Given the bidirectional impact of the effects of GDF15 in different diseases, immunological intervention strategies require differentiation: Agonism of the GDF15–GFRAL pathway reduces caloric intake for obesity management, whereas antagonism of this pathway preserves normal energy intake for treating anorexia, cancer cachexia, and chemotherapy-induced adverse effects. Here, GDF15 is linked to obesity due to melanocortin 4 receptor deficiency.