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

L Yang, CC Chang, Z Sun, D Madsen, H Zhu… - Nature medicine, 2017 - nature.com
L Yang, CC Chang, Z Sun, D Madsen, H Zhu, SB Padkjær, X Wu, T Huang, K Hultman…
Nature medicine, 2017nature.com
Abstract 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 …
Abstract
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.
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