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

Cell Rep. 2022 Aug 23;40(8):111258. doi: 10.1016/j.celrep.2022.111258.

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.

Keywords: CP: Metabolism; GDF15; GFRAL; body weight; diabetes; energy balance; food intake; metformin; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Growth Differentiation Factor 15* / metabolism
  • Humans
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Mice
  • Obesity / metabolism
  • Weight Loss

Substances

  • GDF15 protein, human
  • GFRAL protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Growth Differentiation Factor 15
  • Metformin