Growth Differentiation Factor 15 (GDF15) is a stress-responsive cytokine that links peripheral cellular stress to central regulation of appetite and energy balance. Through its receptor, GFRAL, in the hindbrain, GDF15 activates neural pathways that suppress food intake and regulate body weight. These findings have generated considerable interest in targeting the GDF15–GFRAL pathway for obesity treatment. However, the distinct contributions of endogenous GDF15 signalling and pharmacological administration, and their implications for therapeutic efficacy, remain incompletely understood. Defining the cellular sources and physiological context of GDF15 may help explain variation in treatment responses and inform strategies to harness this pathway for metabolic benefit. Our Recent studies using myeloid-specific Gdf15 deletion suggest that myeloid-derived GDF15 contributes to circulating GDF15 levels and restrains food intake and visceral fat accumulation during high-fat feeding. These findings highlight a potential link among immune-cell stress responses, central appetite regulation and adipose tissue metabolism, with macrophages as an important source of endogenous GDF15.