A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites
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Biochemistry of a ketone body shunt pathway and anti-obesity metabolites.
This is a biomedical study of ketone metabolism and obesity in mice and humans.
Biochemistry paper identifying a ketone metabolite pathway; domain molecular biology.
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.
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The record
- Venue
- Cell
- Topic
- Diet and metabolism studies
- Field
- Medicine
- Canadian institutions
- University of British Columbia, Okanagan CampusUniversity of British Columbia
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of General Medical SciencesNational Heart, Lung, and Blood InstituteNational Institute on AgingCereal Partners WorldwideOno Pharma FoundationH. Lundbeck A/SWu Tsai Neurosciences Institute, Stanford UniversityNational Institutes of HealthU.S. Department of AgricultureUniversidad de GranadaLundbeckfondenNational Institute of Diabetes and Digestive and Kidney DiseasesOvarian Cancer Research AllianceEli Lilly and CompanyCanadian Institutes of Health ResearchAmerican Heart AssociationStanford Bio-X
- Keywords
- Ketone bodiesAmino acidKetosisKetoneBiologyBiochemistryMetabolismEnzymeMetabolic pathwayInternal medicineEndocrinologyChemistryMedicineOrganic chemistry
- Has abstract in OpenAlex
- yes