{"doi":"10.1016/j.cell.2024.10.032","title":"A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites","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.","journal":"Cell","year":2024,"id":417706,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":63,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1204053,"name":"Mengjie Wang","orcid":"0000-0003-2124-3215","position":1,"is_corresponding":false},{"id":259635,"name":"Veronica L. 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Svensson","orcid":"0000-0001-5376-5128","position":20,"is_corresponding":false},{"id":304594,"name":"Emily L. Goldberg","orcid":"0000-0002-3848-6590","position":21,"is_corresponding":false},{"id":819,"name":"Christopher D. Gardner","orcid":"0000-0002-7596-1530","position":22,"is_corresponding":false},{"id":246591,"name":"Jonathan P. Little","orcid":"0000-0002-9796-2008","position":23,"is_corresponding":false},{"id":218279,"name":"Steven M. Banik","orcid":"0000-0002-0544-6488","position":24,"is_corresponding":false},{"id":267310,"name":"Yong Xu","orcid":"0000-0002-4908-1572","position":25,"is_corresponding":false},{"id":259637,"name":"Jonathan Z. 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