Moya-Garzon, M. D.; Wang, M.; Li, V. L.; Wei, W.; Tung, A. S.-H.; Raun, S. H.; Zhao, M.; Coassolo, L.; Islam, H.; Oliveira, B.; Dai, Y.; Spaas, J.; Delgado-Gonzalez, A.; Donoso, K.; Alvarez-Buylla, A.; Franco-Montalban, F.; Letian, A.; Ward, C.; Liu, L.; Svensson, K. J.; Goldberg, E. L.; Gardner, C. D.; Little, J. P.; Banik, S. M.; Xu, Y.; Long, J. Z.

{beta}-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.