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

Metformin is a blood-glucose-lowering medication with physiological effects that extend beyond its anti -dia-betic indication. Recently, it was reported that metformin lowers body weight via induction of growth differenti-ation factor 15 (GDF15), which suppresses food intake by binding to the GDNF family receptor a-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 met-formin. 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.

Automated summary

Metformin has been widely used, but the mechanism of its weight loss effect is not fully understood. This study confirms that metformin can increase the levels of GDF15 in the body, but the role of the GDF15-GFRAL pathway in mediating the weight loss effect of metformin remains controversial. The results suggest that the effects of metformin on energy balance may not solely depend on the GDF15-GFRAL pathway.