Growth differentiation factor 15 (GDF15), a distant member of the transforming 
growth factor (TGF)-β family, is a secreted protein that circulates as a 25-kDa 
dimer. In humans, elevated GDF15 correlates with weight loss, and the 
administration of GDF15 to mice with obesity reduces body weight, at least in 
part, by decreasing food intake. The mechanisms through which GDF15 reduces body 
weight remain poorly understood, because the cognate receptor for GDF15 is 
unknown. Here we show that recombinant GDF15 induces weight loss in mice fed a 
high-fat diet and in nonhuman primates with spontaneous obesity. Furthermore, we 
find that GDF15 binds with high affinity to GDNF family receptor α-like (GFRAL), 
a distant relative of receptors for a distinct class of the TGF-β superfamily 
ligands. Gfral is expressed in neurons of the area postrema and nucleus of the 
solitary tract in mice and humans, and genetic deletion of the receptor 
abrogates the ability of GDF15 to decrease food intake and body weight in mice. 
In addition, diet-induced obesity and insulin resistance are exacerbated in 
GFRAL-deficient mice, suggesting a homeostatic role for this receptor in 
metabolism. Finally, we demonstrate that GDF15-induced cell signaling requires 
the interaction of GFRAL with the coreceptor RET. Our data identify GFRAL as a 
new regulator of body weight and as the bona fide receptor mediating the 
metabolic effects of GDF15, enabling a more comprehensive assessment of GDF15 as 
a potential pharmacotherapy for the treatment of obesity.