GFRAL (GDNF family receptor alpha like) is a brainstem-restricted receptor that specifically binds growth differentiation factor 15 (GDF15) to regulate appetite and energy homeostasis 1. Upon GDF15 binding, GFRAL forms a signaling complex with the RET tyrosine kinase receptor in neurons of the area postrema and nucleus tractus solitarius, activating MAPK and AKT signaling pathways 1. This GDF15-GFRAL signaling axis mediates appetite suppression and weight loss by reducing food intake and maintaining energy expenditure during caloric restriction 2. The pathway operates largely independently of other appetite-regulating hormones like leptin and ghrelin 1. GFRAL activation triggers aversive responses including nausea and food avoidance, which serve as protective mechanisms against cellular stress and potential toxins 3. Therapeutically, the GDF15-GFRAL pathway shows promise for treating obesity and metabolic diseases, with interventions like metformin and ketogenic diets working through this mechanism 43. Additionally, genetic variants in GFRAL have been implicated in pregnancy-related nausea and vomiting, suggesting placental GDF15 may utilize this pathway to promote dietary caution during pregnancy 5. The pathway represents a unique stress-response system that translates cellular distress signals into behavioral adaptations promoting survival.