GDF15

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Growth/differentiation factor 15 is a protein that in humans is encoded by the GDF15 gene. GDF15 was first identified as Macrophage inhibitory cytokine-1 (MIC-1).

It is a protein belonging to the transforming growth factor beta superfamily. Under normal conditions, GDF15 is expressed in low concentrations in most organs and is upregulated because of injury to organs such as the liver, kidney, heart and lung.[1][2][3][4] Its chemical formula is:C1076H1710O316N324S24.[5]

In one study among Scottish males, median (97.5th percentile), GDF-15 concentration at age <30 years was 537 (1,135) pg/mL, rising to 931 (2,492) pg/mL at 50–59 years, and 2,152 (5,972) pg/mL at ≥80 years. In Scottish females, median GDF-15 at age <30 years was 628 (2,195) pg/mL, 881 (2,323) pg/mL at 50–59 years, and 1847 (6,830) pg/mL at ≥80 years. Among those known to be pregnant, median GDF-15 was 19,311 pg/mL.[6]

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.[1][7][8][9]

Clinical significance

GDF15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer.[10] In cardiovascular tissues it is shown that GDF15 concentrations increase in response to atherosclerosis, ischemia/reperfusion injury and heart failure.[11] 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.[12]

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.[13]

Metformin was shown to cause increased levels of GDF15. This increase mediates the effect of body weight loss by metformin.[14] Further study has shown weight loss is promoted by maintaining energy expenditure in addition to appetite suppression.[15]

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.[16]

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.[16]

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.[17]

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.[18]

It has been also associated as a causal factor in hyperemesis gravidarum, severe morning sickness.[19]

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.[20][21]

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.[19][22]

References

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  1. ^ a b Page Module:Citation/CS1/styles.css has no content.Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG (June 2005). "Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury". Shock. 23 (6): 543–548. PMID 15897808.
  2. ^ Page Module:Citation/CS1/styles.css has no content.Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ (May 2000). "Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury". Molecular and Cellular Biology. 20 (10): 3742–3751. doi:10.1128/MCB.20.10.3742-3751.2000. PMC 85678. PMID 10779363.
  3. ^ Page Module:Citation/CS1/styles.css has no content.Ago T, Sadoshima J (February 2006). "GDF15, a cardioprotective TGF-beta superfamily protein". Circulation Research. 98 (3): 294–297. doi:10.1161/01.RES.0000207919.83894.9d. PMID 16484622.
  4. ^ Page Module:Citation/CS1/styles.css has no content.Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, et al. (October 1997). "MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily". Proceedings of the National Academy of Sciences of the United States of America. 94 (21): 11514–11519. Bibcode:1997PNAS...9411514B. doi:10.1073/pnas.94.21.11514. PMC 23523. PMID 9326641.
  5. ^ Page Module:Citation/CS1/styles.css has no content."Expasy - ProtParam". web.expasy.org. Retrieved 2026-01-24.
  6. ^ Page Module:Citation/CS1/styles.css has no content.Welsh P, Kimenai DM, Marioni RE, Hayward C, Campbell A, Porteous D, et al. (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. 60 (11): 1820–1829. doi:10.1515/cclm-2022-0135. PMC 9524804. PMID 35976089.
  7. ^ Page Module:Citation/CS1/styles.css has no content.Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, et al. (October 2007). "Growth differentiation factor 15 for risk stratification and selection of an invasive treatment strategy in non ST-elevation acute coronary syndrome". Circulation. 116 (14): 1540–1548. doi:10.1161/CIRCULATIONAHA.107.697714. PMID 17848615.
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  9. ^ Page Module:Citation/CS1/styles.css has no content.Rochette L, Méloux A, Zeller M, Cottin Y, Vergely C (August 2020). "Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1866 (8) 165798. doi:10.1016/j.bbadis.2020.165798. PMID 32304740. S2CID 215819153.
  10. ^ Page Module:Citation/CS1/styles.css has no content.Wallentin L, Zethelius B, Berglund L, Eggers KM, Lind L, Lindahl B, et al. (2013). "GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men". PLOS ONE. 8 (12) e78797. Bibcode:2013PLoSO...878797W. doi:10.1371/journal.pone.0078797. PMC 3846468. PMID 24312445.
  11. ^ Page Module:Citation/CS1/styles.css has no content.Wollert KC, Kempf T, Wallentin L (January 2017). "Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease". Clinical Chemistry. 63 (1): 140–151. doi:10.1373/clinchem.2016.255174. PMID 28062617.
  12. ^ Page Module:Citation/CS1/styles.css has no content.Hagström E, James SK, Bertilsson M, Becker RC, Himmelmann A, Husted S, et al. (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. 37 (16): 1325–1333. doi:10.1093/eurheartj/ehv491. PMID 26417057.
  13. ^ Page Module:Citation/CS1/styles.css has no content.Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE, Ahasic AM, et al. (August 2019). "GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance". Cell. 178 (5): 1231–1244.e11. doi:10.1016/j.cell.2019.07.033. PMC 6863354. PMID 31402172.
  14. ^ Page Module:Citation/CS1/styles.css has no content.Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, et al. (February 2020). "GDF15 mediates the effects of metformin on body weight and energy balance". Nature. 578 (7795): 444–448. doi:10.1038/s41586-019-1911-y. PMC 7234839. PMID 31875646.
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  16. ^ a b Page Module:Citation/CS1/styles.css has no content.Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR (October 2021). "GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease". Nature Reviews. Endocrinology. 17 (10): 592–607. doi:10.1038/s41574-021-00529-7. PMID 34381196. S2CID 236972376.
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