Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemistry, Stanford University, Stanford, CA, USA.
Nature. 2022 Jun;606(7915):785-790. doi: 10.1038/s41586-022-04828-5. Epub 2022 Jun 15.
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2 cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
锻炼可预防肥胖、2 型糖尿病和其他心血管代谢疾病。然而，介导身体活动代谢益处的分子和细胞机制仍不清楚。在这里，我们表明运动刺激 N-乳酰苯丙氨酸（Lac-Phe）的产生，这是一种血液传播的信号代谢物，可抑制进食和肥胖。Lac-Phe 由乳酸和苯丙氨酸在包括巨噬细胞、单核细胞和其他位于不同器官的免疫和上皮细胞在内的 CNDP2 细胞中生物合成。在饮食诱导的肥胖小鼠中，药物介导的 Lac-Phe 增加可减少食物摄入，而不影响运动或能量消耗。慢性给予 Lac-Phe 可减少脂肪量和体重，并改善葡萄糖稳态。相反，在运动训练后，小鼠中 Lac-Phe 生物合成的基因缺失会增加食物摄入和肥胖。最后，在人类和赛马中也观察到循环 Lac-Phe 的大量活动诱导性增加，从而将这种代谢物确定为与多种活动方式和哺乳动物物种相关的与身体活动相关的分子效应物。这些数据定义了一种保守的运动诱导代谢物，可控制食物摄入并影响全身能量平衡。
