Lac-Phe mediates the effects of metformin on food intake and body weight

Authors: XIAO, SHUKE - Stanford University School Of Medicine; LI, VERONICA - Stanford University School Of Medicine; LYU, XUCHAO - Stanford University School Of Medicine; CHEN, XUDONG - Stanford University; WEI, WEI - Stanford University School Of Medicine; ABBASI, FAHIM - Stanford University; KNOWLES, JOSHUA - Stanford University School Of Medicine; TUNG, ALAN - Stanford University School Of Medicine; DENG, SHULIANG - Beth Israel Deaconess Medical Center; TIWARI, GAURAV - Beth Israel Deaconess Medical Center; SHI, XU - Beth Israel Deaconess Medical Center; ZHENG, SHUNING - Beth Israel Deaconess Medical Center; FARRELL, LAURIE - Beth Israel Deaconess Medical Center; CHEN, ZSU - Beth Israel Deaconess Medical Center; TAYLOR, KENT - Harbor-Ucla Medical Center; GUO, XIUQING - Harbor-Ucla Medical Center; GOODARZI, MARK - Cedars-Sinai Medical Center; WOOD, ALEXIS - Children'S Nutrition Research Center (CNRC); CHEN, Y - Harbor-Ucla Medical Center; LANGE, LESLIE - University Of Colorado; RICH, STEPHEN - University Of Virginia; ROTTER, JEROME - Harbor-Ucla Medical Center; CLISH, CLARY - Broad Institute Of Mit/harvard; TAHIR, USMAN - Beth Israel Deaconess Medical Center; GERSZTEN, ROBERT - Beth Israel Deaconess Medical Center; BENSON, MARK - Beth Israel Deaconess Medical Center; LONG, JONATHAN - Stanford University School Of Medicine

Submitted to: Nature Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/30/2024
Publication Date: 3/18/2024
Citation: Xiao, S., Li, V.L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J.W., Tung, A.S., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z.Z., Taylor, K.D., Guo, X., Goodarzi, M.O., Wood, A.C., Chen, Y.D., Lange, L.A., Rich, S.S., Rotter, J.I., Clish, C.B., Tahir, U.A., Gerszten, R.E., Benson, M.D., Long, J.Z. 2024. Lac-Phe mediates the effects of metformin on food intake and body weight. Nature Metabolism. https://www.nature.com/articles/s42255-024-00999-9.
DOI: https://doi.org/10.1038/s42255-024-00999-9

Interpretive Summary: Metformin is a drug used to help people with type 2 diabetes manage their blood sugar levels. Although this is the primary benefit of taking this medicine, it was also found that metformin causes significant weight loss. However, the mechanism by which weight loss occurred was not well understood. When analyzing all the small molecules ("metabolites") in the blood of people taking metformin, and correlating these to weight changes occurring while on the drug, Lac-Phe, a metabolite that is released during intense exercise that has appetite suppressing properties, was identified as one of the mediating mechanisms. This information may contribute to the development of new therapeutic options designed to treat / prevent obesity.

Technical Abstract: 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.