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GDF15

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GDF15
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGDF15, GDF-15, MIC-1, MIC1, NAG-1, PDF, PLAB, PTGFB, growth differentiation factor 15, TGF-PL
External IDsOMIM: 605312; MGI: 1346047; HomoloGene: 3576; GeneCards: GDF15; OMA:GDF15 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

9518

23886

Ensembl

ENSG00000130513

ENSMUSG00000038508

UniProt

Q99988

Q9Z0J7

RefSeq (mRNA)

NM_004864

NM_011819
NM_001330687

RefSeq (protein)

NP_004855

NP_001317616
NP_035949

Location (UCSC)Chr 19: 18.37 – 18.39 MbChr 8: 71.08 – 71.09 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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 or MIC-1.[5]

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 upregulated because of injury of organs such as liver, kidney, heart and lung.[6][7][8]

Function

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The function of GDF15 is not fully clear but it seems to have a role in regulating inflammatory pathways and to be involved in regulating apoptosis, angiogenesis, cell repair and cell growth, which are biological processes observed in cardiovascular and neoplastic disorders.[6][9][10][11]

Clinical significance

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GDF15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer.[12] In cardiovascular tissues it is shown that GDF15 concentrations increase in response to atherosclerosis, ischemia/reperfusion injury and heart failure.[13] 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.[14]

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.[15]

Metformin was shown to cause increased levels of GDF15. This increase mediates the effect of body weight loss by metformin.[16] Further study has shown weight loss is promoted by maintaining energy expenditure in addition to appetite suppression.[17]

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.[18]

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.[18]

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.[19]

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.[20]

It has been also associated as a causal factor in hyperemesis gravidarum, a severe form of morning sickness.[21]

Therapeutics development

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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.[22]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000130513 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000038508 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ 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.
  6. ^ a b 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.
  7. ^ 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.
  8. ^ 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.
  9. ^ 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.
  10. ^ Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, et al. (February 2006). "The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury". Circulation Research. 98 (3): 351–360. doi:10.1161/01.RES.0000202805.73038.48. PMID 16397141. S2CID 8401462.
  11. ^ 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.
  12. ^ 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.
  13. ^ Wollert KC, Kempf T, Wallentin L (2017-01-01). "Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease". Clinical Chemistry. 63 (1): 140–151. doi:10.1373/clinchem.2016.255174. ISSN 0009-9147. PMID 28062617.
  14. ^ Hagström E, James SK, Bertilsson M, Becker RC, Himmelmann A, Husted S, et al. (2016-04-21). "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. ISSN 0195-668X. PMID 26417057.
  15. ^ 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.
  16. ^ 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.
  17. ^ Wang D, Townsend LK, DesOrmeaux GJ, Frangos SM, Batchuluun B, Dumont L, et al. (July 2023). "GDF15 promotes weight loss by enhancing energy expenditure in muscle". Nature. 619 (7968): 143–150. Bibcode:2023Natur.619..143W. doi:10.1038/s41586-023-06249-4. PMC 10322716. PMID 37380764.
  18. ^ a b 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.
  19. ^ Wang D, Townsend LK, DesOrmeaux GJ, Frangos SM, Batchuluun B, Dumont L, et al. (July 2023). "GDF15 promotes weight loss by enhancing energy expenditure in muscle". Nature. 619 (7968): 143–150. Bibcode:2023Natur.619..143W. doi:10.1038/s41586-023-06249-4. PMC 10322716. PMID 37380764.
  20. ^ Wedel S, Martic I, Guerrero Navarro L, Ploner C, Pierer G, Jansen-Dürr P, et al. (January 2023). "Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts". Aging Cell. 22 (1): e13752. doi:10.1111/acel.13752. PMC 9835581. PMID 36547021.
  21. ^ Fejzo M, Rocha N, Cimino I, Lockhart SM, Petry CJ, Kay RG, et al. (2023). "GDF15 linked to maternal risk of nausea and vomiting during pregnancy". Nature. 625 (7996): 760–767. doi:10.1038/s41586-023-06921-9. PMC 10808057. PMID 38092039. S2CID 266233306.
  22. ^ "Pfizer Presents Positive Data from Phase 2 Study of Ponsegromab in Patients with Cancer Cachexia | Pfizer". www.pfizer.com. Retrieved 2024-10-28.
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