GFRAL, short for Glial cell line-derived neurotrophic factor (GDNF) receptor alpha-like, is a receptor for Growth Differentiation Factor 15 (GDF15) [1-7, 10]. It belongs to the GFRα family and signals through the Ret coreceptor. The GDF15-GFRAL pathway is crucial in regulating energy homeostasis, appetite, and metabolism [1-3, 5-8, 10]. It has potential implications for diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and anorexia-cachexia syndrome [1,3,6]. Genetic models, like knockout mice, are valuable tools in studying GFRAL's function.

In GFRAL-knockout mice, GDF15-mediated reductions in food intake and body weight were abolished, indicating that GFRAL is required for the 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 [4]. Additionally, antibody-mediated inhibition of GDF15-GFRAL activity reversed cancer cachexia in mice, uncovering a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue [5].

In conclusion, GFRAL plays a vital role in energy homeostasis and metabolism. Studies using GFRAL knockout mouse models have revealed its significance in obesity and cancer cachexia, highlighting its potential as a therapeutic target for these disease areas.