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

Maria Dolores Moya-Garzon; Mengjie Wang; Veronica L Li; Xuchao Lyu; Wei Wei; Alan Sheng-Hwa Tung; Steffen H Raun; Meng Zhao; Laetitia Coassolo; Hashim Islam; Barbara Oliveira; Yuqin Dai; Jan Spaas; Antonio Delgado-Gonzalez; Kenyi Donoso; Aurora Alvarez-Buylla; Francisco Franco-Montalban; Anudari Letian; Catherine P Ward; Lichao Liu; Katrin J Svensson; Emily L Goldberg; Christopher D Gardner; Jonathan P Little; Steven M Banik; Yong Xu; Jonathan Z Long

doi:10.1016/j.cell.2024.10.032

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

Cell. 2024 Nov 7:S0092-8674(24)01214-5. doi: 10.1016/j.cell.2024.10.032. Online ahead of print.

Authors

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: [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.