Yang L, et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of
the ligand. Nat Med. 2017 Aug 28. doi: 10.1038/nm.4394.
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.