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β-Hydroxybutyrate: A Signaling Metabolite
Open accessAbstract
Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.
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“The higher rate of sustained remission in the present investigation may be due to sustained carbohydrate restriction and the metabolic benefits attributed to nutritional ketosis [28], as well as the ongoing level of support provided from the care team in this care model.”
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“For instance, the β-hydroxybutyrate (BHB) ketone can provide pivotal energy when the body’s glucose supply is too low (Newman and Verdin, 2017).”
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“BHB is synthesized from fatty acids in the liver and can be released from the liver into other tissues after exercise, and it plays a role as a signaling metabolite in a variety of diseases [126].”
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“49 In the present study, both L- 3-OHB and D- 3-OHB infusions suppressed circulating FFA levels consistent with the observations in clinical studies using D/L- 3-OHB infusions.”
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“HDAC acetylation and activation of MEF2 could also be a direct effect of the primary ketone, βHB (26).”
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Ketone bodies as chemical signals for the immune system
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“Among these mechanisms, improved mitochondrial function, ATP synthesis, mitochondrial biogenesis, the stimulation of the antioxidant defense, decreased reactive oxygen species and anti-inflammatory effects, are mainly suggested to contribute to the alleviation of AD pathology and cognitive impairment in AD mice models…”
BackgroundInfluentialEffects of Fasting on the Physiological and Psychological Responses in Middle-Aged Men
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“β-hydroxybutyrate, together with another ketone body—acetoacetate, significantly nourishes the brain in a state of fasting [53,56,57], and the first of these compounds is an active signaling molecule for many cells [9,10], and cortisol is an important determinant of the body’s stress response [58].”
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“Beyond direct receptor signaling, β HB can also inhibit histone deacetylases or can act as a histone modification to regulate gene expression (Newman & Verdin, 2017 ).”
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“This metabolic pathway highlights the significance of BHB as an alternative energy substrate during periods of low carbohydrate availability, prolonged exercise, and fasting [15,16].”
Protocol for the Use of the Ketogenic Diet in Preclinical and Clinical Practice
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“β-OHB, which accounts for approximately 70% of the total ketone bodies, is produced by the liver and transported to the heart and kidney (19, 20, 30).”
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“In addition to being a metabolic substrate, BHB also acts as a signalling molecule, modulating intracellular activity in cells across the body, such as regulating gene expression through inhibition of class I histone deacetylases (HDACs) via competitive inhibition [62].”
BackgroundAging Biomarkers and Novel Targets for Anti-Aging Interventions
Xu, K., Guo, Y., Li, Z., & Wang, Z. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-25650-0_3 · Cited by 22
Norgren, J., Sindi, S., Matton, A., Kåreholt, I., Akenine, U., Nordin, K., Rosenborg, S., Ngandu, T., & Kivipelto, M. (2019) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00454.2019 · Cited by 20
“BHB further acts as an epigenetic signal molecule (20).”
BackgroundStubbs, B. J., Koutnik, A. P., Volek, J. S., & Newman, J. C. (2020) · GeroScience · doi:10.1007/s11357-020-00277-y · Cited by 22
Self-citationA ketogenic diet impacts markers of mitochondrial mass in a tissue specific manner in aged mice
Zhou, Z., Hagopian, K., López-Domínguez, J. A., Kim, K., Jasoliya, M., Roberts, M. N., Cortopassi, G. A., Showalter, M. R., Roberts, B. S., González-Reyes, J. A., et al. (2021) · Aging · doi:10.18632/aging.202834 · Cited by 19
“mitochondrial enzymes under KD [22], but whether these modifications to citrate synthase, Complex I, or Complex IV impact enzyme activities is not clear [23, 24].”
BackgroundSuresh, V. V., Sivaprakasam, S., Bhutia, Y. D., Prasad, P. D., Thangaraju, M., & Ganapathy, V. (2025) · Biomolecules · doi:10.3390/biom15040580 · Cited by 19
“…dehydrogenase-1 (BDH1) using NADH as the electron donor. β -Hydroxybutyrate is a chiral molecule because of the asymmetry of carbon-3 due to the presence of the hydroxyl group and therefore can exist either as an R (also known as the D-form) or S (also known as the L-form) enantiomer [7].”
Hein, Z. M., Arbain, M. F. F., Kumar, S., Mehat, M. Z., Hamid, H. A., Ramli, M. D. C., & Nassir, C. M. N. C. M. (2025) · Nutrients · doi:10.3390/nu17142266 · Cited by 25
“BHB also upregulates key regulators of mitochondrial biogenesis, such as PGC-1 α and mitochondrial transcription factor A (TFAM), primarily through sirtuin activation [64].”
ACSS2 coupled with KAT7 regulates histone β-hydroxybutyrylation to enhance transcription
Wang, S., Niu, Z., Zhang, Y., Liu, R., Zhu, R., Sun, Y., Han, Y., Wang, A., Zhang, J., Zhang, H., et al. (2025) · Science Advances · doi:10.1126/sciadv.adv8448 · Cited by 22
“Ketone bodies serve as fatty acid–derived carbon fuels that, in turn, provide an energy source to other tissues such as the brain and heart for the generation of acetyl–coenzyme A (CoA) ( 3 – 5 ).”
Berger, B., Jenetzky, E., Köblös, D., Stange, R., Baumann, A., Simstich, J., Michalsen, A., Schmelzer, K., & Martin, D. D. (2021) · Nutrition · doi:10.1016/j.nut.2021.111169 · Cited by 19
Brain on food: The neuroepigenetics of nutrition
Vaziri, A., & Dus, M. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.105099 · Cited by 24
Hou, W., Liu, G., Ren, X., Liu, X., He, L., & Huang, H. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/4592170 · Cited by 19
“A noteworthy example is β-hydroxybutyrate (BHB), an intermediate product of liver fatty acid oxidation and decomposition [11].”
Metabolite signaling in the heart
Flam, E. L., & Arany, Z. P. (2023) · Nature Cardiovascular Research · doi:10.1038/s44161-023-00270-6 · Cited by 19
SGLT-2 Inhibitors for Non-Alcoholic Fatty Liver Disease: A Review
Xu, R., Lian, D., Xie, Y., Chen, Z., Wang, Y., Mu, L., Wang, Y., & Zhang, B. (2023) · Frontiers in Bioscience-Landmark · doi:10.31083/j.fbl2807134 · Cited by 22
“…to increased HIC by reducing plasma TG concentration and elevating plasma β -hydroxybutyrate (BHB, is the most abundant ketone body in mammals; it is synthesized in the liver from fatty acids [124]), and manifested as the reduction of intrahepatic TG content and improvement of fatty liver [121].”
Backgroundβ-hydroxybutyrate: A crucial therapeutic target for diverse liver diseases
Li, K., Wang, W., Jia-bin, W., & Xiao, W. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115191 · Cited by 21
Lysine Β-Hydroxybutyrylation Improves Stability of COVID-19 Antibody
Li, Z., Zhang, Y., Han, M., Deng, H., Wu, F., Liu, G., & Chen, G. (2021) · Biomacromolecules · doi:10.1021/acs.biomac.1c01435 · Cited by 19
β-Hydroxybutyrate Facilitates Postinfarction Cardiac Repair via Targeting PHD2
Wang, C., Xu, W., Jiang, S., Wu, Y., Shu, J., Gao, X., & Huang, K. (2025) · Circulation Research · doi:10.1161/circresaha.124.325179 · Cited by 18
Precision Nutrition and Gut–Brain Axis Modulation in the Prevention of Neurodegenerative Diseases
Tuigunov, D. N., Sinyavskiy, Y. A., Nurgozhin, T. S., Zholdassova, Z., Smagul, G., Omarov, Y., Dolmatova, O., Yeshmanova, A., & Omarova, I. (2025) · Nutrients · doi:10.3390/nu17193068 · Cited by 24
“Under conditions of food restriction, a metabolic shift occurs from glucose to ketone bodies, primarily β -hydroxybutyrate, which penetrates the BBB and is used by neurons as an energy source, reducing oxidative stress and stimulating the production of key neurotrophic factors [242].”
β-hydroxybutyrate enhances the metabolic fitness of CAR T cells in cancer
Liu, S., Guruprasad, P., Ramasubramanian, R., Madhu, B., Paruzzo, L., Han, K., Kelly, A. R., Shestov, A. A., Xu, H. N., Carturan, A., et al. (2026) · Cell · doi:10.1016/j.cell.2026.02.004 · Cited by 19
Veldscholte, K., Cramer, A. B. G., Joosten, K., & Verbruggen, S. C. A. T. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.07.030 · Cited by 19
Wang, F., Xu, C., Su, C., Li, J., & Lin, J. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.926128 · Cited by 18
“β-Hydroxybutyrate (BHB), an inhibitor of class I histone deacetylases (HDACs), is a ketone body metabolite that is mainly derived from the brain, liver, heart, and skeletal muscles in times of caloric restriction, fasting or low-carbohydrate ketogenic diet (Newman and Verdin, 2017; Huang et al., 2018).”
BackgroundExploring the role of ketone bodies in the diagnosis and treatment of psychiatric disorders
Omori, N. E., Malys, M. K., Woo, G. H., & Mansor, L. S. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1142682 · Cited by 19
“The ratio of circulating βHB and AcAc is regulated largely by the liver and is proportional to the ratio of Frontiers in Psychiatry 03 frontiersin.org reduced and oxidized nicotinamide adenine dinucleotide (NADH/ NAD+; 30).”
BackgroundBanerjee, R., Zhu, Y. G., Brownrigg, G. P., Moravcova, R., Rogalski, J. C., Foster, L. J., Johnson, J. D., & Kolic, J. (2024) · Endocrinology · doi:10.1210/endocr/bqae079 · Cited by 18
“Of the 3 ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetyl CoA) found in mammals, beta-hydroxybutyrate ( β HB) is the most abundant (5).”
BackgroundInfluentialAnti-Aging Effect of the Ketone Metabolite β-Hydroxybutyrate in Drosophila Intestinal Stem Cells
Park, J., & Kim, Y.-J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21103497 · Cited by 18
“Ketone bodies are small molecules that are synthesized in the liver from fats during fasting, prolonged exercise, or under conditions of restricted carbohydrate supply [17,18].”
BackgroundInfluentialIn silico Assessment of Pharmacological Profile of Low Molecular Weight Oligo-Hydroxyalkanoates
Roman, D. L., Isvoran, A., Filip, M., Ostafe, V., & Zinn, M. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.584010 · Cited by 18
“A high quantity of 3HB could be harmful because it may conduct to acidosis (Newman and Verdin, 2017).”
BackgroundRole of ketones, ketogenic diets and intermittent fasting in ICU
Gunst, J., Casaer, M. P., Langouche, L., & den Berghe, G. V. (2021) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000000841 · Cited by 19
Dearlove, D., Soto-Mota, A., Hauton, D., Pinnick, K. E., Evans, R. D., Miller, J. J. J. J., Fischer, R., McCullagh, J., Hodson, L., Clarke, K., et al. (2022) · Physiological Reports · doi:10.14814/phy2.15309 · Cited by 20
“Given the growing list of ketone signaling effects on human physiology and metabolism (Newman & Verdin, 2017), it is plausible that ketone supplementation (Ex Ket) may have blunted adaptive responses versus CHO.”
BackgroundEhtiati, S., Hatami, B., Khatami, S. H., Tajernarenj, K., Abdi, S., Sirati‐Sabet, M., Hashemi, S. A. H. G., Ahmadzade, R., Hamed, N., Goudarzi, M., et al. (2025) · Journal of Cellular Biochemistry · doi:10.1002/jcb.70050 · Cited by 17
Small-molecule metabolome identifies potential therapeutic targets against COVID-19
Bennet, S., Kaufmann, M., Takami, K., Sjaarda, C. P., Douchant, K., Moslinger, E., Wong, H., Reed, D. E., Ellis, A. K., Vanner, S. J., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-14050-y · Cited by 17
Sangalli, J. R., Nociti, R. P., del Collado, M., Sampaio, R. V., da Silveira, J. C., Perecin, F., Smith, L. C., Ross, P. J., & Meirelles, F. V. (2022) · Molecular Reproduction and Development · doi:10.1002/mrd.23630 · Cited by 17
Effects of the Ketogenic diet in overweight divers breathing Enriched Air Nitrox
Bosco, G., Rizzato, A., Quartesan, S., Camporesi, E. M., Mangar, D., Paganini, M., Cenci, L., Malacrida, S., Mrakic‐Sposta, S., Moretti, S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-20933-w · Cited by 17
Bharmal, S. H., Pendharkar, S. A., Singh, R. G., Cameron‐Smith, D., & Petrov, M. S. (2018) · Archives of Physiology and Biochemistry · doi:10.1080/13813455.2018.1534242 · Cited by 17
Effect of poly(3-hydroxyalkanoates) as natural polymers on mesenchymal stem cells
Voinova, V. V., Bonartseva, G. A., & Bonartsev, A. P. (2019) · World Journal of Stem Cells · doi:10.4252/wjsc.v11.i10.764 · Cited by 17
Application of nutrient essentiality criteria to dietary carbohydrates
Tondt, J., Yancy, W. S., & Westman, E. C. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000050 · Cited by 19
Qi, H., Gu, L., Xu, D., Liu, K., Zhou, M., Wang, Y., Wang, X., Li, Y., & Qi, J. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174012 · Cited by 17
Paracrine Behaviors Arbitrate Parasite-Like Interactions Between Tumor Subclones
Noble, R., Walther, V., Roumestand, C., Hibner, U., Hochberg, M., & Lassus, P. (2021) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2021.675638 · Cited by 17
“…of 4T07 with BHB upregulates MCT1, consistent with a positive feedback loop that could increase the transport of this ketone body into the dominant cell line (Supplementary Figure 4C). β -Hydroxybutyrate can be metabolized and used as a nutrient to replace glucose (Newman and Verdin, 2017).”
Metabolomics profiling predicts outcome of tocilizumab in rheumatoid arthritis: an exploratory study
Murillo‐Saich, J., Díaz‐Torné, C., Ortiz, M. A., Coras, R., Alabarse, P. V. G., Pedersen, A., Corominas, H., Vidal, S., & Gumá, M. (2021) · Metabolomics · doi:10.1007/s11306-021-01822-2 · Cited by 17
Impact of intermittent fasting on human health: an extended review of metabolic cascades
Ahmed, A., Saeed, F., Arshad, M. U., Afzaal, M., Imran, A., Ali, S. W., Niaz, B., Ahmad, A., & Imran, M. (2018) · International Journal of Food Properties · doi:10.1080/10942912.2018.1560312 · Cited by 16
Ketogenic therapy towards precision medicine for brain diseases
Liu, Y., Fan, L., Yang, H., Wang, D., Liu, R., Shan, T., & Xia, X. (2024) · Frontiers in Nutrition · doi:10.3389/fnut.2024.1266690 · Cited by 16
“In particular, BHB, in addition to its role as an energy source, also has a variety of molecular signaling and regulatory functions in a wide range of human diseases (39).”
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Metadata
- Authors
- Newman, J. C., & Verdin, E.
- Affiliations
- Gladstone Institutes (US)
- ORCID
- Verdin, Eric
- Venue
- Annual Review of Nutrition
- Publisher
- Annual Reviews
- Published
- 2017-08-21
- Volume
- 37
- Issue
- 1
- Pages
- 51-76
- ISSN
- 0199-9885 (ISSN-L)
- 1545-4312
- PMC
- PMC6640868
- OpenAlex
- W2747163024
- Cited by
- 872
- References
- 163
- Citations by year
- 2026: 146 · 2025: 160 · 2024: 126 · 2023: 100 · 2022: 106 · 2021: 99 · 2020: 72 · 2019: 38 · 2018: 24 · 2017: 1
- FWCI
- 4.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Annual Review of Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (K08AG048354)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK085610)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Diet and metabolism studies
- Health Sciences › Medicine › Physiology (medical) › Dietary Effects on Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- beta-hydroxybutyrate, ketone bodies, signal transduction, epigenetic regulation, energy metabolism, fasting, starvation, physical activity, nutritional stress, aging
- MeSH terms
- Aging, Animals, Humans, Liver, Starvation, Signal Transduction, 3-Hydroxybutyric Acid, Epigenesis, Genetic
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