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.


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


  • Metformin
  • Hypoglycemic Agents
  • Phenylalanine
  • Dipeptides
  • N-lactoyl-phenylalanine

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