A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites
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.
Authors
- Jonathan P. Little (ORCID: https://orcid.org/0000-0002-9796-2008)
- Xuchao Lyu
- Bárbara Oliveira (ORCID: https://orcid.org/0000-0002-3270-5780)
- Steven M. Banik (ORCID: https://orcid.org/0000-0002-0544-6488)
- Francisco Franco-Montalbán (ORCID: https://orcid.org/0000-0001-6539-1653)
- Jan Spaas (ORCID: https://orcid.org/0000-0002-4953-2505)
- Christopher D. Gardner (ORCID: https://orcid.org/0000-0002-7596-1530)
- Katrin J. Svensson (ORCID: https://orcid.org/0000-0001-5376-5128)
- Veronica L. Li (ORCID: https://orcid.org/0000-0001-8888-3853)
- Antonio Delgado‐González (ORCID: https://orcid.org/0000-0002-4760-8174)
- Laetitia Coassolo (ORCID: https://orcid.org/0000-0003-2138-4819)
- Aurora Alvarez‐Buylla (ORCID: https://orcid.org/0000-0001-6256-0300)
- Steffen H. Raun (ORCID: https://orcid.org/0000-0003-2050-505X)
- Jonathan Z. Long (ORCID: https://orcid.org/0000-0003-2631-7463)
- Alan Sheng-Hwa Tung (ORCID: https://orcid.org/0000-0002-0669-1928)
- Hashim Islam (ORCID: https://orcid.org/0000-0002-7145-0522)
- Yong Xu (ORCID: https://orcid.org/0000-0002-4908-1572)
- Anudari Letian (ORCID: https://orcid.org/0000-0001-8813-6567)
- María Dolores Moya-Garzón (ORCID: https://orcid.org/0000-0001-7212-9880)
- Catherine Ward (ORCID: https://orcid.org/0000-0001-8539-0535)
- Meng Zhao (ORCID: https://orcid.org/0000-0002-5415-8335)
- Emily L. Goldberg (ORCID: https://orcid.org/0000-0002-3848-6590)
- Wei Wei (ORCID: https://orcid.org/0000-0001-8110-0705)
- Lichao Liu (ORCID: https://orcid.org/0000-0002-2859-1063)
- Yuqin Dai
- Kenyi Donoso
- Mengjie Wang (ORCID: https://orcid.org/0000-0003-2124-3215)
Institutions
- University of Copenhagen (DK)
- University of British Columbia (CA)
- Universidad de Granada (ES)
- University of California, San Francisco (US)
- Cardiovascular Institute of the South (US)
- Stanford Medicine (US)
- Children's Nutrition Research Center at Baylor College of Medicine (US)
- University of British Columbia, Okanagan Campus (CA)
- Stanford University (US)
Publication Details
- Journal
- Cell
- Published
- 2024-11-12
- DOI
- https://doi.org/10.1016/j.cell.2024.10.032
- Citations
- 46
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 15.02
Funders
- U.S. Department of Agriculture
- American Heart Association
- Eli Lilly and Company
- Ovarian Cancer Research Alliance
- Lundbeckfonden
- Universidad de Granada
- H. Lundbeck A/S
- Ono Pharma Foundation
- National Institutes of Health
- Stanford Bio-X
- Wu Tsai Neurosciences Institute, Stanford University
- Cereal Partners Worldwide
- Canadian Institutes of Health Research