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

Growth differentiation factor 15 (GDF15; also known as MIC-1) is a divergent member of the TGF-[beta] 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 [alpha]-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.
Author(s): Linda Yang [1]; Chih-Chuan Chang [1]; Zhe Sun [1]; Dennis Madsen [2]; Haisun Zhu [1]; Søren B Padkjaer [2]; Xiaoai Wu [1]; Tao Huang [1]; Karin Hultman [2]; Sarah [...]