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.

中文翻译：

---

β-羟基丁酸酯分流途径产生抗肥胖酮代谢物


β-羟基丁酸酯 （BHB） 是一种丰富的酮体。迄今为止，所有已知的 BHB 代谢途径都涉及 BHB 和初级能量中间体的相互转化。在这里，我们通过 BHB 和游离氨基酸的 CNDP2 依赖性酶促结合确定了以前未描述的 BHB 次级代谢途径。这种 BHB 分流途径产生一个抗肥胖酮代谢物家族，即 BHB 氨基酸。小鼠 CNDP2 的基因消融消除了组织氨基酸 BHB 酰化活性并降低了 BHB 氨基酸水平。最丰富的 BHB 氨基酸 BHB-Phe 是 Lac-Phe 的酮症诱导同系物，可激活下丘脑和脑干神经元并抑制进食。相反，CNDP2-KO 小鼠在补充外源性酮酯或生酮饮食后表现出食物摄入量和体重增加。CNDP2 依赖性氨基酸 BHB 酰化和 BHB 氨基酸代谢物在人类中也是保守的。因此，酶促氨基酸 BHB 酰化定义了酮分流途径和与能量平衡相关的生物活性酮代谢物。