Children’s Nutrition Research Center Staff Publications

Language

English

Publication Date

1-9-2025

Journal

Cell

DOI

10.1016/j.cell.2024.10.032

PMID

39536746

PMCID

PMC11724754

PubMedCentral® Posted Date

1-9-2026

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, 3-Hydroxybutyric Acid, Mice, Mice, Knockout, Obesity, Humans, Ketones, Diet, Ketogenic, Ketone Bodies, Mice, Inbred C57BL, Male, Amino Acids, BHB, enzyme, ketone, metabolite, metabolomics, obesity

Published Open-Access

yes

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