A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites

Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Alan Sheng Hwa Tung, Steffen H. Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P. Ward, Lichao LiuKatrin J. Svensson, Emily L. Goldberg, Christopher D. Gardner, Jonathan P. Little, Steven M. Banik, Yong Xu*, Jonathan Z. Long

*Corresponding author for this work

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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.

Original languageEnglish
JournalCell
Volume188
Issue number1
Pages (from-to)175-186
ISSN0092-8674
DOIs
Publication statusPublished - 2025

Bibliographical note

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© 2024 The Author(s)

Keywords

  • BHB
  • enzyme
  • ketone
  • metabolite
  • metabolomics
  • obesity

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