A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

doi:10.1016/j.cell.2024.10.032

. 2025 Jan 9;188(1):175-186.e20.

doi: 10.1016/j.cell.2024.10.032. Epub 2024 Nov 12.

A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

Maria Dolores Moya-Garzon¹, Mengjie Wang², Veronica L Li³, Xuchao Lyu¹, Wei Wei⁴, Alan Sheng-Hwa Tung⁴, Steffen H Raun⁵, Meng Zhao⁶, Laetitia Coassolo⁶, Hashim Islam⁷, Barbara Oliveira⁷, Yuqin Dai⁸, Jan Spaas⁹, Antonio Delgado-Gonzalez¹⁰, Kenyi Donoso¹¹, Aurora Alvarez-Buylla¹², Francisco Franco-Montalban¹³, Anudari Letian¹⁴, Catherine P Ward¹⁵, Lichao Liu¹⁶, Katrin J Svensson⁶, Emily L Goldberg¹⁴, Christopher D Gardner¹⁵, Jonathan P Little⁷, Steven M Banik¹⁷, Yong Xu¹⁸, Jonathan Z Long¹⁹

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
² USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁵ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷ School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
⁸ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹⁰ Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
¹¹ Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Biology, Stanford University, Stanford, CA, USA.
¹³ Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Campus de Cartuja sn, 18071 Granada, Spain.
¹⁴ Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Department of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹⁸ USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: yongx@bcm.edu.
¹⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. Electronic address: jzlong@stanford.edu.

PMID: 39536746
PMCID: PMC11724754 (available on 2026-01-09)
DOI: 10.1016/j.cell.2024.10.032

A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

Maria Dolores Moya-Garzon et al. Cell. 2025.

. 2025 Jan 9;188(1):175-186.e20.

doi: 10.1016/j.cell.2024.10.032. Epub 2024 Nov 12.

Authors

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
² USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
³ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Department of Biology, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁵ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷ School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada.
⁸ Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹⁰ Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA.
¹¹ Department of Urology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Biology, Stanford University, Stanford, CA, USA.
¹³ Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Campus de Cartuja sn, 18071 Granada, Spain.
¹⁴ Department of Physiology, University of California, San Francisco, San Francisco, CA, USA.
¹⁵ Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
¹⁶ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁷ Department of Chemistry, Stanford University, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
¹⁸ USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA. Electronic address: yongx@bcm.edu.
¹⁹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Sarafan ChEM-H, Stanford University, Stanford, CA, USA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA; The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. Electronic address: jzlong@stanford.edu.

PMID: 39536746
PMCID: PMC11724754 (available on 2026-01-09)
DOI: 10.1016/j.cell.2024.10.032

Abstract

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.

Keywords: BHB; enzyme; ketone; metabolite; metabolomics; obesity.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests A provisional patent application has been filed by Stanford University on BHB-amino acids for the treatment of cardiometabolic disease.

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References

1. Newman JC, and Verdin E (2017). β-Hydroxybutyrate: A Signaling Metabolite. Annu. Rev. Nutr. 37, 51–76. - PMC - PubMed
1. Puchalska P, and Crawford PA (2021). Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu. Rev. Nutr. 41, 49–77. - PMC - PubMed
1. Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R, et al. (2014). The b-hydroxybutyrate receptor HCA 2 activates a neuroprotective subset of macrophages. Nat. Commun. 5, 1–11. - PubMed
1. Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, and Tsujimoto G (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108, 8030–8035. - PMC - PubMed
1. Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, et al. (2016). Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol. Cell 62, 194–206. - PMC - PubMed

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[1] Newman JC, and Verdin E (2017). β-Hydroxybutyrate: A Signaling Metabolite. Annu. Rev. Nutr. 37, 51–76. - PMC - PubMed

[2] Newman JC, and Verdin E (2017). β-Hydroxybutyrate: A Signaling Metabolite. Annu. Rev. Nutr. 37, 51–76. - PMC - PubMed

[3] Puchalska P, and Crawford PA (2021). Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu. Rev. Nutr. 41, 49–77. - PMC - PubMed

[4] Puchalska P, and Crawford PA (2021). Metabolic and Signaling Roles of Ketone Bodies in Health and Disease. Annu. Rev. Nutr. 41, 49–77. - PMC - PubMed

[5] Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R, et al. (2014). The b-hydroxybutyrate receptor HCA 2 activates a neuroprotective subset of macrophages. Nat. Commun. 5, 1–11. - PubMed

[6] Rahman M, Muhammad S, Khan MA, Chen H, Ridder DA, Müller-Fielitz H, Pokorná B, Vollbrandt T, Stölting I, Nadrowitz R, et al. (2014). The b-hydroxybutyrate receptor HCA 2 activates a neuroprotective subset of macrophages. Nat. Commun. 5, 1–11. - PubMed

[7] Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, and Tsujimoto G (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108, 8030–8035. - PMC - PubMed

[8] Kimura I, Inoue D, Maeda T, Hara T, Ichimura A, Miyauchi S, Kobayashi M, Hirasawa A, and Tsujimoto G (2011). Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc. Natl. Acad. Sci. U. S. A. 108, 8030–8035. - PMC - PubMed

[9] Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, et al. (2016). Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol. Cell 62, 194–206. - PMC - PubMed

[10] Xie Z, Zhang D, Chung D, Tang Z, Huang H, Dai L, Qi S, Li J, Colak G, Chen Y, et al. (2016). Metabolic Regulation of Gene Expression by Histone Lysine β-Hydroxybutyrylation. Mol. Cell 62, 194–206. - PMC - PubMed

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A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

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A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

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