GDNF family receptor alpha-like (GFRAL) (GFRAL)

The Growth differentiation factor 15 (GDF15) receptor system is a specialized signaling axis primarily composed of the GDNF family receptor alpha-like (GFRAL) and its co-receptor, the RET tyrosine kinase. Discovered as the cognate receptor for GDF15 in 2017, GFRAL is uniquely expressed in the hindbrain, specifically within the area postrema and the nucleus of the solitary tract. This localization allows the system to act as a central integrator of peripheral stress signals, as GDF15 levels rise significantly in response to tissue injury, inflammation, and metabolic stress. Activation of the GFRAL-RET complex by GDF15 triggers a neuronal circuit that suppresses appetite and promotes weight loss, often referred to as an "emergency" metabolic pathway. In disease states, the GDF15 receptor system plays a dual role: its overactivation by tumor-secreted GDF15 is a primary driver of cancer-induced cachexia and nausea, while its therapeutic activation is being explored as a strategy for treating obesity and type 2 diabetes. Pharmacological modulation of this system involves two main approaches: GFRAL agonists (or GDF15 analogs) to induce weight loss, and GFRAL or GDF15 antagonists to alleviate wasting syndromes and hyperemesis gravidarum. While agonists have shown robust weight loss in preclinical models, human clinical trials have faced challenges such as modest efficacy and dose-limiting gastrointestinal side effects like nausea. Conversely, antagonists like ponsegromab have demonstrated significant promise in reversing weight loss and improving appetite in patients with cancer cachexia.

Other names

Growth differentiation factor 15 receptorGDF15 receptorGFR-alpha-likeGDF15RGFRAL-RET receptor complex

GFRAL agonism (to reduce appetite and body weight); GFRAL antagonism (to prevent weight loss and nausea); GDF15 neutralization (to inhibit receptor system activation)