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 metabolic benefits attributed to nutritional ketosis, as well as ongoing support from care team.
“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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Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening K ATP Channels
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“The nonmetabolized enantiomer S-BHB did not have a similar effect on neuron firing (78); a later study showed that the change in KATP channel opening is due to reduced glycolysis in the presence of BHB (76) and that providing sufficient BHB and oxygen to maintain normal cellular ATP production can prevent the change i…”
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“The mitochondrial BHB:AcAc equilibrium is so closely linked to the NAD:NADH equilibrium that early metabolic studies of the liver used the former as a proxy for the latter (65).”
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“Neither BHB nor acetoacetate alters GABA currents in cultured rodent cortical neurons (22) or in rat hippocampal neurons (127).”
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How to Define the Latent Reservoir: Tools of the Trade
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Creatine kinase is required for swelling-activated K-Cl cotransport in dog red blood cells
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Effects of intermittent fasting on health, aging, and disease
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From discoveries in ageing research to therapeutics for healthy ageing
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“Recently, ketone bodies have attracted attention as not only an energy source of the brain, but also a substance correcting metabolic disease and preventing aging and cancer [25].”
BackgroundEffects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases
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BackgroundKetone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet
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β-Hydroxybutyrate suppresses colorectal cancer
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“[49] found that increased acetyl-CoA favors both enzymatic and nonenzymatic protein acetylation, specifically in the mitochondria, which improves overall mitochondrial function.”
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Ketosis Ameliorates Renal Cyst Growth in Polycystic Kidney Disease
Torres, J. A., Kruger, S. L., Broderick, C., Amarlkhagva, T., Agrawal, S., Dodam, J. R., Mrug, M. M., Lyons, L. A., & Weimbs, T. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.09.012 · Cited by 223 · see citing works
Beyond histone acetylation—writing and erasing histone acylations
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High-fat diet-activated fatty acid oxidation mediates intestinal stemness and tumorigenicity
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“BOHB is a terminally oxidized lipid byproduct of FAO that has energetic and signaling properties (Newman and Verdin, 2017; Puchalska and Crawford, 2017) and further serves as a class 1 histone deacetylase inhibitor to reinforce the NOTCH program in ISCs (Cheng et al.”
BackgroundChaudhary, M. R., Chaudhary, S., Sharma, Y., Singh, T. A., Mishra, A. K., Sharma, S. G., & Mehdi, M. M. (2023) · Biogerontology · doi:10.1007/s10522-023-10050-1 · Cited by 210 · see citing works
“BHB levels increase with fasting, reaching millimolar concentrations after 8–12 h of intermittent fasting (Wright et al. 2006; Newman and Verdin 2017; Persynaki et al. 2017).”
BackgroundKetogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development
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3-Hydroxybutyrate as a Metabolite and a Signal Molecule Regulating Processes of Living Organisms
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“The S-3-HB enantiomer can also bind to some cell receptors, but less strongly than R-3-HB [1].”
BackgroundInfluentialMaximizing Cellular Adaptation to Endurance Exercise in Skeletal Muscle
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Salt-Responsive Metabolite, β-Hydroxybutyrate, Attenuates Hypertension
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“Interestingly, both exercise and calorie-restriction are associated with increased circulating levels of ketone bodies such as β-Hydroxybutyrate (βOHB) (Evans et al., 2017; Mahoney et al., 2006; Newman and Verdin, 2017; Sutton et al., 2018; Veech et al., 2017; Wang et al., 2017).”
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“Another SCFA, beta-hydroxybutyrate, is produced endogenously from fatty acid oxidation and acts as a redox signaling molecule [13].”
BackgroundTurning back time with emerging rejuvenation strategies
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The physiology of bilirubin: health and disease equilibrium
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p53 β-hydroxybutyrylation attenuates p53 activity
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Ketone Body, 3-Hydroxybutyrate: Minor Metabolite - Major Medical Manifestations
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Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation
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The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology
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β-hydroxybutyrate as an Anti-Aging Metabolite
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BDNF Impact on Biological Markers of Depression—Role of Physical Exercise and Training
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“Newman and Verdin [122] maintain that β-hydroxybutyrate is not only an exercise metabolite but also a significant releasing molecule.”
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Molecular basis for hierarchical histone de-β-hydroxybutyrylation by SIRT3
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“Elevated blood ketone concentrations occur within 2–4 days of an HFD [24, 25].”
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“Others believe that KB can reduce histone deacetylation, which acts as active signalling molecules and promotes important epigenetic modifications(76,81).”
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Nutritional Ketosis Increases NAD+/NADH Ratio in Healthy Human Brain: An in Vivo Study by 31P-MRS
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Function and mechanism of histone β-hydroxybutyrylation in health and disease
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“Succinyl-CoA is then converted to succinate by succinyl-CoA-synthetase, generating GTP. Succinate is oxidized to the four-carbon fumarate by succinic dehydrogenase, producing FADH2.”
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“19 87 However, in metabolically unstable patients, especially when ketosis may need to be induced, reducing the upper reference interval to 3.0 mmol/L may be preferable, while ensuring close monitoring of and no trending down-wards of serum bicarbonate.”
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Ketone Bodies Attenuate Wasting in Models of Atrophy
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Utility of Ketone Supplementation to Enhance Physical Performance: A Systematic Review
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“βHB has been suggested to function as a signaling metabolite (20), acting independently of changes in macronutrient intake to alter substrate oxidation during exercise (18, 21).”
From Obesity to Hippocampal Neurodegeneration: Pathogenesis and Non-Pharmacological Interventions
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“Apart from being an alternative energy substrate during fasting, ketones serve signaling roles, may stimulate autophagy and enhance muscle regeneration [67, 68].”
BackgroundInvestigating Ketone Bodies as Immunometabolic Countermeasures against Respiratory Viral Infections
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Self-citationExogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future
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“As reviewed elsewhere [4, 5, 255], there are cellular signalling and metabolic effects common to AcAc and R-βHB, but there are also several intriguing differences between the molecules that may be avenues for future research exploring the performance and therapeutic potential of the various forms of EKS.”
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Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer
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“The ketogenic diet is said to affect glucose metabolism [25] and gene expression [26,27] because of changes in the metabolic environment and ketone bodies acting as signal molecules [28].”
BackgroundBeta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator
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A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites
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 · see citing works
Metabolic reprogramming in ischemic stroke: when glycolytic overdrive meets lipid storm
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“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 68 · see citing works
“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 · see citing works
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 66 · see citing works
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 65 · see citing works
“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
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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 64 · see citing works
“Increasing evidence indicates that alterations in DNA profiles can lead to changes in gene expression [84,85].”
BackgroundLi, B., Yu, Y., Liu, K., Zhang, Y., Geng, Q., Zhang, F., Li, Y., & Qi, J. (2020) · Diabetologia · doi:10.1007/s00125-020-05305-2 · Cited by 64 · see citing works
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 · see citing works
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 · see citing works
“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].”
BackgroundAlternative 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 · see citing works
NAD(H) in mitochondrial energy transduction: implications for health and disease
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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
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Impact of Geroscience on Therapeutic Strategies for Older Adults With Cardiovascular Disease
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Self-citationCommon and divergent molecular mechanisms of fasting and ketogenic diets
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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].”
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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 54 · see citing works
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 54 · see citing works
“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 53 · see citing works
“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 52 · see citing works
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 · see citing works
- 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 › Diet and metabolism studies
- Health Sciences › Medicine › Physiology › 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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