biostudies-literatureUnknownXiao SNCATS NIH HHSNIDDK NIH HHSNHLBI NIH HHSMetformin 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 <i>in vitro</i>. 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 bioRxiv : the preprint server for biology2023.11.02.565321https://www.ebi.ac.uk/biostudies/studies/S-EPMC10635077biostudies-literatureLac-Phe mediates the anti-obesity effect of metformin.PMC10635077UL1 TR001420K08 HL145095UL1 TR001881N01 HC095166N01 HC095165N01 HC095168N01 HC095167N01 HC09516975N92020D00007N01 HC095160N01 HC095162N01 HC095161N01 HC095164N01 HC09516375N92020D0000175N92020D00002P30 DK04056175N92020D0000575N92020D0000675N92020D0000375N92020D00004UL1 TR000040HHSN268201500003CUL1 TR001079N01 HC095159R01 HL151855UM1 DK078616P30 DK063491R01 HL105756HHSN268201500003IDeng SGerszten RERotter JILi VLGuo XLyu XChen ZZRich SSClish CBWei WShi XFarrell LTiwari GLong JZIda Chen YDChen XTahir UAKnowles JWTaylor KDBenson MDWood ACZheng SAbbasi FXiao SGoodarzi MOLange LAfalseLac-Phe mediates the anti-obesity effect of metformin.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 <i>in vitro</i>. 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 2023-01-01T00:00:00Z2023 Nov2026-06-08T03:27:25.587Z2026-06-08T03:14:21.513ZS-EPMC106350773796139410.1101/2023.11.02.565321