GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand

Nat Med. 2017 Oct;23(10):1158-1166. doi: 10.1038/nm.4394. Epub 2017 Aug 28.


Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-β superfamily and is associated with body-weight regulation in humans and rodents. However, the cognate receptor of GDF15 is unknown. Here we show that GDF15 binds specifically to GDNF family receptor α-like (GFRAL) with high affinity, and that GFRAL requires association with the coreceptor RET to elicit intracellular signaling in response to GDF15 stimulation. We also found that GDF15-mediated reductions in food intake and body weight of mice with obesity were abolished in GFRAL-knockout mice. We further found that GFRAL expression was limited to hindbrain neurons and not present in peripheral tissues, which suggests that GDF15-GFRAL-mediated regulation of food intake is by a central mechanism. Lastly, given that GDF15 did not increase energy expenditure in treated mice with obesity, the anti-obesity actions of the cytokine are likely driven primarily by a reduction in food intake.

MeSH terms

  • Animals
  • Eating / drug effects*
  • Eating / genetics
  • Energy Metabolism / drug effects*
  • Energy Metabolism / genetics
  • Flow Cytometry
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / drug effects*
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
  • Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism
  • Growth Differentiation Factor 15 / pharmacology*
  • HEK293 Cells
  • Humans
  • In Vitro Techniques
  • Mice
  • Mice, Knockout
  • Obesity / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Surface Plasmon Resonance
  • Weight Loss / drug effects*
  • Weight Loss / genetics


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