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.

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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.

References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases

Research Materials

Miscellaneous