bioRxiv : the preprint server for biology · 2024
A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.
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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
Аннотация
β-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.