Cited by 873Diet and metabolism studiesDietary Effects on HealthMetabolism and Genetic Disorders

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β-Hydroxybutyrate: A Signaling Metabolite

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Newman, John C., Verdin, Eric·2017·Annual Review of Nutrition

DOI 10.1146/annurev-nutr-071816-064916PMC PMC6640868

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Abstract

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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β-Hydroxybutyrate enhances malate dehydrogenase 2 β-hydroxybutyrylation to alleviate hepatic steatosis in MASLD
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“3F , S3C-E). β-Hydroxybutyrate dehydrogenase 1 (BDH1) serves as the principal rate‐limiting enzyme in ketone body metab - olism, playing a key role in the interconversion of aceto - acetic acid (AcAc) and β‐OHB [ 23 ].”
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Medium-chain triglycerides and ketogenic diet prevent alterations of the gut microbiome in transgenic Alzheimer’s disease mice
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“Theclassiclow-carbohydrate,high-fatketogenicdiet triggers an energetic metabolic switch from glucose to the use of ketones derived from hepatic oxidation of fatty acids 10 .”
Ketogenesis is Dispensable for the Metabolic Adaptations to Caloric Restriction
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“…β -HB, that go beyond their function as energy substrates: not only can it function as a molecule that indirectly modulates epigenetic states [118], such as by serving as an inhibitor of histone deacetylases (HDACs) [116], but it has also been identified as the direct donor constituting a…”
Hepatic HMGCS2-derived β-hydroxybutyrate attenuates hippocampal insulin resistance and neuroinflammation to promote MASLD-induced cognitive function
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“Downregulation of HMGCS2 and reduced BHB levels have been observed in MASLD, whereas enhanced HMGCS2 or BHB supplementation improves hepatic steatosis and glucose homeostasis (Asif et al. 2022; Croci et al. 2013; Nasser et al. 2022; Ohashi et al. 2019; Yan et al. 2022 (Lin et al. 2022; Shamsi et al. 2024; Yomogida et…”
Nuclear OXCT1 attenuates histone β-hydroxybutyrylation-mediated MHC-I transcription
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“Ketogenesis is a metabolic pathway that generates ketone bodies from fatty acids when carbohydrate or oxygen availability is low [64].”
Background
Rationale and protocol for a safety, tolerability and feasibility randomized, parallel arm, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanisms
Stubbs, B. J., Azañedo, G. A., Peralta, S., Diaz, S. R., Gray, W., Alexander, L. E. C., Silverman-Martin, W., Garcia, T. Y., Blonquist, T. M., Upadhyay, V., et al. (2024) · PLoS ONE · doi:10.1371/journal.pone.0307951 · Cited by 5
Self-citation
Ketone monoester ingestion improves cardiac function in adults with type 2 diabetes: a double-blind, placebo-controlled, randomized, crossover trial
Perissiou, M., SAYNOR, Z. L., Feka, K., Edwards, C., James, T. J., Corbett, J., Mayes, H. S., Shute, J. K., Cummings, M., Black, M. I., et al. (2025) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00800.2024 · Cited by 5
β-hydroxybutyrate inhibits Plasmodium falciparum development and confers protection against malaria in mice
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“A ketone body refers to one of three distinct small molecules, acetoacetic acid (AcAc), β-hydroxybutyrate (βOHB) and acetone, which are synthesized primarily in the liver from fats 12 .”
Ketone metabolites in metabolic dysfunction-associated steatotic liver disease progression: optimizing keto-therapeutic strategies
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3-Hydroxybutyrate, a metabolite in sustaining neuronal cell vitality: a mendelian randomization and in vitro experimentation
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“In earlier studies, it was noted that 3HB is signi�cantly elevated during fasting, ketogenic diet, exercise, or when the organism develops insulin resistance [58, 59].”
Analysis of HMGCS2 Expression and TG Lipidomics in the Perirenal Adipose Tissue of Obese Diabetic Nephropathy Mice
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“A number of physiologic mechanisms exist in animals to combat negative energy balance; one example is production of b-hydroxybutyrate (BHB), a ketone body that is produced by excess b-oxidation of fatty acids in the liver (Newman and Verdin 2017).”
Background
Oxfendazole induces protein catabolism and gluconeogenesis in experimental neurocysticercosis
Correia, L. T. B., de Lima, N. F., Gomes, T. C., Guerra, C. H. D. S., da Costa, T. L., & Vinaud, M. C. (2022) · Acta Tropica · doi:10.1016/j.actatropica.2022.106571 · Cited by 3
Dialysis as a Novel Adjuvant Treatment for Malignant Cancers
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The association of hypoglycemia with outcome of critically ill children in relation to nutritional and blood glucose control strategies
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Background
AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation
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The Ketogenic Diet Metabolite β-Hydroxybutyrate Promotes Mitochondrial Elongation via Deacetylation in HeLa Cells and Improves Autism-like Behavior in ZebrafishPreprint
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Rationale and protocol for a safety, tolerability and feasibility randomized, parallel group, double-blind, placebo-controlled, pilot study of a novel ketone ester targeting frailty via immunometabolic geroscience mechanismsPreprint
Stubbs, B. J., Azañedo, G. A., Peralta, S., Diaz, S. R., Gray, W., Alexander, L. E. C., Silverman-Martin, W., Garcia, T. Y., Blonquist, T. M., Upadhyay, V., et al. (2023) · medRxiv · doi:10.1101/2023.10.25.23297571 · Cited by 3
Self-citation
Unravelling the Signature Follicular Fluid Metabolites in Dairy Cattle Follicles Growing Under Negative Energy Balance: An In Vitro Approach
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“This aceto-acetyl-CoA is, further, the acetyl-CoA that enters the Kreb cycle to produce ATPs [75].”
Effectiveness of Exogenous Ketone Salts in Enhancing Circulating Acetoacetate Levels—A Pilot Study in Healthy Adults
Holland, A. M., Moore, A. R., & Bederman, I. R. (2025) · Nutrients · doi:10.3390/nu17101665 · Cited by 2
“…samples were immediately centrifuged for 10 min at 13,000 rpm at 4 °C. ,000 rpm at 4 ◦ C. Plasma was then transferred into a tube containing NaB2H4 to convert plasma AcAc to Plasma was then transferred into a tube containing NaB2H4 to convert plasma AcAc to deuterated beta-hydroxybutyrate…”
Influential
Compensation Response to Hepatic Gluconeogenesis via β‐Hydroxybutyrylation of FBP1 and PCK1 in Dairy Cows
Feng, D., Wang, G., Zhu, Y., Zheng, Y., Yao, J., Chen, L., & Deng, L. (2025) · Animal Research and One Health · doi:10.1002/aro2.70022 · Cited by 2
Sex-dependent effects of a gestational ketogenic diet on offspring birth and lifespan
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“Besides its metabolic role, BHB acts as a direct and indirect signaling molecule, for instance in epigenetic regulation, through direct histone β -hydroxybutyrylation and also indirectly by modifying histone acetylation and methylation, as well as by regulating catabolism [13,14].”
Optimizing Mitochondrial Targeting With Bioactive Compounds: Dietary Pattern Considerations for Patients With Chronic Kidney Disease
Cecchini, V., Troise, D. E., Sabatino, A., Cicirelli, A., Hallergård, G., Avesani, C. M., & Stenvinkel, P. (2025) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2025.08.002 · Cited by 4
Risk stratification of patients with diffuse large B-cell lymphoma using plasma NMR-based metabolomics at diagnosis
Montagne, A., Bertho, G., Παπαστεργίου, Θ., Chartier, L., Ricci, R., Jardin, F., Ghesquières, H., Rossi, C., Morschhauser, F., Haïoun, C., et al. (2025) · Blood Advances · doi:10.1182/bloodadvances.2025017248 · Cited by 2
“28 33-35 In tumors with upregulated lipogenesis and fatty acid oxidation, production of 2-amino-butyrate may increase as part of the metabolic reprogramming to manage oxidative stress induced by lipid turnover.”
A combination of a ketogenic diet and high-dose vitamin C did not prove superior in enhancing doxorubicin efficiency in vivo
Al-Jada, D. N., Takruri, H. R., Talib, W. H., Hajeer, M., Alsafadi, D. B., Shahin, N. A., & Ahram, M. A. (2025) · Mediterranean Journal of Nutrition and Metabolism · doi:10.1177/1973798x251391703 · Cited by 2
“58 Prior research has demonstrated HDAC inhibitors ’ capacity to suppress HIF function by diminishing HIF-1 α levels or repressing its transactivation activity.”

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
DOI: 10.1146/annurev-nutr-071816-064916
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
Licence: www.annualreviews.org/licenses/tdm (tdm)
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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β-Hydroxybutyrate: A Signaling Metabolite

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