b-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 BHBamino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of LacPhe 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.
b-hydroxybutyrate shunt pathway generates antiobesity ketone metabolites
