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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cell |
| Vol/bind | 188 |
| Udgave nummer | 1 |
| Sider (fra-til) | 175-186 |
| ISSN | 0092-8674 |
| DOI | |
| Status | Udgivet - 2025 |
Bibliografisk note
Funding Information:We thank members of the Long and Svensson laboratories for helpful discussions, Dr. Paul J. Emmerson (Eli Lilly & Co.) for sharing the anti-GFRAL neutralizing antibody, and the Centro de Supercomputaci\u00F3n de la Universidad de Granada (CSIRC) for computing resources. This work was supported by the NIH (DK124265 and DK130541 to J.Z.L.; DK125260, DK111916, and P30DK116074 to K.J.S.; GM113854 to V.L.L.; HD112123 to M.W.; K99AR081618 to M.Z.; T32HL161270 to C.P.W.; R00AG058801 to E.L.G.; and T32GM136631 to A.S.-H.T.), the Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute (research grant to J.Z.L.), the Ono Pharma Foundation (research grant to J.Z.L.), the Stanford Wu Tsai Human Performance Alliance (research grant to J.Z.L. and fellowship to X.L. and M.D.M.-G.), the Stanford Bio-X (SIGF graduate student fellowship to V.L.L.), the Jacob Churg Foundation (research grants to J.Z.L. and K.J.S.), the American Heart Association (fellowship #905674 to M.Z.), the Stanford School of Medicine (Dean's postdoctoral fellowship to L.C.), the Independent Research Fund Denmark (2030-00007A to S.H.R.), the Lundbeck Foundation (R380-2021-1451 to S.H.R.), the American Heart Association (24POST1196199 to W.W.), the CIHR (PJ9-166217 and PJT-169116 to J.P.L.), the Ovarian Cancer Research Alliance (MIG-2023-2-1015 to A.D.-G.), the Fundaci\u00F3n Alfonso Martin Escudero (fellowship to M.D.M.-G. and A.D.-G.), and USDA/CRIS (51000-064-01S to Y.X.).
Funding Information:
We thank members of the Long and Svensson laboratories for helpful discussions, Dr. Paul Emmerson (Eli Lilly & Co.) for sharing the anti-GFRAL neutralizing antibody, and the Centro de Supercomputaci\u00F3n de la Universidad de Granada (CSIRC) for computing resources. This work was supported by the NIH ( DK124265 and DK130541 to J.Z.L.; DK125260 , DK111916 , and P30DK116074 to K.J.S.; GM113854 to V.L.L.; HD112123 to M.W.; K99AR081618 to M.Z.; T32HL161270 to C.P.W.; R00AG058801 to E.L.G.; and T32GM136631 to A.S.-H.T.), the Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute (research grant to J.Z.L.), the Ono Pharma Foundation (research grant to J.Z.L.), the Stanford Wu Tsai Human Performance Alliance (research grant to J.Z.L. and fellowship to X.L. and M.D.M.-G.), the Stanford Bio-X (SIGF graduate student fellowship to V.L.L.), the Jacob Churg Foundation (research grants to J.Z.L. and K.J.S.), the American Heart Association (fellowship # 905674 to M.Z.), the Stanford School of Medicine (Dean\u2019s postdoctoral fellowship to L.C.), the Independent Research Fund Denmark ( 2030-00007A to S.H.R.), the Lundbeck Foundation ( R380-2021-1451 to S.H.R.), the American Heart Association ( 24POST1196199 to W.W.), the CIHR ( PJ9-166217 and PJT-169116 to J.P.L.), the Ovarian Cancer Research Alliance ( MIG-2023-2-1015 to A.D.-G.), the Fundaci\u00F3n Alfonso Martin Escudero (fellowship to M.D.M.-G. and A.D.-G.), and USDA/CRIS ( 51000-064-01S to Y.X.).
Publisher Copyright:
© 2024 The Author(s)