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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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Moya-Garzón, M. D., Wang, M., Li, V. L., Lyu, X., Wei, W., Tung, A. S.-H., Raun, S. H., Zhao, M., Voilquin, L., Islam, H., et al. (2024) · Cell · doi:10.1016/j.cell.2024.10.032 · Cited by 69
Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm
Wang, Y., Ge, M., Wang, J., Xu, Y., Wang, N., & Xu, S. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-08114-w · Cited by 83
“First, the neurovascular unit serves as a metabolic nexus, modulated by hepatic ketogenesis fl ooding the blood-stream with neuroprotective β -hydroxybutyrate [10, 51], adipose lipolysis fueling in fl ammatory storms [12, 130], and skeletal muscle myokines in fl uencing penumbral resilience [188].”
The Promise of Niacin in Neurology
Wuerch, E. C., Urgoiti, G. B. R., & Yong, V. W. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01376-2 · Cited by 75
“During periods of fasting or exercise, Hcar2 on adipocytes is activated by ketone bodies such as β-hydroxybutyrate, one of its primary endogenous ligands [72].”
BackgroundKetone body oxidation increases cardiac endothelial cell proliferation
Weis, E., Puchalska, P., Nelson, A. B., Taylor, J., Moll, I., Hasan, S. S., Dewenter, M., Hagenmueller, M., Fleming, T. H., Poschet, G., et al. (2022) · EMBO Molecular Medicine · doi:10.15252/emmm.202114753 · Cited by 67
Ketone bodies as epigenetic modifiers
Ruan, H., & Crawford, P. A. (2018) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000475 · Cited by 71
Lucente, J. D., Persico, G., Zhou, Z., Jin, L., Ramsey, J. J., Rutkowsky, J. M., Montgomery, C. B., Tomilov, A. A., Kim, K., Giorgio, M., et al. (2024) · Communications Biology · doi:10.1038/s42003-024-05860-z · Cited by 70
“BHB penetrates the blood-brain barrier and signals downstream pathways through its hydroxycarboxylic acid receptor (HCAR2) and can also be used as a neural energy source 17,18 .”
Food as circadian time cue for appetitive behavior
Mistlberger, R. E. (2020) · F1000Research · doi:10.12688/f1000research.20829.1 · Cited by 67
Ketone Bodies Promote Amyloid-β1–40 Clearance in a Human in Vitro Blood–Brain Barrier Model
Versele, R., Corsi, M., Fuso, A., Sevin, E., Businaro, R., Gosselet, F., Fénart, L., & Candela, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21030934 · Cited by 66
“Increasing evidence indicates that alterations in DNA profiles can lead to changes in gene expression [84,85].”
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Understanding Dietary Intervention-Mediated Epigenetic Modifications in Metabolic Diseases
Asif, S., Morrow, N. M., Mulvihill, E. E., & Kim, K.-H. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.590369 · Cited by 69
Tsilingiris, D., Tzeravini, E., Koliaki, C. C., Dalamaga, Μ., & Kokkinos, A. D. (2021) · Current Obesity Reports · doi:10.1007/s13679-021-00434-0 · Cited by 60
“In the setting of prolonged fasting and energy depletion, available acetyl-CoA enters the ketogenic pathway in liver mitochondria, so that the resulting ketone bodies can be used as energy substrates by energy-demanding tissues such as the heart muscle and the brain [12].”
BackgroundNAD(H) in mitochondrial energy transduction: implications for health and disease
Walker, M. A., & Tian, R. (2018) · Current Opinion in Physiology · doi:10.1016/j.cophys.2018.03.011 · Cited by 59
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Ketogenic diet restrains aging-induced exacerbation of coronavirus infection in mice
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Infancy Dietary Patterns, Development, and Health: An Extensive Narrative Review
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“It is a strict diet consisting of minimal carbohydrate and protein intake and increased fat intake, looking to mimic the body’s response to starvation by using fat as the primary energy source in the absence of an adequate dietary carbohydrate source looking to induce ketosis [215].”
BackgroundInvited review: Ketone biology—The shifting paradigm of ketones and ketosis in the dairy cow
Rico, J. E., & Barrientos-Blanco, M. A. (2024) · Journal of Dairy Science · doi:10.3168/jds.2023-23904 · Cited by 67
Alternative Dietary Patterns for Americans: Low-Carbohydrate Diets
Volek, J. S., Phinney, S. D., Krauss, R. M., Johnson, R. J., Saslow, L. R., Gower, B., Yancy, W. S., King, J. C., Hecht, F. M., Teicholz, N., et al. (2021) · Nutrients · doi:10.3390/nu13103299 · Cited by 57
Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease
Forman, D. E., Kuchel, G. A., Newman, J. C., Kirkland, J. L., Volpi, E., Taffet, G. E., Barzilai, N., Pandey, A., Kitzman, D. W., Libby, P., et al. (2023) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2023.05.038 · Cited by 64
Self-citationCommon and divergent molecular mechanisms of fasting and ketogenic diets
Paoli, A., Tinsley, G. M., Mattson, M. P., Vivo, I. D., Dhawan, R., & Moro, T. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.10.001 · Cited by 63
Ketone therapy for heart failure: current evidence for clinical use
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Downregulation of HDAC9 by the ketone metabolite β‐hydroxybutyrate suppresses vascular calcification
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“Physiologically, BHB levels are elevated by prolonged fasting, high-intensity exercise, or a low-carbohydrate ketogenic diet, serving as a vital alternative metabolic fuel [12].”
BackgroundLuo, S., Yang, M., Han, Y., Zhao, H., Jiang, N., Li, L., Chen, W., Li, C., Yang, J., Liu, Y., et al. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109101 · Cited by 54
Benlloch, M., López‐Rodriguez, M. M., Cuerda‐Ballester, M., Drehmer, E., Carrera, S., Cerón, J. M. C., Tvarijonaviciute, A., Chirivella, J., Fernández, D., & Ortí, J. E. D. L. R. (2019) · Nutrients · doi:10.3390/nu11051156 · Cited by 55
Lilja, S., Oldenburg, J., Pointner, A., Dewald, L., Lerch, M. L., Hippe, B., Switzeny, O. J., & Haslberger, A. G. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/4793125 · Cited by 58
“BHB in a physiological concentration of 4mM, which can be reached after a 5 days fasting period [24], reduced CDKN1a gene expression significantly (p < 0:05).”
BackgroundHomilius, C., Seefeldt, J. M., Axelsen, J. B., Pedersen, T. M., Sørensen, T., Nielsen, R. R., Wiggers, H., Hansen, J., Matchkov, V. V., Bøtker, H. E., et al. (2023) · Basic Research in Cardiology · doi:10.1007/s00395-023-01008-y · Cited by 56
“L-3-OHB is either absent or only present at very low concentration in the human circulation [43].”
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“8 As BHB readily enters the brain, 51 we consider that the 1 mM BHB concentration we used in most of our experiments should approximate the actual brain BHB concentrations microglia are exposed to following ketogenic dietary regimens or exercise.”
BackgroundMethodResultInfluentialGPCRs involved in metabolic diseases: pharmacotherapeutic development updates
Jin, C., Chen, H., Xie, L. H., Zhou, Y., Liu, L., & Wu, J. H. (2024) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01215-2 · Cited by 54
A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity
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Self-citationKraeuter, A.-K., van den Buuse, M., & Sarnyai, Z. (2018) · Schizophrenia Research · doi:10.1016/j.schres.2018.11.011 · Cited by 52
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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