Author:
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,Letian Anudari,Ward Catherine,Liu Lichao,Svensson Katrin J.,Goldberg Emily L.,Gardner Christopher D.,Little Jonathan P.,Banik Steven M.,Xu Yong,Long Jonathan Z.
Abstract
Summaryβ-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids. This BHB-ylation reaction produces a family of endogenous 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. Administration of BHB-Phe, the most abundant BHB-amino acid, to obese mice activates neural populations in the hypothalamus and brainstem and suppresses feeding and body weight. Conversely, CNDP2-KO mice exhibit increased food intake and body weight upon ketosis stimuli. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, the metabolic pathways of BHB extend beyond primary metabolism and include secondary ketone metabolites linked to energy balance.
Publisher
Cold Spring Harbor Laboratory