美国斯坦福大学Jonathan Z. Long等研究人员合作发现，β-羟基丁酸分支途径生成抗肥胖酮体代谢产物。相关论文于2024年11月12日在线发表在《细胞》杂志上。
研究人员发现了一个先前未描述的β-羟基丁酸（BHB）二级代谢途径。该途径通过CNDP2依赖的酶促结合作用，将BHB与游离氨基酸结合。这个BHB分支途径生成了一类抗肥胖的酮体代谢产物——BHB-氨基酸。
小鼠中CNDP2基因的删除消除了组织中氨基酸BHB-化合物的活性，并降低了BHB-氨基酸的水平。最丰富的BHB-氨基酸，即BHB-苯丙氨酸（BHB-Phe），是一个可以诱导酮症的类似物Lac-Phe，能够激活下丘脑和脑干神经元，并抑制进食。
相反，CNDP2基因敲除的小鼠在外源性酮体酯补充或生酮饮食后，表现出食物摄入量增加和体重增加。CNDP2依赖的氨基酸BHB-化合物及BHB-氨基酸代谢物在人类中也具有保守性。因此，酶促氨基酸BHB-化合物定义了一个酮体分支途径，并与能量平衡相关的生物活性酮体代谢产物。
研究人员表示，BHB是一种丰富的酮体。目前已知的所有BHB代谢途径，都涉及BHB与主要能量中间体的相互转化。
附：英文原文
Title: A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites
Author: Maria Dolores Moya-Garzon, Mengjie Wang, Veronica L. Li, Xuchao Lyu, Wei Wei, Alan Sheng-Hwa Tung, Steffen H. Raun, Meng Zhao, Laetitia Coassolo, Hashim Islam, Barbara Oliveira, Yuqin Dai, Jan Spaas, Antonio Delgado-Gonzalez, Kenyi Donoso, Aurora Alvarez-Buylla, Francisco Franco-Montalban, Anudari Letian, Catherine P. Ward, Lichao Liu, Katrin J. Svensson, Emily L. Goldberg, Christopher D. Gardner, Jonathan P. Little, Steven M. Banik, Yong Xu, Jonathan Z. Long
Issue&Volume: 2024-11-12
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.
DOI: 10.1016/j.cell.2024.10.032
Source: https://www.cell.com/cell/abstract/S0092-8674(24)01214-5