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Lac-Phe mediates the effects of metformin on food intake and body weight.
Xiao, Shuke; Li, Veronica L; Lyu, Xuchao; Chen, Xudong; Wei, Wei; Abbasi, Fahim; Knowles, Joshua W; Tung, Alan Sheng-Hwa; Deng, Shuliang; Tiwari, Gaurav; Shi, Xu; Zheng, Shuning; Farrell, Laurie; Chen, Zsu-Zsu; Taylor, Kent D; Guo, Xiuqing; Goodarzi, Mark O; Wood, Alexis C; Chen, Yii-Der Ida; Lange, Leslie A; Rich, Stephen S; Rotter, Jerome I; Clish, Clary B; Tahir, Usman A; Gerszten, Robert E; Benson, Mark D; Long, Jonathan Z.
Affiliation
  • Xiao S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Li VL; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Lyu X; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Chen X; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Wei W; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Abbasi F; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Knowles JW; Department of Chemistry, Stanford University, Stanford, CA, USA.
  • Tung AS; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • Deng S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Tiwari G; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Shi X; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Zheng S; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • Farrell L; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
  • Chen ZZ; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • Taylor KD; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Guo X; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Goodarzi MO; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Wood AC; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Chen YI; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Lange LA; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Rich SS; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • Rotter JI; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • Clish CB; Stanford Prevention Research Center, Stanford University School of Medicine, Stanford, CA, USA.
  • Tahir UA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Gerszten RE; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Benson MD; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Long JZ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Nat Metab ; 6(4): 659-669, 2024 Apr.
Article in En | MEDLINE | ID: mdl-38499766
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Body Weight / Eating / Metformin Limits: Animals / Humans / Male Language: En Journal: Nat Metab Year: 2024 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Body Weight / Eating / Metformin Limits: Animals / Humans / Male Language: En Journal: Nat Metab Year: 2024 Document type: Article