GFRAL, Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-like, is a distant orphan member of the GFRα family. It serves as the high-affinity receptor for Growth Differentiation Factor 15 (GDF15), a cytokine of the glial cell line-derived neurotrophic factor family within the TGF-β superfamily. GFRAL signals through the Ret coreceptor. The GDF15-GFRAL pathway is crucial for regulating energy homeostasis, appetite, and body-weight [1,2,3,4,5].

Genetic models, especially GFRAL-knockout (KO) mice, have been instrumental in understanding its function. In GFRAL-KO mice, GDF15-mediated reductions in food intake and body weight were abolished, indicating GFRAL is required for these anti-obesity effects of GDF15 [2]. Diet-induced obesity and insulin resistance were exacerbated in GFRAL-deficient mice, suggesting a homeostatic role for this receptor in metabolism [5]. Additionally, a therapeutic antagonistic monoclonal antibody targeting GFRAL reversed excessive lipid oxidation and prevented cancer cachexia in tumor-bearing mice, uncovering a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue [6].

In conclusion, GFRAL is essential for mediating the metabolic effects of GDF15, playing a key role in regulating food intake, body weight, and metabolism. Studies using GFRAL-KO mouse models have provided significant insights into its functions in obesity and cancer cachexia, highlighting its potential as a therapeutic target for these metabolic disorders [2,5,6].