Growth/differentiation factor 15 (GDF15), also known as MIC-1, is a distant 
member of the transforming growth factor-β (TGF-β) superfamily and has been 
implicated in various biological functions, including cancer cachexia, renal and 
heart failure, atherosclerosis and metabolism. A connection between GDF15 and 
body-weight regulation was initially suggested on the basis of an observation 
that increasing GDF15 levels in serum correlated with weight loss in individuals 
with advanced prostate cancer. In animal models, overexpression of GDF15 leads 
to a lean phenotype, hypophagia and other improvements in metabolic parameters, 
suggesting that recombinant GDF15 protein could potentially be used in the 
treatment of obesity and type 2 diabetes. However, the signaling and mechanism 
of action of GDF15 are poorly understood owing to the absence of a clearly 
identified cognate receptor. Here we report that GDNF-family receptor α-like 
(GFRAL), an orphan member of the GFR-α family, is a high-affinity receptor for 
GDF15. GFRAL binds to GDF15 in vitro and is required for the metabolic actions 
of GDF15 with respect to body weight and food intake in vivo in mice. Gfral-/- 
mice were refractory to the effects of recombinant human GDF15 on body-weight, 
food-intake and glucose parameters. Blocking the interaction between GDF15 and 
GFRAL with a monoclonal antibody prevented the metabolic effects of GDF15 in 
rats. Gfral mRNA is highly expressed in the area postrema of mouse, rat and 
monkey, in accordance with previous reports implicating this region of the brain 
in the metabolic actions of GDF15 (refs. 4,5,6). Together, our data demonstrate 
that GFRAL is a receptor for GDF15 that mediates the metabolic effects of GDF15.