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

Authors: MOYA-GARZON, MARIA DOLORES - Stanford University School Of Medicine; WANG, MENGJIE - Children'S Nutrition Research Center (CNRC); LI, VERONICA - Stanford University School Of Medicine; LYU, XUCHAO - Stanford University School Of Medicine; WEI, WEI - Stanford University School Of Medicine; TUNG, ALAN SHENG-HWA - Stanford University School Of Medicine; RAUN, STEFFEN - University Of Copenhagen; ZHAO, MENG - Stanford University School Of Medicine; COASSOLO, LAETITIA - Stanford University School Of Medicine; ISLAM, HASHIM - University Of British Columbia; OLIVEIRA, BARBARA - University Of British Columbia; DAI, YUQIN - Stanford University; SPAAS, JAN - Stanford University School Of Medicine; DELGADO-GONZALEZ, ANTONIO - Stanford University; DONOSO, KENYI - Stanford University School Of Medicine; ALVAREZ-BUYLLA, AURORA - Stanford University; FRANCO-MONTALBAN, FRANCISCO - Universidad De Granada; LETIAN, ANUDARI - University Of California San Francisco (UCSF); WARD, CATHERINE - Stanford University School Of Medicine; LIU, LICHAO - Stanford University School Of Medicine; SVENSSON, KATRIN - Stanford University School Of Medicine; GOLDBERG, EMILY - University Of California San Francisco (UCSF); GARDNER, CHRISTOPHER - Stanford University School Of Medicine; LITTLE, JONATHAN - University Of British Columbia; BANIK, STEVEN - Stanford University; XU, YONG - Children'S Nutrition Research Center (CNRC); LONG, JONATHAN - Stanford University School Of Medicine

Submitted to: Cell
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/16/2024
Publication Date: 11/12/2024
Citation: Moya-Garzon, M., Wang, M., Li, V.L., Lyu, X., Wei, W., Tung, A., 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.P., Liu, L., Svensson, K.J., Goldberg, E.L., Gardner, C.D., Little, J.P., Banik, S.M., Xu, Y., Long, J.Z. 2024. A B-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites. Cell. 188:175-186. https://doi.org/10.1016/j.cell.2024.10.032.
DOI: https://doi.org/10.1016/j.cell.2024.10.032

Interpretive Summary: ß-Hydroxybutyrate (BHB) is a common ketone body involved in energy metabolism. Until now, all known BHB metabolic pathways have focused on its conversion into key energy molecules. In this study, we discovered a new metabolic pathway where the enzyme CNDP2 links BHB to free amino acids, creating a group of anti-obesity molecules called BHB-amino acids. When CNDP2 is removed in mice, this process stops, leading to lower levels of BHB-amino acids. The most common of these, BHB-Phe, is a ketosis-triggered molecule similar to Lac-Phe that activates brain regions controlling appetite and reduces food intake. In contrast, mice without CNDP2 eat more and gain weight when given ketone supplements or a ketogenic diet. This process also occurs in humans, showing that amino acid BHB-ylation plays a role in regulating energy balance and metabolism.

Technical Abstract: ß-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.