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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“In animal cells, BHB acts as a signaling metabolite with various direct effects, including competitively inhibiting HDAC enzymes, binding to cell surface receptors, modulating ion channel activity, and post-translationally modifying proteins 47 .”
Beta-hydroxybutyrate dampens adipose progenitors’ profibrotic activation through canonical Tgfβ signaling and non-canonical ZFP36-dependent mechanisms
Lecoutre, S., Merabtene, F., HACHEM, E.-K., Gamblin, C., Rouault, C., Sokolovska, N., Soula, H., Lai, W., Blackshear, P., Clément, K., et al. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101512 · Cited by 11
Metabolomic Response throughout 16 Weeks of Combined Aerobic and Resistance Exercise Training in Older Women with Metabolic Syndrome
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“[56] showed increases in 3-hydroxybutyrate with exercise training and this increase was associated with increased glucose metabolism, lower serum triglycerides and reduced hepatic lipid content [56], as well as improved energy production in brain and skeletal muscle [57,58].”
Background
Low Glucose plus β-Hydroxybutyrate Induces an Enhanced Inflammatory Response in Yak Alveolar Macrophages via Activating the GPR109A/NF-κB Signaling Pathway
Qi, J., Yang, Q., Xia, Q., Huang, F., Guo, H., Cui, H., Xie, Y., Ren, Z., Gou, L., Cai, D., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241411331 · Cited by 12
Multiomics analyses reveal dynamic bioenergetic pathways and functional remodeling of the heart during intermittent fasting
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A very-low carbohydrate content in a high-fat diet modifies the plasma metabolome and impacts systemic inflammation and experimental atherosclerosis
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The role of novel protein acylations in cancer
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Maternal gut Bifidobacterium breve modifies fetal brain metabolism in germ-free mice
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“Studies are also needed to monitor the growth and behaviour of offspring into adult-life.”
Comprehensive Overview of Ketone Bodies in Cancer Metabolism: Mechanisms and Application
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Ketogenic Metabolism in Neurodegenerative Diseases: Mechanisms of Action and Therapeutic Potential
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“KBs show potential as signaling molecules, influencing mitochondrial function, gene expression, and redox balance, thereby exhibiting neuroprotective, anti-inflammatory, and anti-cancer effects [24,35].”
Influential
Association between Fasting Ketonuria and Advanced Liver Fibrosis in Non-Alcoholic Fatty Liver Disease Patients without Prediabetes and Diabetes Mellitus
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Ketogenic diet: new avenues to overcome colorectal cancer
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PLIS : A metabolomic response monitor to a lifestyle intervention study in older adults
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Effects of an exogenous ketone ester using multi-omics in skeletal muscle of aging C57BL/6J male mice
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Effects of ketone supplements on blood β-hydroxybutyrate, glucose and insulin: A systematic review and three-level meta-analysis
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Central Treatment of Ketone Body in Rainbow Trout Alters Liver Metabolism Without Apparently Altering the Regulation of Food Intake
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Starvation promotes histone lysine butyrylation in the liver of male but not female mice
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Acutely increased β-hydroxybutyrate plays a role in the prefrontal cortex to escape stressful conditions during the acute stress response
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Western and ketogenic diets in neurological disorders: can you tell the difference?
Habashy, K. J., Ahmad, F. A., Ibeh, S., Mantash, S., Kobeissy, F., Issa, H., Habis, R., Tfaily, A., Nabha, S. M., Harati, H., et al. (2022) · Nutrition Reviews · doi:10.1093/nutrit/nuac008 · Cited by 12
Ketone body β-hydroxybutyrate-mediated histone β-hydroxybutyrylation upregulates lipolysis and attenuates metabolic syndrome
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Acute ingestion of a ketone monoester, whey protein, or their co-ingestion in the overnight postabsorptive state elicit a similar stimulation of myofibrillar protein synthesis rates in young males: a double-blind randomized trial
Hannaian, S. J., Lov, J., Hawley, S., Dargegen, M., Malenda, D., Gritsas, A., Gouspillou, G., Morais, J. A., & Churchward‐Venne, T. A. (2024) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2024.01.004 · Cited by 10
“…amino acid. source, β -OHB (the primary ketone body in circulation) is now recognized as a signaling metabolite that can modulate an array of physiologic functions, such as substrate metabolism, in ﬂ ammation, oxidative stress, and gene expression in multiple organs including skeletal muscle [2].”
Background
Targeting apoptosis and unfolded protein response: the impact of β-hydroxybutyrate in clear cell renal cell carcinoma under glucose-deprived conditions
Roohy, F., Siri, M., Kohansal, K., Ghalandari, A., Rezaei, R., Maleki, M. H., Shams, M., Monsef, A., & Dastghaib, S. (2024) · Molecular Biology Reports · doi:10.1007/s11033-023-08977-2 · Cited by 11
“As a result, this strategy may limit the energy available to cancer cells while allowing other cell types to receive energy by consuming ketone bodies, particularly β-hydroxybutyrate (BHB), which is a large reservoir of keton bodies in blood circulation (7, 8).”
Fiber rich food suppressed airway inflammation, GATA3 + Th2 cells, and FcεRIα+ eosinophils in asthma
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“3-Hydroxybutyric acid, which is also named as β -Hydroxybutyric acid, was found to be the major ketone body produced in the liver from fatty acids as a result of low carbohydrate/low calorie diet, which modulates the gut microbiota into “keto microbiota” (41).”
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“Furthermore, the ketogenic diet can reduce oxidative stress and inflammation, further supporting mitochondrial function and overall cellular resilience [22, 26, 27].”
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“Oxidative stress has widespread effects, caus - ing changes in lipid peroxidation, protein and DNA oxida - tion, inflammation, altered immune response, decreased DNA methylation, and epigenetic dysregulation (Bjørklund et al. 2020 ).”
Cognitive impairment caused by compromised hepatic ketogenesis is prevented by endurance exercise
Kelty, T. J., Kerr, N. R., Chou, C. H., Shryack, G. E., Taylor, C. L., Krause, A. A., Knutson, A. R., Bunten, J., Childs, T. E., Meers, G. M.-E., et al. (2025) · The Journal of Physiology · doi:10.1113/jp287573 · Cited by 10
“…barrier (BBB) (Hasselbalch et al., 1995) and elicit similar neuroprotective effects observed from endurance exercise (Kovács et al., 2021). β -Hydroxybutyrate (BHB) is the most abundant ketone body in mammals (Newman & Verdin, 2017) and is increasingly recognized as a signalling metabolite.”
Co-targeting of metabolism using dietary and pharmacologic approaches reduces breast cancer metastatic burden
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High‐Fat Diet‐Induced Fatty Liver Is Associated with Immunosuppressive Response during Sepsis in Mice
Wang, F., Cen, Z., Liu, Z., Gan, J., Zhang, X., Cui, Q., Gong, S., Chang, P., & Chen, P. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5833857 · Cited by 11
“Recent discoveries have demonstrated the pleiotropic function of BHB, as a signaling metabolite mediating inflammation, oxidative stress, and gene expression [25].”
Background
VLCKD in Combination with Physical Exercise Preserves Skeletal Muscle Mass in Sarcopenic Obesity after Severe COVID-19 Disease: A Case Report
Camajani, E., Feraco, A., Basciani, S., Gnessi, L., Barrea, L., Armani, A., & Caprio, M. (2022) · Healthcare · doi:10.3390/healthcare10030573 · Cited by 11
REGLIV: Molecular regulation data of diverse living systems facilitating current multiomics research
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“…enzymes, improving ROS management via histone deacetylase inhibition, upregulation of NAD + sirtuin activity and directly modulating chromatin via beta-hydroxybutyrylation, resulting in decreased basal ROS levels, increasing cellular resilience and survival capac-Antioxidants ity [46,70,102].”
Background
Neuropeptide Y and orexin immunoreactivity in the sparrow brain coincide with seasonal changes in energy balance and steroids
Fokidis, H. B., Ma, C., Radin, B., Prior, N., Adomat, H., Guns, E., & Soma, K. K. (2018) · The Journal of comparative neurology · doi:10.1002/cne.24535 · Cited by 11
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Background
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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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