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.