| First Author | Xiao S | Year | 2024 |
| Journal | Nat Metab | Volume | 6 |
| Issue | 4 | Pages | 659-669 |
| PubMed ID | 38499766 | Mgi Jnum | J:360268 |
| Mgi Id | MGI:7797630 | Doi | 10.1038/s42255-024-00999-9 |
| Citation | Xiao S, et al. (2024) Lac-Phe mediates the effects of metformin on food intake and body weight. Nat Metab 6(4):659-669 |
| abstractText | 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. |
