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Lac-Phe mediates the anti-obesity effect of metformin.
Xiao, Shuke; Li, Veronica L; Lyu, Xuchao; Chen, Xudong; Wei, Wei; Abbasi, Fahim; Knowles, Joshua W; Deng, Shuliang; Tiwari, Gaurav; Shi, Xu; Zheng, Shuning; Farrell, Laurie; Chen, Zsu-Zsu; Taylor, Kent D; Guo, Xiuqing; Goodarzi, Mark O; Wood, Alexis C; Ida Chen, Yii-Der; 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; Department of Chemistry, Stanford University, Stanford, CA, USA.
  • Abbasi F; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Knowles JW; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Deng S; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • Tiwari G; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Shi X; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Zheng S; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Farrell L; Wu Tsai Human Performance Alliance, Stanford University, Stanford, CA, USA.
  • Chen ZZ; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA, USA.
  • Taylor KD; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
  • Guo X; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • Goodarzi MO; Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • Wood AC; Stanford Diabetes Research Center, Stanford University, Stanford, CA, USA.
  • Ida Chen YD; 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; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
  • Gerszten RE; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
  • Benson MD; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
  • Long JZ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA.
bioRxiv ; 2023 Nov 04.
Article in En | MEDLINE | ID: mdl-37961394
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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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2023 Document type: Article Affiliation country: United States Country of publication: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Language: En Journal: BioRxiv Year: 2023 Document type: Article Affiliation country: United States Country of publication: United States