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

Affiliations

• Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
• Department of Chemistry, Stanford University, Stanford, CA, USA
• Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
• Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
• Department of Biology, Stanford University, Stanford, CA, USA
• Sarafan ChEM-H, Stanford University, Stanford, CA, USA
• Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA
• Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA
• Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
• Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
• School of Health and Exercise Sciences, University of British Columbia, Kelowna, BC, Canada
• Departamento de Química Farmacéutica y Orgánica, Universidad de Granada, Campus de Cartuja sn, 18071 Granada, Spain
• Department of Physiology, University of California, San Francisco, San Francisco, CA, USA
• Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
• USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
• The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA

PMID:  #  DOI: 10.1016/j.cell.2024.10.032

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.

β-羟基丁酸（BHB）是一种重要的酮体。至今，已知的所有BHB代谢途径都涉及BHB与主要能量中间体的相互转化。在本研究中，我们发现了一条之前未被描述过的BHB二级代谢途径，依赖CNDP2酶将BHB与游离氨基酸结合。这条BHB旁路途径产生了一类具有抗肥胖作用的酮体代谢物——BHB-氨基酸。在小鼠中，敲除CNDP2基因会导致组织中BHB与氨基酸结合的活性消失，同时BHB-氨基酸水平降低。最为丰富的BHB-氨基酸——BHB-苯丙氨酸（BHB-Phe），是一种酮症诱导的LacPhe类似物，能够激活下丘脑和脑干的神经元，并抑制食欲。相反，CNDP2基因敲除的小鼠在外源性酮体酯补充或摄入生酮饮食后，会表现出食欲增加和体重增加的现象。CNDP2依赖的BHB-氨基酸结合反应及其代谢物在人体中也有所保留。因此，氨基酸BHB-化合反应定义了一个新的酮体旁路途径，并与能量平衡相关的生物活性酮体代谢物相联系。

关键词：β-羟基丁酸，酮体，减肥，司美格鲁肽，Semaglutide，替尔泊肽，Tirzepatide，中和抗体，佰乐博，佰乐博生物