
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.09.612087
preprint
1
Article
A secondary β-hydroxybutyrate metabolic pathway linked to energy balance
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.
09 9 2024
2024.09.09.612087https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.09.612087
nihpp-2024.09.09.612087.pdf
Summary

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.
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