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

  • Cell. 2025 Jan 9;188(1):175-186.e20. doi: 10.1016/j.cell.2024.10.032.
Maria Dolores Moya-Garzon  1 ,  Mengjie Wang  2 ,  Veronica L Li  3 ,  Xuchao Lyu  1 ,  Wei Wei  4 ,  Alan Sheng-Hwa Tung  4 ,  Steffen H Raun  5 ,  Meng Zhao  6 ,  Laetitia Coassolo  6 ,  Hashim Islam  7 ,  Barbara Oliveira  7 ,  Yuqin Dai  8 ,  Jan Spaas  9 ,  Antonio Delgado-Gonzalez  10 ,  Kenyi Donoso  11 ,  Aurora Alvarez-Buylla  12 ,  Francisco Franco-Montalban  13 ,  Anudari Letian  14 ,  Catherine P Ward  15 ,  Lichao Liu  16 ,  Katrin J Svensson  6 ,  Emily L Goldberg  14 ,  Christopher D Gardner  15 ,  Jonathan P Little  7 ,  Steven M Banik  17 ,  Yong Xu  18 ,  Jonathan Z Long  19
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: [email protected].
  • 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: [email protected].
PMID: 39536746 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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