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Lac-Phe mediates the anti-obesity effect of metformin. bioRxiv : the preprint server for biology Xiao, S., Li, V. L., Lyu, X., Chen, X., Wei, W., Abbasi, F., Knowles, J. W., Deng, S., Tiwari, G., Shi, X., Zheng, S., Farrell, L., Chen, Z. Z., Taylor, K. D., Guo, X., Goodarzi, M. O., Wood, A. C., Ida 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. 2023

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 levels in 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.

View details for DOI 10.1101/2023.11.02.565321

View details for PubMedID 37961394

View details for PubMedCentralID PMC10635077