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

This study identifies a secondary BHB metabolic pathway in which the enzyme CNDP2 conjugates BHB with free amino acids to produce BHB-amino acids. Genetic ablation of CNDP2 in mice eliminated tissue amino acid BHB-ylation activity and reduced BHB-amino acid levels. The most abundant of these, BHB-Phe, activates hypothalamic and brainstem neurons and suppresses feeding. CNDP2-knockout mice showed increased food intake and body weight after ketone ester supplementation or a ketogenic diet, and the pathway was reported to be conserved in humans.