Lac-Phe mediates the anti-obesity effect of metformin

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; Jonathan Z Long

doi:10.1101/2023.11.02.565321

Lac-Phe mediates the anti-obesity effect of metformin

bioRxiv [Preprint]. 2023 Nov 4:2023.11.02.565321. doi: 10.1101/2023.11.02.565321.

Authors

Shuke Xiao^{1

2

3}, Veronica L Li^{1

4

2

3

5}, Xuchao Lyu^{1

2

3

5}, Xudong Chen^{6

7}, Wei Wei^{1

2}, Fahim Abbasi^{3

8}, Joshua W Knowles^{3

8

9

10}, Shuliang Deng¹¹, Gaurav Tiwari¹¹, Xu Shi¹¹, Shuning Zheng¹¹, Laurie Farrell¹¹, Zsu-Zsu Chen¹¹, Kent D Taylor¹², Xiuqing Guo¹², Mark O Goodarzi¹³, Alexis C Wood¹⁴, Yii-Der Ida Chen¹², Leslie A Lange¹⁵, Stephen S Rich¹⁶, Jerome I Rotter¹², Clary B Clish¹⁷, Usman A Tahir¹¹, Robert E Gerszten^{11

17}, Mark D Benson¹¹, Jonathan Z Long^{1

2

18

3

9

5}

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
² Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
³ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
⁴ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁵ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
⁶ Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
⁷ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
⁸ Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
¹² The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
¹³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
¹⁴ USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX USA.
¹⁵ Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
¹⁷ Broad Institute of Harvard and MIT, Cambridge, MA.
¹⁸ Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA.

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.

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Abstract

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