GDF15

Function

The precise biological role of GDF15 remains to be fully elucidated, but it is recognized as a key modulator of inflammatory pathways. Furthermore, it regulates fundamental cellular processes including apoptosis, angiogenesis, cell repair, and growth, which are crucial in the pathophysiology of cardiovascular and neoplastic diseases.

Clinical significance

GDF15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer. In cardiovascular tissues it is shown that GDF15 concentrations increase in response to atherosclerosis, ischemia/reperfusion injury and heart failure. In patients with coronary artery disease (CAD), GDF15 is shown to be associated with adverse outcome such as mortality, myocardial infarction, stroke and with bleeding.

However, elevated GDF15 levels in diseases such as cancer and heart disease may be the result of inflammation caused by these diseases. Note that GDF15 is necessary for surviving both bacterial and viral infections, as well as sepsis. The protective effects of GDF15 were largely independent of pathogen control or the magnitude of inflammatory response, suggesting a role in disease tolerance.

Metformin was shown to cause increased levels of GDF15. This increase mediates the effect of body weight loss by metformin. Further study has shown weight loss is promoted by maintaining energy expenditure in addition to appetite suppression.

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.

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.

Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake.

Fibroblast-specific loss of GDF15 expression in a model of 3D reconstructed human skin induced epidermal thinning, a hallmark of skin aging. GDF15 plays a so far undisclosed role in mitochondrial homeostasis to delay both the onset of cellular senescence and the appearance of age-related changes in a 3D human skin model.

It has been also associated as a causal factor in hyperemesis gravidarum, severe morning sickness.

Therapeutics development

GDF15 is being evaluated as a therapeutic target for treatment of cancer cachexia. In September 2024, Pfizer disclosed that the anti-GDF15 monoclonal antibody ponsegromab led to significant increases in body weight in patients with non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

GDF15 could be evaluated as a therapeutic target for treatment of hyperemesis gravidarum, severe morning sickness, by building up a tolerance before pregnancy to the excessively 10,000 pg/mL increasing levels that the fetus produces as it develops.

References

References

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4. (February 2006). "GDF15, a cardioprotective TGF-beta superfamily protein". Circulation Research.
5. (October 2022). "Reference ranges for GDF-15, and risk factors associated with GDF-15, in a large general population cohort". Clinical Chemistry and Laboratory Medicine.
6. (June 2005). "Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury". Shock.
7. (October 2007). "Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome". Circulation.
8. (February 2006). "The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury". Circulation Research.
9. (August 2020). "Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease.
10. (2013). "GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men". PLOS ONE.
11. (January 2017). "Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease". Clinical Chemistry.
12. (April 2016). "Growth differentiation factor-15 level predicts major bleeding and cardiovascular events in patients with acute coronary syndromes: results from the PLATO study". European Heart Journal.
13. (August 2019). "GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance". Cell.
14. (February 2020). "GDF15 mediates the effects of metformin on body weight and energy balance". Nature.
15. (July 2023). "GDF15 promotes weight loss by enhancing energy expenditure in muscle". Nature.
16. (October 2021). "GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease". Nature Reviews. Endocrinology.
17. (July 2023). "GDF15 promotes weight loss by enhancing energy expenditure in muscle". Nature.
18. (January 2023). "Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts". Aging Cell.
19. (2023). "GDF15 linked to maternal risk of nausea and vomiting during pregnancy". Nature.
20. "Pfizer Presents Positive Data from Phase 2 Study of Ponsegromab in Patients with Cancer Cachexia {{!}} Pfizer".
21. (December 2024). "Ponsegromab for the Treatment of Cancer Cachexia". The New England Journal of Medicine.
22. University of Cambridge. (2024-01-03). "Morning Sickness Solution? Cambridge’s Breakthrough in Pregnancy Nausea Treatment".