Lac-Phe Mediates the Effects of Metformin on Food Intake and Body Weight

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2024 Mar 19

PMID 38499766

Authors

Shuke Xiao

Veronica L Li

Xuchao Lyu

Xudong Chen

Wei Wei

Fahim Abbasi

Joshua W Knowles

Alan Sheng-Hwa Tung

Shuliang Deng

Gaurav Tiwari

Xu Shi

Shuning Zheng

Laurie Farrell

Zsu-Zsu Chen

Kent D Taylor

Xiuqing Guo

Mark O Goodarzi

Alexis C Wood

Yii-Der Ida Chen

Leslie A Lange

Stephen S Rich

Jerome I Rotter

Clary B Clish

Usman A Tahir

Robert E Gerszten

Mark D Benson

Jonathan Z Long

Affiliations

Soon will be listed here.

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.

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