We further demonstrated that it prophylactically and therapeutically normalised body weight and alleviated metabolic dysfunction in a GDF15/GFRAL-dependent manner without the induction of nausea/malaise and any other pathological changes in both mice with high-fat diet-induced obesity and cynomolgus macaques with spontaneous obesity. This evidence concerns the gene GDF15 and obesity due to melanocortin 4 receptor deficiency.