Growth and differentiation factor 15 (GDF15)

Growth and differentiation factor 15 (GDF15) is a stress-responsive cytokine and a distant member of the transforming growth factor-beta (TGF-beta) superfamily [1, 2]. It is primarily recognized for its role in regulating energy homeostasis and appetite through its interaction with the glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the RET co-receptor in the hindbrain [4, 9]. While expressed at low levels under physiological conditions, GDF15 is significantly upregulated in response to various stressors, including inflammation, tissue injury, and malignancy [6, 15]. In clinical settings, elevated circulating levels of GDF15 serve as a potent biomarker for disease severity and mortality in cardiovascular disease, chronic kidney disease, and several types of cancer [13, 16, 20]. Therapeutically, GDF15 is a dual-purpose target. In oncology, neutralizing monoclonal antibodies like ponsegromab are being developed to inhibit GDF15-mediated anorexia and cachexia, aiming to improve patient weight and physical function [2, 13]. Conversely, GDF15 agonists and recombinant proteins are being explored as treatments for obesity and type 2 diabetes due to their ability to suppress food intake and promote weight loss [1, 10]. Additionally, GDF15 has been linked to hyperemesis gravidarum, suggesting potential applications in managing severe pregnancy-related nausea [11, 18]. However, therapeutic development must account for the protein's pleiotropic effects, including its context-dependent role in tumor progression and its potential to induce nausea [8, 16].

Other names

Macrophage inhibitory cytokine-1MIC-1NSAID-activated gene 1 proteinNAG-1Placental transformation growth factor-betaPTGFBPlacental bone morphogenetic proteinPLABProstate-derived factorPDF

GDF15 acts as a stress-induced ligand that binds to the glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the RET co-receptor in the hindbrain to modulate appetite and metabolic stress. Therapeutic inhibition involves neutralizing monoclonal antibodies to block this axis for the treatment of cancer cachexia and hyperemesis gravidarum, while therapeutic agonism utilizes recombinant proteins or modulators to activate the pathway for weight loss in obesity.