GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Growth differentiation factor 15 (GDF15) is a member of the TGF beta superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15-GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases. The expression of growth differentiation factor 15 (GDF15) is increased under conditions of cellular stress as well as by metformin and exercise. This Review highlights mechanisms of GDF15 production and secretion, GDF15 signalling, and the relevance of GDF15 in obesity and metabolic diseases.

Automated summary

Growth differentiation factor 15 (GDF15) expression is induced by cellular stress, metformin, and exercise. Its effects on food intake and inflammation are mediated through specific receptors and signaling pathways, making it a promising target for the treatment of metabolic diseases such as obesity and diabetes.