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

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

doi:10.1038/s42255-024-00999-9

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

Nat Metab. 2024 Apr;6(4):659-669. doi: 10.1038/s42255-024-00999-9. Epub 2024 Mar 18.

Authors

Shuke Xiao^{1

2

3}, Veronica L Li^{1

2

3

4

5}, Xuchao Lyu^{1

2

3

5}, Xudong Chen^{6

7}, Wei Wei^{1

2

3}, Fahim Abbasi^{3

8}, Joshua W Knowles^{3

8

9

10}, Alan Sheng-Hwa Tung^{1

2

3}, 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 Benson^#¹¹, Jonathan Z Long^#^{18

19

20

21

22}

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, USA.
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, USA.
¹³ Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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, USA.
¹⁷ Broad Institute of Harvard and MIT, Cambridge, MA, USA.
¹⁸ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.
¹⁹ Sarafan ChEM-H, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
²⁰ Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
²¹ Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA. jzlong@stanford.edu.
²² Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA. jzlong@stanford.edu.

^# Contributed equally.

PMID: 38499766
DOI: 10.1038/s42255-024-00999-9

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Body Weight* / drug effects
Dipeptides / pharmacology
Eating* / drug effects
Humans
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use
Male
Metformin* / pharmacology
Mice
Phenylalanine / metabolism
Phenylalanine / pharmacology

Substances

Metformin
Hypoglycemic Agents
Phenylalanine
Dipeptides
N-lactoyl-phenylalanine

Grants and funding

P30 DK116074/DK/NIDDK NIH HHS/United States