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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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Lin, D., Zhang, L., Huang, C., & Shao, W. (2026) · iScience · doi:10.1016/j.isci.2026.115024 · Cited by 35
“53,55,56 Additionally, β -HB has been shown to inhibit histone deacetylases (HDACs), supporting anti-inflammatory and antioxidative responses, further contributing to skeletal muscle health.”
HDAC1 and HDAC2 independently regulate common and specific intrinsic responses in murine enteroids
Gonneaud, A., Turgeon, N., Jones, C. M., Couture, C., Lévesque, D., Boisvert, F., Boudreau, F., & Asselin, C. (2019) · Scientific Reports · doi:10.1038/s41598-019-41842-6 · Cited by 30
Grigolon, R. B., Gerchman, F., Schöffel, A. C., Hawken, E. R., Gill, H., Vázquez, G. H., Mansur, R. B., McIntyre, R. S., & Brietzke, E. M. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109947 · Cited by 32
Does nutrition for cancer patients feed the tumour? A clinical perspective
Bozzetti, F., & Stanga, Z. G. (2020) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2020.103061 · Cited by 29
The Ketogenic Diet in the Treatment of Post-concussion Syndrome—A Feasibility Study
Rippee, M. A., Chen, J., & Taylor, M. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00160 · Cited by 29
Intermittent fasting for obesity and related disorders: unveiling myths, facts, and presumptions
Halpern, B., & Mendes, T. B. (2021) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000322 · Cited by 31
“A couple of published reviews have deeply discussed several of the above-mentioned molecular mechanisms (1-3,9,11), and we will focus this manuscript on human data from this point on.”
BackgroundInfluentialBharmal, S. H., Cho, J., Ramos, G. C. A., Ko, J., Cameron‐Smith, D., & Petrov, M. S. (2020) · Journal of Nutrition · doi:10.1093/jn/nxaa417 · Cited by 30
Overview of key molecular and pharmacological targets for diabetes and associated diseases
Shahcheraghi, S. H., Aljabali, A. A. A., Zoubi, M. S. A., Mishra, V. K., Charbe, N. B., Haggag, Y. A., Shrivastava, G., Almutary, A. G., Alnuqaydan, A. M., Barh, D., et al. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.119632 · Cited by 28
Li, Z., Zhang, S., Zhang, Y., Chen, J., Wu, F., Liu, G., & Chen, G. (2021) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202100533 · Cited by 29
Kackley, M. L., Short, J. A., Hyde, P. N., LaFountain, R. A., Buga, A., Miller, V. J., Dickerson, R. M., Sapper, T. N., Barnhart, E. C., Krishnan, D. K., et al. (2020) · Journal of the American College of Nutrition · doi:10.1080/07315724.2020.1752846 · Cited by 31
Shahpasand, S., Khatami, S. H., Ehtiati, S., Alehossein, P., Salmani, F., Toutounchi, A. H., Zarei, T., Shahmohammadi, M. R., Khodarahmi, R., Aghamollaii, V., et al. (2024) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2024.109693 · Cited by 29
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
Madhavan, S. S., Diaz, S. R., Peralta, S., Nomura, M., King, C. D., Ceyhan, K. E., Lin, A., Bhaumik, D., Foulger, A., Shah, S., et al. (2024) · Cell chemical biology · doi:10.1016/j.chembiol.2024.11.001 · Cited by 29
Self-citationHinzman, C. P., Baulch, J. E., Mehta, K. Y., Girgis, M. J., Bansal, S., Gill, K., Li, Y., Limoli, C. L., & Cheema, A. K. (2019) · Scientific Reports · doi:10.1038/s41598-019-45970-x · Cited by 28
Marunaka, Y. (2021) · Biochemical Society Transactions · doi:10.1042/bst20200667 · Cited by 28
Ogłodek, E. A., & Pilis, W. (2021) · Global Advances in Health and Medicine · doi:10.1177/21649561211031178 · Cited by 28
New insights of epigenetics in vascular and cellular senescence
Zhu, M., Ding, Q., Lin, Z., Chen, X., Chen, S., & Zhu, Y. Z. (2021) · Journal of Translational Internal Medicine · doi:10.2478/jtim-2021-0049 · Cited by 28
“[66] The oxidized form (NAD+) of nicotinamide adenine dinucleotide (NAD) is a cofactor of sirtuins and PARP, and NAD is consumed in the process deacetylation of sirtuins and ADP-ribosylation of PARP.[67] Therefore, sirtuins and PARP regulate the cell function from gene expression and DNA damage through fatty acid meta…”
BackgroundInfluentialKetone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection
Hirschberger, S., Gellert, L. M., Effinger, D., Muenchhoff, M., Herrmann, M., Briegel, J., Zwißler, B., & Kreth, S. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.923502 · Cited by 28
Epigenome Modulation Induced by Ketogenic Diets
Ungaro, P., Nettore, I. C., Franchini, F., Palatucci, G., Muscogiuri, G., Colao, A., & Macchia, P. E. (2022) · Nutrients · doi:10.3390/nu14153245 · Cited by 32
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“A KD, where fats are high and carbohydrates are limited, similar to fasting (Newman & Verdin, 2017) and exercise (Sleiman et al., 2016) results in the production of ketones such as β- hydroxybutyrate (BHB) by the liver.”
BackgroundMcKenzie, A. L., Athinarayanan, S. J., Van Tieghem, M. R., Volk, B. M., Roberts, C. G. P., Adams, R. N., Volek, J. S., Phinney, S. D., & Hallberg, S. J. (2024) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2024.111898 · Cited by 25
Buga, A., Harper, D. G., Sapper, T. N., Hyde, P. N., Fell, B., Dickerson, R. M., Stoner, J. T., Kackley, M. L., Crabtree, C. D., Decker, D. D., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0296523 · Cited by 26
The role of short-chain fatty acids in cancer prevention and cancer treatment
Kalyanaraman, B., Cheng, G., & Hardy, M. (2024) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2024.110172 · Cited by 29
“Beta-hydroxybutyrate, an analogue of butyrate, is generated from fatty acid oxidation and acts as an endogenous redox signaling molecule [9].”
Reversible histone deacetylase activity catalyzes lysine acylation
Tsusaka, T., Najar, M. A., Schwarz, B. H., Bohrnsen, E., Osés-Prieto, J. A., Neudorf, H., Lee, C., Little, J. P., Burlingame, A. L., Bosio, C. M., et al. (2025) · Nature Chemical Biology · doi:10.1038/s41589-025-01869-5 · Cited by 29
Fais, S., & Marunaka, Y. (2020) · Cancers · doi:10.3390/cancers12113226 · Cited by 28
“β-hydroxybutyric acid (β-hydroxybutyrate−/H+) is one of major ketone bodies [60,62,63] and exists as its ionized form, since the pKa of β-hydroxybutyrate is ~4.”
BackgroundVestergaard, E. T., Zubanovic, N. B., Rittig, N. F., Møller, N., Kuhre, R. E., Holst, J. J., Rehfeld, J. F., & Thomsen, H. H. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14402 · Cited by 27
“This results in the formation of lipid intermediates as alternative fuel sources for oxidative metabolism, particularly in the brain, with beta-hydroxybutyrate (BHB) being a key player that not only provides the required energy supply but also may exert anorexigenic effects.6 As an alternative to prolonged fasting or…”
MethodInfluentialRole of Ketogenic Diets in Multiple Sclerosis and Related Animal Models: An Updated Review
Lin, W., Lin, S.-J., Liao, P.-Y., Suresh, D., Hsu, T., & Wang, P. (2022) · Advances in Nutrition · doi:10.1093/advances/nmac065 · Cited by 30
The therapeutic potential of ketones in cardiometabolic disease: impact on heart and skeletal muscle
Soni, S., Dakhili, S. A. T., Ussher, J. R., & Dyck, J. R. B. (2024) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00501.2023 · Cited by 28
Effects of an Exogenous Ketone Supplement on Five‐Kilometer Running Performance
Prins, P., Koutnik, A. P., D’Agostino, D. P., Rogers, C. Q., Seibert, J. F., Breckenridge, J. A., Jackson, D. S., Ryan, E. J., Buxton, J. D., & Ault, D. L. (2020) · Journal of Human Kinetics · doi:10.2478/hukin-2019-0114 · Cited by 26
“S-βHB may play an important role in signaling that is being investigated for its protective effects (Newman and Verdin, 2017).”
BackgroundExercise, Neuroprotective Exerkines, and Parkinson’s Disease: A Narrative Review
Mitchell, A. K., Bliss, R. R., & Church, F. (2024) · Biomolecules · doi:10.3390/biom14101241 · Cited by 33
Xu, B.-T., Wan, S., Wu, Q., Xing, Y.-H., He, Y., Huang, W. G., Long, Y., Zhang, C., Xu, Y., & Jiang, Z. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02646-3 · Cited by 26
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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