. T., Wang Z., Gao J., et al. . (2004). Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193. 10.1038/nature02488
    1. Helmholz H. F., Keith H. M. (1933). Ten years’ experience in the treatment of epilepsy with ketogenic diet. Arch. Neurol. Psychiatry 29, 808–812. 10.1001/archneurpsyc.1933.02240100127010
    1. Heussinger N., Della Marina A., Beyerlein A., Leiendecker B., Hermann-Alves S., Dalla Pozza R., et al. . (2018). 10 patients, 10 years—long term follow-up of cardiovascular risk factors in Glut1 deficiency treated with ketogenic diet therapies: a prospective, multicenter case series. Clin. Nutr. 37, 2246–2251. 10.1016/j.clnu.2017.11.001
    1. Hirasawa A., Tsumaya K., Awaji T., Katsuma S., Adachi T., Yamada M., et al. . (2005). Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat. Med. 11, 90–94. 10.1038/nm1168
    1. Holmes G. L. (2008). What constitutes a relevant animal model of the ketogenic diet? Epilepsia 49, 57–60. 10.1111/j.1528-1167.2008.01836.x
    1. Inagaki T., Dutchak P., Zhao G., Ding X., Gautron L., Parameswara V., et al. . (2007). Endocrine regulation of the fasting response by PPARα-mediated induction of fibroblast growth factor 21. Cell Metab. 5, 415–425. 10.1016/j.cmet.2007.05.003
    1. Jarrett S. G., Milder J. B., Liang L.-P., Patel M. (2008). The ketogenic diet increases mitochondrial glutathione levels. J. Neurochem. 106, 1044–1051. 10.1111/j.1471-4159.2008.05460.x
    1. Jensen N. J., Wodschow H. Z., Nilsson M., Rungby J. (2020). Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int. J. Mol. Sci. 21:8767. 10.3390/ijms21228767
    1. Jimenez-Blasco D., Busquets-Garcia A., Hebert-Chatelain E., Serrat R., Vicente-Gutierrez C., Ioannidou C., et al. . (2020). Glucose metabolism links astroglial mitochondria to cannabinoid effects. Nature 583, 603–608. 10.1038/s41586-020-2470-y
    1. Juge N., Gray J. A., Omote H., Miyaji T., Inoue T., Hara C., et al. . (2010). Metabolic control of vesicular glutamate transport and release. Neuron 68, 99–112. 10.1016/j.neuron.2010.09.002
    1. Katsu-Jiménez Y., Alves R. M. P., Giménez-Cassina A. (2017). Food for thought: impact of metabolism on neuronal excitability. Exp. Cell Res. 360, 41–46. 10.1016/j.yexcr.2017.03.002
    1. Katsu-Jiménez Y., Giménez-Cassina A. (2019). Fibroblast growth Factor-21 promotes ketone body utilization in neurons through activation of AMP-dependent kinase. Mol. Cell. Neurosci. 101:103415. 10.1016/j.mcn.2019.103415
    1. Keith H. M. (1937). The treatment of epilepsy in children. Can. Med. Assoc. J. 37, 485–489.
    1. Kennedy A. R., Pissios P., Otu H., Roberson R., Xue B., Asakura K., et al. . (2007). A high-fat, ketogenic diet induces a unique metabolic state in mice. Am. J. Physiol. Endocrinol. Metab. 292, E1724–E1739. 10.1152/ajpendo.00717.2006
    1. Kharitonenkov A., DiMarchi R. (2017). Fibroblast growth factor 21 night watch: advances and uncertainties in the field. J. Intern. Med. 281, 233–246. 10.1111/joim.12580
    1. Kim D. Y., Simeone K. A., Simeone T. A., Pandya J. D., Wilke J. C., Ahn Y., et al. . (2015). Ketone bodies mediate antiseizure effects through mitochondrial permeability transition. Ann. Neurol. 78, 77–87. 10.1002/ana.24424
    1. Kimura I., Inoue D., Maeda T., Hara T., Ichimura A., Miyauchi S., et al. . (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U S A 108, 8030–8035. 10.1073/pnas.1016088108
    1. Kossoff E., Cervenka M. (2020). Ketogenic dietary therapy controversies for its second century. Epilepsy Curr 20, 125–129. 10.1177/1535759719890337
    1. Kossoff E. H., Krauss G. L., McGrogan J. R., Freeman J. M. (2003). Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 61, 1789–1791. 10.1212/01.wnl.0000098889.35155.72
    1. Koveal D., Díaz-García C. M., Yellen G. (2020). Fluorescent biosensors for neuronal metabolism and the challenges of quantitation. Curr. Opin. Neurobiol. 63, 111–121. 10.1016/j.conb.2020.02.011
    1. Lauritzen K. H., Morland C., Puchades M., Holm-Hansen S., Hagelin E. M., Lauritzen F., et al. . (2014). Lactate receptor sites link neurotransmission, neurovascular coupling, and brain energy metabolism. Cereb. Cortex 24, 2784–2795. 10.1093/cercor/bht136
    1. Li J., O’Leary E. I., Tanner G. R. (2017). The ketogenic diet metabolite β-hydroxybutyrate (β-HB) reduces incidence of seizure-like activity (SLA) in a Katp- and GABAb-dependent manner in a whole-animal Drosophila melanogaster model. Epilepsy Res. 133, 6–9. 10.1016/j.eplepsyres.2017.04.003
    1. Liang J.-J., Huang L.-F., Chen X.-M., Pan S.-Q., Lu Z.-N., Xiao Z.-M. (2015). Amiloride suppresses pilocarpine-induced seizures via ASICs other than NHE in rats. Int. J. Clin. Exp. Pathol. 8, 14507–14513.
    1. Liang L. P., Ho Y. S., Patel M. (2000). Mitochondrial superoxide production in kainate-induced hippocampal damage. Neuroscience 101, 563–570. 10.1016/s0306-4522(00)00397-3
    1. Liang L.-P., Patel M. (2006). Seizure-induced changes in mitochondrial redox status. Free Radic. Biol. Med. 40, 316–322. 10.1016/j.freeradbiomed.2005.08.026
    1. Liddelow S. A., Barres B. A. (2017). Reactive astrocytes: production, function, and therapeutic potential. Immunity 46, 957–967. 10.1016/j.immuni.2017.06.006
    1. Liddelow S. A., Guttenplan K. A., Clarke L. E., Bennett F. C., Bohlen C. J., Schirmer L., et al. . (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487. 10.1038/nature21029
    1. Likhodii S. S., Serbanescu I., Cortez M. A., Murphy P., Snead O. C., III., Burnham W. M. (2003). Anticonvulsant properties of acetone, a brain ketone elevated by the ketogenic diet. Ann. Neurol. 54, 219–226. 10.1002/ana.10634
    1. Longo V. D., Mattson M. P. (2014). Fasting: molecular mechanisms and clinical applications. Cell Metab. 19, 181–192. 10.1016/j.cmet.2013.12.008
    1. Lutas A., Yellen G. (2013). The ketogenic diet: metabolic influences on brain excitability and epilepsy. Trends Neurosci. 36, 32–40. 10.1016/j.tins.2012.11.005
    1. Ma W., Berg J., Yellen G. (2007). Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J. Neurosci. 27, 3618–3625. 10.1523/JNEUROSCI.0132-07.2007
    1. Maciejewski-Lenoir D., Richman J. G., Hakak Y., Gaidarov I., Behan D. P., Connolly D. T. (2006). Langerhans cells release prostaglandin D2 in response to nicotinic acid. J. Invest. Dermatol. 126, 2637–2646. 10.1038/sj.jid.5700586
    1. Manville R. W., Papanikolaou M., Abbott G. W. (2020). M-channel activation contributes to the anticonvulsant action of the ketone body β-hydroxybutyrate. J. Pharmacol. Exp. Ther. 372, 148–156. 10.1124/jpet.119.263350
    1. Marosi K., Kim S. W., Moehl K., Scheibye-Knudsen M., Cheng A., Cutler R., et al. . (2016). 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J. Neurochem. 139, 769–781. 10.1111/jnc.13868
    1. Martínez-François J. R., Fernández-Agüera M. C., Nathwani N., Lahmann C., Burnham V. L., Danial N. N., et al. . (2018). BAD and KATP channels regulate neuron excitability and epileptiform activity. eLife 7:e32721. 10.7554/eLife.32721
    1. Martini T., Ripperger J. A., Chavan R., Stumpe M., Netzahualcoyotzi C., Pellerin L., et al. . (2021). The hepatic monocarboxylate transporter 1 (MCT1) contributes to the regulation of food anticipation in mice. Front. Physiol. 12:665476. 10.3389/fphys.2021.665476
    1. Masino S. A., Li T., Theofilas P., Sandau U. S., Ruskin D. N., Fredholm B. B., et al. . (2011). A ketogenic diet suppresses seizures in mice through adenosine A1 receptors. J. Clin. Invest. 121, 2679–2683. 10.1172/JCI57813
    1. McCann W. P. (1957). The oxidation of ketone bodies by mitochondria from liver and peripheral tissues. J. Biol. Chem. 226, 15–22. 10.1016/s0021-9258(18)64800-8
    1. McDonald T. J. W., Cervenka M. C. (2020). Ketogenic diet therapies for seizures and status epilepticus. Semin. Neurol. 40, 719–729. 10.1055/s-0040-1719077
    1. McGarry J. D., Foster D. W. (1977). Hormonal control of ketogenesis. Biochemical considerations. Arch. Intern. Med. 137, 495–501. 10.1001/archinte.137.4.495
    1. McQuarrie I., Keith H. M. (1927). Epilepsy in children. Am. J. Dis. Child. 34, 1013–1029. 10.1001/archpedi.1927.04130240092013
    1. Mejía-Toiber J., Montiel T., Massieu L. (2006). D-β-hydroxybutyrate prevents glutamate-mediated lipoperoxidation and neuronal damage elicited during glycolysis inhibition in vivo. Neurochem. Res. 31, 1399–1408. 10.1007/s11064-006-9189-5
    1. Milder J. B., Liang L.-P., Patel M. (2010). Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol. Dis. 40, 238–244. 10.1016/j.nbd.2010.05.030
    1. Miletta M. C., Petkovic V., Eblé A., Ammann R. A., Fluck C. E., Mullis P. E. (2014). Butyrate increases intracellular calcium levels and enhances growth hormone release from rat anterior pituitary cells via the G-protein-coupled receptors GPR41 and 43. PLoS One 9:e107388. 10.1371/journal.pone.0107388
    1. Miller C. G., Holmgren A., Arnér E. S. J., Schmidt E. E. (2018). NADPH-dependent and -independent disulfide reductase systems. Free Radic. Biol. Med. 127, 248–261. 10.1016/j.freeradbiomed.2018.03.051
    1. Mironov S. L., Richter D. W. (2000). Intracellular signalling pathways modulate K(ATP) channels in inspiratory brainstem neurones and their hypoxic activation: involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res. 853, 60–67. 10.1016/s0006-8993(99)02234-9
    1. Mitre M., Mariga A., Chao M. V. (2017). Neurotrophin signalling: novel insights into mechanisms and pathophysiology. Clin. Sci. 131, 13–23. 10.1042/CS20160044
    1. Naito S., Ueda T. (1985). Characterization of glutamate uptake into synaptic vesicles. J. Neurochem. 44, 99–109. 10.1111/j.1471-4159.1985.tb07118.x
    1. Neal E. G., Chaffe H., Schwartz R. H., Lawson M. S., Edwards N., Fitzsimmons G., et al. . (2009). A randomized trial of classical and medium-chain triglyceride ketogenic diets in the treatment of childhood epilepsy. Epilepsia 50, 1109–1117. 10.1111/j.1528-1167.2008.01870.x
    1. Nielsen R., Moller N., Gormsen L. C., Tolbod L. P., Hansson N. H., Sorensen J., et al. . (2019). Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 139, 2129–2141. 10.1161/CIRCULATIONAHA.118.036459
    1. Oonthonpan L., Rauckhorst A. J., Gray L. R., Boutron A. C., Taylor E. B. (2019). Two human patient mitochondrial pyruvate carrier mutations reveal distinct molecular mechanisms of dysfunction. JCI Insight 5:e126132. 10.1172/jci.insight.126132
    1. Owen O. E., Morgan A. P., Kemp H. G., Sullivan J. M., Herrera M. G., Cahill G. F., Jr. (1967). Brain metabolism during fasting. J. Clin. Invest. 46, 1589–1595. 10.1172/JCI105650
    1. Paoli A., Bianco A., Damiani E., Bosco G. (2014). Ketogenic diet in neuromuscular and neurodegenerative diseases. Biomed. Res. Int. 2014:474296. 10.1155/2014/474296
    1. Pelicano H., Xu R.-H., Du M., Feng L., Sasaki R., Carew J. S., et al. . (2006). Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 175, 913–923. 10.1083/jcb.200512100
    1. Pérez-Liébana I., Casarejos M. J., Alcaide A., Herrada-Soler E., Llorente-Folch I., Contreras L., et al. . (2020). βOHB protective pathways in aralar-KO neurons and brain: an alternative to ketogenic diet. J. Neurosci. 40, 9293–9305. 10.1523/JNEUROSCI.0711-20.2020
    1. Pfeifer H. H., Thiele E. A. (2005). Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 65, 1810–1812. 10.1212/01.wnl.0000187071.24292.9e
    1. Pflanz N. C., Daszkowski A. W., James K. A., Mihic S. J. (2019). Ketone body modulation of ligand-gated ion channels. Neuropharmacology 148, 21–30. 10.1016/j.neuropharm.2018.12.013
    1. Pierre K., Pellerin L. (2005). Monocarboxylate transporters in the central nervous system: distribution, regulation and function. J. Neurochem. 94, 1–14. 10.1111/j.1471-4159.2005.03168.x
    1. Puchalska P., Crawford P. A. (2017). Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284. 10.1016/j.cmet.2016.12.022
    1. Ratter J. M., Rooijackers H. M., Tack C. J., Hijmans A. G., Netea M. G., De Galan B. E., et al. . (2017). Proinflammatory effects of hypoglycemia in humans with or without diabetes. Diabetes 66, 1052–1061. 10.2337/db16-1091
    1. Ren X., Zou L., Zhang X., Branco V., Wang J., Carvalho C., et al. . (2017). Redox signaling mediated by thioredoxin and glutathione systems in the central nervous system. Antioxid. Redox Signal. 27, 989–1010. 10.1089/ars.2016.6925
    1. Roberts M. N., Wallace M. A., Tomilov A. A., Zhou Z., Marcotte G. R., Tran D., et al. . (2017). A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539.e5–546.e5. 10.1016/j.cmet.2017.08.005
    1. Roehl K., Falco-Walter J., Ouyang B., Balabanov A. (2019). Modified ketogenic diets in adults with refractory epilepsy: efficacious improvements in seizure frequency, seizure severity, and quality of life. Epilepsy Behav. 93, 113–118. 10.1016/j.yebeh.2018.12.010
    1. Sengupta S., Peterson T. R., Laplante M., Oh S., Sabatini D. M. (2010). mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104. 10.1038/nature09584
    1. Shao D., Oka S.-I., Liu T., Zhai P., Ago T., Sciarretta S., et al. . (2014). A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation. Cell Metab. 19, 232–245. 10.1016/j.cmet.2013.12.013
    1. Shimazu T., Hirschey M. D., Newman J., He W., Shirakawa K., Le Moan N., et al. . (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339, 211–214. 10.1126/science.1227166
    1. Si J., Wang Y., Xu J., Wang J. (2020). Antiepileptic effects of exogenous β-hydroxybutyrate on kainic acid-induced epilepsy. Exp. Ther. Med. 20:177. 10.3892/etm.2020.9307
    1. Simeone T. A., Simeone K. A., Stafstrom C. E., Rho J. M. (2018). Do ketone bodies mediate the anti-seizure effects of the ketogenic diet? Neuropharmacology 133, 233–241. 10.1016/j.neuropharm.2018.01.011
    1. Simm P. J., Bicknell-Royle J., Lawrie J., Nation J., Draffin K., Stewart K. G., et al. . (2017). The effect of the ketogenic diet on the developing skeleton. Epilepsy Res. 136, 62–66. 10.1016/j.eplepsyres.2017.07.014
    1. Sleiman S. F., Chao M. V. (2015). Downstream consequences of exercise through the action of BDNF. Brain Plast. 1, 143–148. 10.3233/BPL-150017
    1. Sleiman S. F., Henry J., Al-Haddad R., El Hayek L., Abou Haidar E., Stringer T., et al. . (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. eLife 5:e15092. 10.7554/eLife.15092
    1. Somjen G. G. (1984). Acidification of interstitial fluid in hippocampal formation caused by seizures and by spreading depression. Brain Res. 311, 186–188. 10.1016/0006-8993(84)91416-1
    1. Taggart A. K., Kero J., Gan X., Cai T. Q., Cheng K., Ippolito M., et al. . (2005). (D)-β-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649–26652. 10.1074/jbc.C500213200
    1. Tanner G. R., Lutas A., Martínez-François J. R., Yellen G. (2011). Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons. J. Neurosci. 31, 8689–8696. 10.1523/JNEUROSCI.5951-10.2011
    1. Thiele E. A. (2003). Assessing the efficacy of antiepileptic treatments: the ketogenic diet. Epilepsia 44, 26–29. 10.1046/j.1528-1157.44.s7.4.x
    1. Thio L. L., Wong M., Yamada K. A. (2000). Ketone bodies do not directly alter excitatory or inhibitory hippocampal synaptic transmission. Neurology 54, 325–331. 10.1212/wnl.54.2.325
    1. Ubersax J. A., Ferrell J. E., Jr. (2007). Mechanisms of specificity in protein phosphorylation. Nat. Rev. Mol. Cell Biol. 8, 530–541. 10.1038/nrm2203
    1. Valente-Silva P., Lemos C., Köfalvi A., Cunha R. A., Jones J. G. (2015). Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices. NMR Biomed. 28, 1111–1116. 10.1002/nbm.3355
    1. Vallejo F. A., Shah S. S., De Cordoba N., Walters W. M., Prince J., Khatib Z., et al. . (2020). The contribution of ketone bodies to glycolytic inhibition for the treatment of adult and pediatric glioblastoma. J. Neurooncol. 147, 317–326. 10.1007/s11060-020-03431-w
    1. Veech R. L., Bradshaw P. C., Clarke K., Curtis W., Pawlosky R., King M. T. (2017). Ketone bodies mimic the life span extending properties of caloric restriction. IUBMB Life 69, 305–314. 10.1002/iub.1627
    1. Vicente-Gutierrez C., Bonora N., Bobo-Jimenez V., Jimenez-Blasco D., Lopez-Fabuel I., Fernandez E., et al. . (2019). Astrocytic mitochondrial ROS modulate brain metabolism and mouse behaviour. Nat. Metab. 1, 201–211. 10.1038/s42255-018-0031-6
    1. Von Meyenn F., Porstmann T., Gasser E., Selevsek N., Schmidt A., Aebersold R., et al. . (2013). Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell Metab. 17, 436–447. 10.1016/j.cmet.2013.01.014
    1. Wakade C., Chong R., Bradley E., Thomas B., Morgan J. (2014). Upregulation of GPR109A in Parkinson’s disease. PLoS One 9:e109818. 10.1371/journal.pone.0109818
    1. Wang Y.-Q., Fang Z.-X., Zhang Y.-W., Xie L.-L., Jiang L. (2020). Efficacy of the ketogenic diet in patients with Dravet syndrome: a meta-analysis. Seizure 81, 36–42. 10.1016/j.seizure.2020.07.011
    1. Wang H. S., Pan Z., Shi W., Brown B. S., Wymore R. S., Cohen I. S., et al. . (1998). KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893. 10.1126/science.282.5395.1890
    1. Wolfrum C., Asilmaz E., Luca E., Friedman J. M., Stoffel M. (2004). Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432, 1027–1032. 10.1038/nature03047
    1. Won Y.-J., Lu V. B., Puhl H. L., III., Ikeda S. R. (2013). β-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J. Neurosci. 33, 19314–19325. 10.1523/JNEUROSCI.3102-13.2013
    1. Xu S., Tao H., Cao W., Cao L., Lin Y., Zhao S. M., et al. . (2021). Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis. Signal Transduct. Target Ther. 6:54. 10.1038/s41392-020-00411-4
    1. Yamamoto M., Kensler T. W., Motohashi H. (2018). The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiol. Rev. 98, 1169–1203. 10.1152/physrev.00023.2017
    1. Yang L., Zhao J., Milutinovic P. S., Brosnan R. J., Eger E. I., II., Sonner J. M. (2007). Anesthetic properties of the ketone bodies β-hydroxybutyric acid and acetone. Anesth. Analg. 105, 673–679. 10.1213/01.ane.0000278127.68312.dc
    1. Yermolaieva O., Leonard A. S., Schnizler M. K., Abboud F. M., Welsh M. J. (2004). Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel 1a. Proc. Natl. Acad. Sci. U S A 101, 6752–6757. 10.1073/pnas.0308636100
    1. Youm Y.-H., Nguyen K. Y., Grant R. W., Goldberg E. L., Bodogai M., Kim D., et al. . (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263–269. 10.1038/nm.3804
    1. Yudkoff M., Daikhin Y., Nissim I., Horyn O., Lazarow A., Luhovyy B., et al. . (2005). Response of brain amino acid metabolism to ketosis. Neurochem. Int. 47, 119–128. 10.1016/j.neuint.2005.04.014
    1. Yudkoff M., Daikhin Y., Nissim I., Lazarow A., Nissim I. (2001). Brain amino acid metabolism and ketosis. J. Neurosci. Res. 66, 272–281. 10.1002/jnr.1221
    1. Yuen A. W. C., Walcutt I. A., Sander J. W. (2017). An acidosis-sparing ketogenic (ASK) diet to improve efficacy and reduce adverse effects in the treatment of refractory epilepsy. Epilepsy Behav. 74, 15–21. 10.1016/j.yebeh.2017.05.032
    1. Zamani G. R., Mohammadi M., Ashrafi M. R., Karimi P., Mahmoudi M., Badv R. S., et al. . (2016). The effects of classic ketogenic diet on serum lipid profile in children with refractory seizures. Acta Neurol. Belg. 116, 529–534. 10.1007/s13760-016-0601-x
    1. Zhang Q., Piston D. W., Goodman R. H. (2002). Regulation of corepressor function by nuclear NADH. Science 295, 1895–1897. 10.1126/science.1069300
    1. Zhu F., Shan W., Xu Q., Guo A., Wu J., Wang Q. (2019). Ketone bodies inhibit the opening of acid-sensing ion channels (ASICs) in rat hippocampal excitatory neurons in vitro. Front. Neurol. 10:155. 10.3389/fneur.2019.00155
    1. Ziemann A. E., Schnizler M. K., Albert G. W., Severson M. A., Howard M. A., III., Welsh M. J., et al. . (2008). Seizure termination by acidosis depends on ASIC1a. Nat. Neurosci. 11, 816–822. 10.1038/nn.2132
    1. Zou X., Meng J., Li L., Han W., Li C., Zhong R., et al. . (2016). Acetoacetate accelerates muscle regeneration and ameliorates muscular dystrophy in mice. J. Biol. Chem. 291, 2181–2195. 10.1074/jbc.M115.676510

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