2. Academic Validation
  3. A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

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

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 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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