GDF15 explained

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.[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 upregulated because of injury of organs such as liver, kidney, heart and lung.[2] [3]

Function

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.[4] [5] [6] [7]

Clinical significance

GDF15 has shown to be a strong prognostic protein in patients with different diseases such as heart diseases and cancer.[8] In cardiovascular tissues it is shown that GDF-15 concentrations increase in response to atherosclerosis, ischemia/reperfusion injury and heart failure.[9] In patients with coronary artery disease (CAD), GDF-15 is shown to be associated with adverse outcome such as mortality, myocardial infarction, stroke and with bleeding.[10]

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.[11]

Metformin was shown to cause increased levels of GDF15. This increase mediates the effect of body weight loss by metformin.[12] Further study has shown weight loss is promoted by maintaining energy expenditure in addition to appetite suppression.[13]

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.[14]

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.[14]

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.[15]

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.[16]

It has been also associated as a causal factor in hyperemesis gravidarum, a severe form of morning sickness.[17]

External links

Notes and References

  1. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN . 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 . October 1997 . 9326641 . 23523 . 10.1073/pnas.94.21.11514 . free . 1997PNAS...9411514B .
  2. Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV, Lee SJ . 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 . May 2000 . 10779363 . 85678 . 10.1128/MCB.20.10.3742-3751.2000 .
  3. Ago T, Sadoshima J . GDF15, a cardioprotective TGF-beta superfamily protein . Circulation Research . 98 . 3 . 294–297 . February 2006 . 16484622 . 10.1161/01.RES.0000207919.83894.9d . free .
  4. Zimmers TA, Jin X, Hsiao EC, McGrath SA, Esquela AF, Koniaris LG . Growth differentiation factor-15/macrophage inhibitory cytokine-1 induction after kidney and lung injury . Shock . 23 . 6 . 543–548 . June 2005 . 15897808 .
  5. Wollert KC, Kempf T, Lagerqvist B, Lindahl B, Olofsson S, Allhoff T, Peter T, Siegbahn A, Venge P, Drexler H, Wallentin L . 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 . October 2007 . 17848615 . 10.1161/CIRCULATIONAHA.107.697714 . free .
  6. Kempf T, Eden M, Strelau J, Naguib M, Willenbockel C, Tongers J, Heineke J, Kotlarz D, Xu J, Molkentin JD, Niessen HW, Drexler H, Wollert KC . The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury . Circulation Research . 98 . 3 . 351–360 . February 2006 . 16397141 . 10.1161/01.RES.0000202805.73038.48 . 8401462 .
  7. Rochette L, Méloux A, Zeller M, Cottin Y, Vergely C . Functional roles of GDF15 in modulating microenvironment to promote carcinogenesis . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1866 . 8 . 165798 . August 2020 . 32304740 . 10.1016/j.bbadis.2020.165798 . 215819153 .
  8. Wallentin L, Zethelius B, Berglund L, Eggers KM, Lind L, Lindahl B, Wollert KC, Siegbahn A . GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men . PLOS ONE . 8 . 12 . e78797 . 2013 . 24312445 . 3846468 . 10.1371/journal.pone.0078797 . free . 2013PLoSO...878797W .
  9. Wollert . Kai C . Kempf . Tibor . Wallentin . Lars . 2017-01-01 . Growth Differentiation Factor 15 as a Biomarker in Cardiovascular Disease . Clinical Chemistry . en . 63 . 1 . 140–151 . 10.1373/clinchem.2016.255174 . 28062617 . 0009-9147.
  10. Hagström . Emil . James . Stefan K. . Bertilsson . Maria . Becker . Richard C. . Himmelmann . Anders . Husted . Steen . Katus . Hugo A. . Steg . Philippe Gabriel . Storey . Robert F. . Siegbahn . Agneta . Wallentin . Lars . 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 . en . 37 . 16 . 1325–1333 . 10.1093/eurheartj/ehv491 . 26417057 . 0195-668X.
  11. Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE, Ahasic AM, Herzog EL, Kang I, Pisani MA, Yu S, Zhang C, Ring AM, Young LH, Medzhitov R . GDF15 Is an Inflammation-Induced Central Mediator of Tissue Tolerance . Cell . 178 . 5 . 1231–1244.e11 . August 2019 . 31402172 . 6863354 . 10.1016/j.cell.2019.07.033 .
  12. Coll AP, Chen M, Taskar P, Rimmington D, Patel S, Tadross JA, Cimino I, Yang M, Welsh P, Virtue S, Goldspink DA, Miedzybrodzka EL, Konopka AR, Esponda RR, Huang JT, Tung YC, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GS, Preiss D, Vidal-Puig A, Vallier L, Nair KS, Wareham NJ, Ron D, Gribble FM, Reimann F, Sattar N, Savage DB, Allan BB, O'Rahilly S . GDF15 mediates the effects of metformin on body weight and energy balance . Nature . 578 . 7795 . 444–448 . February 2020 . 31875646 . 7234839 . 10.1038/s41586-019-1911-y .
  13. Wang D, Townsend LK, DesOrmeaux GJ, Frangos SM, Batchuluun B, Dumont L, Kuhre RE, Ahmadi E, Hu S, Rebalka IA, Gautam J, Jabile MJ, Pileggi CA, Rehal S, Desjardins EM, Tsakiridis EE, Lally JS, Juracic ES, Tupling AR, Gerstein HC, Paré G, Tsakiridis T, Harper ME, Hawke TJ, Speakman JR, Blondin DP, Holloway GP, Jørgensen SB, Steinberg GR . GDF15 promotes weight loss by enhancing energy expenditure in muscle . Nature . 619 . 7968 . 143–150 . July 2023 . 37380764 . 10322716 . 10.1038/s41586-023-06249-4 . 2023Natur.619..143W .
  14. Wang D, Day EA, Townsend LK, Djordjevic D, Jørgensen SB, Steinberg GR . GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease . Nature Reviews. Endocrinology . 17 . 10 . 592–607 . October 2021 . 34381196 . 10.1038/s41574-021-00529-7 . 236972376 .
  15. Wang D, Townsend LK, DesOrmeaux GJ, Frangos SM, Batchuluun B, Dumont L, Kuhre RE, Ahmadi E, Hu S, Rebalka IA, Gautam J, Jabile MJ, Pileggi CA, Rehal S, Desjardins EM, Tsakiridis EE, Lally JS, Juracic ES, Tupling AR, Gerstein HC, Paré G, Tsakiridis T, Harper ME, Hawke TJ, Speakman JR, Blondin DP, Holloway GP, Jørgensen SB, Steinberg GR . GDF15 promotes weight loss by enhancing energy expenditure in muscle . Nature . 619 . 7968 . 143–150 . July 2023 . 37380764 . 10.1038/s41586-023-06249-4 . 10322716 . 2023Natur.619..143W .
  16. Wedel S, Martic I, Guerrero Navarro L, Ploner C, Pierer G, Jansen-Dürr P, Cavinato M . Depletion of growth differentiation factor 15 (GDF15) leads to mitochondrial dysfunction and premature senescence in human dermal fibroblasts . Aging Cell . 22 . 1 . e13752 . January 2023 . 36547021 . 9835581 . 10.1111/acel.13752 .
  17. Fejzo M, Rocha N, Cimino I, Lockhart SM, Petry CJ, Kay RG, Burling K, Barker P, George AL, Yasara N, Premawardhena A, Gong S, Cook E, Rimmington D, Rainbow K, Withers DJ, Cortessis V, Mullin PM, MacGibbon KW, Jin E, Kam A, Campbell A, Polasek O, Tzoneva G, Gribble FM, Yeo GS, Lam BY, Saudek V, Hughes IA, Ong KK, Perry JR, Sutton Cole A, Baumgarten M, Welsh P, Sattar N, Smith GC, Charnock-Jones DS, Coll AP, Meek CL, Mettananda S, Hayward C, Mancuso N, O'Rahilly S . GDF15 linked to maternal risk of nausea and vomiting during pregnancy . Nature . 2023 . 625 . 7996 . 760–767 . 10.1038/s41586-023-06921-9 . 38092039 . 266233306 . free . 10808057 .

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