The GDF15-GFRAL pathway is dispensable for the effects of metformin on energy balance

Anders B Klein, Trine S Nicolaisen, Kornelia Johann, Andreas M Fritzen, Cecilie V Mathiesen, Cláudia Gil, Nanna S Pilmark, Kristian Karstoft, Martin B Blond, Jonas S Quist, Randy J Seeley, Kristine Færch, Jens Lund, Maximilian Kleinert*, Christoffer Clemmensen*

*Corresponding author af dette arbejde

Abstract

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. Here, we corroborate that metformin increases circulating GDF15 in mice and humans, but 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.

OriginalsprogEngelsk
Artikelnummer111258
TidsskriftCell reports
Vol/bind40
Udgave nummer8
Sider (fra-til)111258
DOI
StatusUdgivet - 23 aug. 2022

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