Growth Differentiation Factor 15 (GDF15), also known as macrophage inhibitory cytokine-1 (MIC-1), is a protein that plays a role in various physiological processes. It influences health and disease through complex internal signals.
What is GDF 15?
GDF15 is a protein that belongs to the transforming growth factor beta (TGF-β) superfamily, a group of proteins involved in cell growth and development. It is secreted as a larger precursor that is then cleaved to form its active, circulating dimeric protein, which weighs approximately 25 kDa. While present in various tissues, including the prostate, heart, colon, pancreas, liver, and kidney, the placenta expresses high levels of GDF15 under normal physiological conditions related to prenatal development.
This protein functions as a “stress-response hormone,” meaning its levels typically increase when cells or tissues experience duress. Such stressors can include inflammation, injury, metabolic imbalances, or even psychosocial stress. For instance, mitochondrial and endoplasmic reticulum stresses are known to induce GDF15 expression. The elevation of GDF15 signals the body’s response to internal challenges, reflecting efforts to maintain cellular balance.
GDF 15 and Appetite Control
GDF15 plays a significant role in regulating appetite and can induce feelings of nausea and aversion to food. This effect is mediated through its interaction with a specific receptor called glial-derived neurotrophic factor family receptor α-like (GFRAL). GFRAL receptors are found almost exclusively in the area postrema of the brainstem in humans and other mammals. This region of the brainstem is particularly sensitive to circulating substances because it is not protected by the blood-brain barrier.
When GDF15 binds to GFRAL in the brainstem, it triggers signals that reduce food intake and can lead to nausea and vomiting. This mechanism has implications for conditions like obesity, where increasing GDF15 levels could potentially serve as a therapeutic strategy to promote weight loss by curbing appetite. Research has shown that administering GDF15 to rodents can lower their appetite and body weight.
GDF15 is also strongly implicated in hyperemesis gravidarum (HG), a severe form of morning sickness during pregnancy, affecting up to 2% of pregnancies. Women with HG often experience extreme nausea, vomiting, and significant weight loss. Genetic studies have linked high levels of GDF15 to an increased risk of HG. Fetal production of GDF15 and maternal sensitivity to it both contribute to the risk of HG.
GDF 15 in Various Diseases
Beyond its role in appetite regulation, GDF15 levels are elevated in a broad spectrum of chronic diseases, serving as a biomarker for disease outcome in several conditions. In cancer, GDF15 is associated with cachexia, a severe wasting syndrome characterized by involuntary loss of lean body mass. High GDF15 levels correlate with tumor progression, and in some animal models, inhibiting GDF15 has reversed weight loss and restored muscle and fat mass.
GDF15 is also observed at increased levels in cardiovascular diseases, including heart failure, atherosclerosis, and endothelial dysfunction. It is associated with the progression and prognosis of these conditions. Similarly, in chronic kidney disease, elevated GDF15 levels are linked to a decline in kidney function and have prognostic value. In metabolic disorders such as obesity and non-alcoholic steatohepatitis (NASH), GDF15 levels are often increased in both human subjects and animal models. The role of GDF15 in these diverse conditions is complex; it can sometimes be protective against inflammation or tissue injury, while sustained high levels may contribute to disease progression.
Future Therapeutic Directions
The growing understanding of GDF15’s diverse roles has opened avenues for therapeutic development. Scientists are exploring two primary strategies to modulate GDF15 activity for medical benefit. One approach involves increasing GDF15 levels, particularly for treating obesity and metabolic disorders. This aims to leverage GDF15’s appetite-suppressing effects to induce weight loss and improve metabolic health.
Conversely, another strategy focuses on blocking GDF15 activity, especially to alleviate severe nausea and prevent muscle wasting. This could benefit patients with hyperemesis gravidarum, chemotherapy-induced nausea, or cancer cachexia. For instance, a monoclonal antibody, ponsegromab, designed to inhibit GDF15, has shown promising results in increasing body weight and improving appetite and physical activity in patients with cancer cachexia. These therapeutic interventions target the GDF15-GFRAL pathway, aiming to restore proper energy balance and reduce disease-associated symptoms.