RT Journal Article
SR Electronic
T1 The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.02.16.480373
DO 10.1101/2022.02.16.480373
A1 Anders B. Klein
A1 Trine S. Nicolaisen
A1 Kornelia Johann
A1 Andreas M. Fritzen
A1 Cecilie V. Mathiesen
A1 Cláudia Gil
A1 Nanna S. Pilmark
A1 Kristian Karstoft
A1 Martin B. Blond
A1 Jonas S. Quist
A1 Randy J. Seeley
A1 Kristine Færch
A1 Jens Lund
A1 Maximilian Kleinert
A1 Christoffer Clemmensen
YR 2022
UL http://biorxiv.org/content/early/2022/02/19/2022.02.16.480373.abstract
AB Metformin is a blood glucose lowering medication with physiological effects that extend beyond its anti-diabetic indication. Recently, it was reported that metformin lowers body weight via induction of growth differentiation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor α-like (GFRAL) in the hindbrain. At the same time, we demonstrated that recombinant GDF15 suppresses voluntary exercise in a GFRAL-dependent fashion. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but that it does not reduce voluntary running activity in mice. Unexpectedly, we fail to confirm previous reports that the GDF15-GFRAL pathway is necessary for the weight-lowering effects of metformin. Instead, our studies in wild-type, GDF15 knockout and GFRAL knockout mice suggest that the GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance. The data presented here question whether metformin is a sufficiently strong stimulator of GDF15 to drive anorexia and weight loss and emphasize that additional work is needed to untangle the relationship among metformin, GDF15 and energy balance.Competing Interest StatementA.B.K. and C.C. are co-founders of Ousia Pharma ApS, a biotech company developing therapeutics for obesity. JSQ and KF have received research funding from Novo Nordisk. R.J.S. has received research support from Novo Nordisk and Astra Zeneca. R.J.S. has served as a paid consultant for Novo Nordisk, Scohia, Fractyl, and ShouTi Pharma. R.J.S. has equity positions in Calibrate and Rewind. The other authors declare no competing interests