A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites Moya-Garzon, Maria Dolores Wang, Mengjie Li, Veronica L. Lyu, Xuchao Wei, Wei Tung, Alan Sheng-Hwa Raun, Steffen H. Zhao, Meng Coassolo, Laetitia Islam, Hashim Oliveira, Barbara Dai, Yuqin Spaas, Jan Delgado-Gonzalez, Antonio Donoso, Kenyi Alvarez-Buylla, Aurora Franco-Montalban, Francisco Anudari, Anudari Ward, Catherine P. Liu, Lichao Svensson, Katrin J. Goldberg, Emily L. Gardner, Christopher D. Little, Jonathan P. Banik, Steven M. Xu, Yong Long, Jonathan Z. BHB metabolomics enzyme obesity ketone metabolite 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. 2025-10-28T07:52:40Z 2025-10-28T07:52:40Z 2025-01-09 journal article https://hdl.handle.net/10481/107504 10.1016/j.cell.2024.10.032 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional