Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. There is ongoing debate about the mechanisms that mediate metformin’s effects on energy balance. Here, we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite N-lactoyl-phenylalanine (Lac-Phe) in cells, in mice and two independent human cohorts. Metformin drives Lac-Phe biosynthesis through the inhibition of complex I, increased glycolytic flux and intracellular lactate mass action. Intestinal epithelial CNDP2⁺ cells, not macrophages, are the principal in vivo source of basal and metformin-inducible Lac-Phe. Genetic ablation of Lac-Phe biosynthesis in male mice renders animals resistant to the effects of metformin on food intake and body weight. Lastly, mediation analyses support a role for Lac-Phe as a downstream effector of metformin’s effects on body mass index in participants of a large population-based observational cohort, the Multi-Ethnic Study of Atherosclerosis. Together, these data establish Lac-Phe as a critical mediator of the body weight-lowering effects of metformin.

二甲双胍是一种广泛使用的抗糖尿病药物，也可以减轻体重。关于二甲双胍对能量平衡的影响机制一直存在争论。在这里，我们证明二甲双胍是细胞、小鼠和两个独立的人类群体中抑制食欲代谢物N-乳酰基苯丙氨酸 (Lac-Phe) 的强大药理学诱导剂。二甲双胍通过抑制复合物 I、增加糖酵解通量和细胞内乳酸质量作用来驱动 Lac-Phe 生物合成。肠上皮 CNDP2 ⁺细胞（而非巨噬细胞）是体内基础 Lac-Phe 和二甲双胍诱导型 Lac-Phe 的主要来源。雄性小鼠 Lac-Phe 生物合成的基因消除使动物对二甲双胍对食物摄入和体重的影响产生抵抗力。最后，中介分析支持 Lac-Phe 作为二甲双胍对体重指数影响的下游效应器的作用，该研究是基于大型人群的观察队列（动脉粥样硬化多种族研究）的参与者。总之，这些数据表明 Lac-Phe 是二甲双胍减肥作用的关键介质。