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

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. 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.

GDF15 knockout does not substantially impact perinatal body weight or neonatal outcomes in mice

“…It is possible that under conditions of elevated somatic stress other than pregnancy, GDF15 plays a larger role. It is also possible that the deletion of GDF15 during mouse pregnancy is of little effect because GDF15 in circulation increases only modestly in rodents (2-fold) compared to humans and primates (75-100 fold in primates and humans, respectively) (41).…”