Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases.
The potential to target GDF15 in the treatment of energy-intake disorders, including obesity and anorexia, is an area of intense investigation, but has been limited by the lack of an identified receptor, signaling mechanism, and target tissue.
Inhibiting MIC-1/GDF15 or its receptor GFRAL are high-value potential targets for treatment of anorexia/cachexia syndrome in patients whose elevated serum levels may justify its use.
GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss.
In particular, MIC-1 may contribute to the proliferation, migration, invasion, metastases, and treatment resistance of cancer cells as well as tumor-induced anorexia and weight loss in the late stages of cancer.
Thus, MIC-1 is a newly defined central regulator of appetite and a potential target for the treatment of both cancer anorexia and weight loss, as well as of obesity.