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 Vad Mathiesen, Cláudia Gil, Nanna S. Pilmark, Kristian Karstoft, Martin Bæk Blond, Jonas Salling Quist, Randy J. Seeley, Kristine Færch, Jens Lund, Maximilian Kleinert, Christoffer Clemmensen
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.