PREreviews of “Lac-Phe mediates the anti-obesity effect of metformin”

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Lac-Phe mediates the anti-obesity effect of metformin

by Shuke Xiao, Veronica L. Li, Xuchao Lyu, Xudong Chen, Wei Wei, Fahim Abbasi, Joshua W. Knowles, 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, and Jonathan Z. Long

Posted: November 4, 2023
Server: bioRxiv
DOI: 10.1101/2023.11.02.565321

Abstract

Metformin is a widely prescribed anti-diabetic medicine that also reduces body weight. The mechanisms that mediate metformin’s effects on energy balance remain incompletely defined. Here we show that metformin is a powerful pharmacological inducer of the anorexigenic metabolite Lac-Phe in mice as well as in two independent human cohorts. In cell culture, metformin drives Lac-Phe biosynthesis via inhibition of complex I, increased glycolytic flux, and intracellular lactate mass action. Other biguanides and structurally distinct inhibitors of oxidative phosphorylation also increase Lac-Phe levelsin vitro. Genetic ablation of CNDP2, the principal biosynthetic enzyme for Lac-Phe, in mice renders animals resistant to metformin’s anorexigenic and anti-obesity effects. Mediation analyses also support a role for Lac-Phe in metformin’s effect on body mass index in humans. These data establish the CNDP2/Lac-Phe pathway as a critical mediator of the effects of metformin on energy balance.

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PREreview by Elena Sena et al. of the ASAPbio Metabolism Crowd

Authored by Elena Sena, Femi Arogundade, and Pablo Ranea-Robles of the ASAPbio Metabolism Crowd

This review reflects comments and contributions from Elena Sena, Femi Arogundade & Pablo Ranea-Robles. Review synthesized by Pablo Ranea-Robles.
This study by Xiao et al. delves into an intriguing connection between metformin effects on body weight and a recently discovered exercise-induced…

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PREreviews of Lac-Phe mediates the anti-obesity effect of metformin

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