Diabetes Metab J.  2020 Jun;44(3):363-371. 10.4093/dmj.2020.0087.

The Role of Growth Differentiation Factor 15 in Energy Metabolism

• Chang JY
• Hong HJ
• Kang SG
• Kim JT
• Zhang BY
• Shong M

• KMID: 2512994
• DOI: http://doi.org/10.4093/dmj.2020.0087

Abstract

Growth differentiation factor 15 (GDF15) is receiving great interest beyond its role as an aging and disease-related biomarker. Recent discovery of its receptor, glial cell line-derived neurotrophic factor (GDNF) family receptor α-like (GFRAL), suggests a central role in appetite regulation. However, there is also considerable evidence that GDF15 may have peripheral activity through an as-of-yet undiscovered mode of action. This raises the question as to whether increased GDF15 induction during pathophysiologic conditions also suppresses appetite. The present review will briefly introduce the discovery of GDF15 and describe the different contexts under which GDF15 is induced, focusing on its induction during mitochondrial dysfunction. We will further discuss the metabolic role of GDF15 under various pathophysiological conditions and conclude with possible therapeutic applications.

Keyword

GDF15 protein, human; Metabolism; Mitochondria

Reference

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. Proc Natl Acad Sci U S A. 1997; 94:11514–11519. PMID: 9326641.

2. Baek SJ, Kim KS, Nixon JB, Wilson LC, Eling TE. Cyclooxygenase inhibitors regulate the expression of a TGF-beta superfamily member that has proapoptotic and antitumorigenic activities. Mol Pharmacol. 2001; 59:901–908. PMID: 11259636.

3. Li PX, Wong J, Ayed A, Ngo D, Brade AM, Arrowsmith C, Austin RC, Klamut HJ. Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J Biol Chem. 2000; 275:20127–20135. PMID: 10777512.

4. Paralkar VM, Vail AL, Grasser WA, Brown TA, Xu H, Vukicevic S, Ke HZ, Qi H, Owen TA, Thompson DD. Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J Biol Chem. 1998; 273:13760–13767. PMID: 9593718.

5. Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA, Higbee J, Kutach A, Joo W, Gao Z, Fu D, To C, Mondal K, Li B, Kekatpure A, Wang M, Laird T, Horner G, Chan J, McEntee M, Lopez M, Lakshminarasimhan D, White A, Wang SP, Yao J, Yie J, Matern H, Solloway M, Haldankar R, Parsons T, Tang J, Shen WD, Alice Chen Y, Tian H, Allan BB. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017; 550:255–259. PMID: 28953886.

6. Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R, Jorgensen SB, Lee-Ng KK, Zhang HP, Wu L, Marquis CP, Jiang L, Husaini Y, Lin S, Herzog H, Brown DA, Sainsbury A, Breit SN. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS One. 2013; 8:e55174. PMID: 23468844.

7. Chung HK, Ryu D, Kim KS, Chang JY, Kim YK, Yi HS, Kang SG, Choi MJ, Lee SE, Jung SB, Ryu MJ, Kim SJ, Kweon GR, Kim H, Hwang JH, Lee CH, Lee SJ, Wall CE, Downes M, Evans RM, Auwerx J, Shong M. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol. 2017; 216:149–165. PMID: 27986797.

8. Khan NA, Nikkanen J, Yatsuga S, Jackson C, Wang L, Pradhan S, Kivela R, Pessia A, Velagapudi V, Suomalainen A. mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab. 2017; 26:419–428. PMID: 28768179.

9. Melvin A, Lacerda E, Dockrell HM, O'Rahilly S, Nacul L. Circulating levels of GDF15 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Transl Med. 2019; 17:409. PMID: 31801546.

10. Ost M, Igual Gil C, Coleman V, Keipert S, Efstathiou S, Vidic V, Weyers M, Klaus S. Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress. EMBO Rep. 2020; 21:e48804. PMID: 32026535.

11. Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A, Miedzybrodzka EL, Cimino I, Maurin AC, Roberts GP, Meek CL, Virtue S, Sparks LM, Parsons SA, Redman LM, Bray GA, Liou AP, Woods RM, Parry SA, Jeppesen PB, Kolnes AJ, Harding HP, Ron D, Vidal-Puig A, Reimann F, Gribble FM, Hulston CJ, Farooqi IS, Fafournoux P, Smith SR, Jensen J, Breen D, Wu Z, Zhang BB, Coll AP, Savage DB, O'Rahilly S. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 2019; 29:707–718. PMID: 30639358.

12. Baek SJ, Eling T. Growth differentiation factor 15 (GDF15): a survival protein with therapeutic potential in metabolic diseases. Pharmacol Ther. 2019; 198:46–58. PMID: 30790643.

13. Ji X, Zhao L, Ji K, Zhao Y, Li W, Zhang R, Hou Y, Lu J, Yan C. Growth differentiation factor 15 is a novel diagnostic biomarker of mitochondrial diseases. Mol Neurobiol. 2017; 54:8110–8116. PMID: 27889897.

14. Kleinert M, Clemmensen C, Sjoberg KA, Carl CS, Jeppesen JF, Wojtaszewski JFP, Kiens B, Richter EA. Exercise increases circulating GDF15 in humans. Mol Metab. 2018; 9:187–191. PMID: 29398617.

15. 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. 2019; 178:1231–1244. PMID: 31402172.

16. Tanaka T, Biancotto A, Moaddel R, Moore AZ, Gonzalez-Freire M, Aon MA, Candia J, Zhang P, Cheung F, Fantoni G, Semba RD, Ferrucci L. CHI consortium. Plasma proteomic signature of age in healthy humans. Aging Cell. 2018; 17:e12799. PMID: 29992704.

17. Wang T, Liu J, McDonald C, Lupino K, Zhai X, Wilkins BJ, Hakonarson H, Pei L. GDF15 is a heart-derived hormone that regulates body growth. EMBO Mol Med. 2017; 9:1150–1164. PMID: 28572090.

18. Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F, Wu L, Yaghoutyfam N, Marquis CP, Stattin P, Pedersen NL, Adami HO, Gronberg H, Breit SN, Brown DA. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell. 2010; 9:1057–1064. PMID: 20854422.

19. Wollert KC. Growth-differentiation factor-15 in cardiovascular disease: from bench to bedside, and back. Basic Res Cardiol. 2007; 102:412–415. PMID: 17546529.

20. Xu J, Kimball TR, Lorenz JN, Brown DA, Bauskin AR, Klevitsky R, Hewett TE, Breit SN, Molkentin JD. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ Res. 2006; 98:342–350. PMID: 16397142.

21. 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. Circ Res. 2006; 98:351–360. PMID: 16397141.

22. Artz A, Butz S, Vestweber D. GDF-15 inhibits integrin activation and mouse neutrophil recruitment through the ALK-5/TGF-βRII heterodimer. Blood. 2016; 128:529–541. PMID: 27235139.

23. Groschel K, Schnaudigel S, Edelmann F, Niehaus CF, Weber-Kruger M, Haase B, Lahno R, Seegers J, Wasser K, Wohlfahrt J, Vollmann D, Stahrenberg R, Wachter R. Growth-differentiation factor-15 and functional outcome after acute ischemic stroke. J Neurol. 2012; 259:1574–1579. PMID: 22231869.

24. O'Donoghue ML, Morrow DA, Cannon CP, Jarolim P, Desai NR, Sherwood MW, Murphy SA, Gerszten RE, Sabatine MS. Multimarker risk stratification in patients with acute myocardial infarction. J Am Heart Assoc. 2016; 5:e002586. PMID: 27207959.

25. Yuan Z, Li H, Qi Q, Gong W, Qian C, Dong R, Zang Y, Li J, Zhou M, Cai J, Wang Z, Chen A, Ye X, Zhao Q. Plasma levels of growth differentiation factor-15 are associated with myocardial injury in patients undergoing off-pump coronary artery bypass grafting. Sci Rep. 2016; 6:28221. PMID: 27311391.

26. Wang J, Wei L, Yang X, Zhong J. Roles of growth differentiation factor 15 in atherosclerosis and coronary artery disease. J Am Heart Assoc. 2019; 8:e012826. PMID: 31432727.

27. Abulizi P, Loganathan N, Zhao D, Mele T, Zhang Y, Zwiep T, Liu K, Zheng X. Growth differentiation factor-15 deficiency augments inflammatory response and exacerbates septic heart and renal injury induced by lipopolysaccharide. Sci Rep. 2017; 7:1037. PMID: 28432312.

28. Kim JM, Kosak JP, Kim JK, Kissling G, Germolec DR, Zeldin DC, Bradbury JA, Baek SJ, Eling TE. NAG-1/GDF15 transgenic mouse has less white adipose tissue and a reduced inflammatory response. Mediators Inflamm. 2013; 2013:641851. PMID: 23737651.

29. Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. 2014; 5:614. PMID: 25506346.

30. Jung SB, Choi MJ, Ryu D, Yi HS, Lee SE, Chang JY, Chung HK, Kim YK, Kang SG, Lee JH, Kim KS, Kim HJ, Kim CS, Lee CH, Williams RW, Kim H, Lee HK, Auwerx J, Shong M. Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat Commun. 2018; 9:1551. PMID: 29674655.

31. Choi MJ, Jung SB, Lee SE, Kang SG, Lee JH, Ryu MJ, Chung HK, Chang JY, Kim YK, Hong HJ, Kim H, Kim HJ, Lee CH, Mardinoglu A, Yi HS, Shong M. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia. 2020; 63:837–852. PMID: 31925461.

32. Modi A, Dwivedi S, Roy D, Khokhar M, Purohit P, Vishnoi J, Pareek P, Sharma S, Sharma P, Misra S. Growth differentiation factor 15 and its role in carcinogenesis: an update. Growth Factors. 2019; 37:190–207. PMID: 31693861.

33. Eling TE, Baek SJ, Shim M, Lee CH. NSAID activated gene (NAG-1), a modulator of tumorigenesis. J Biochem Mol Biol. 2006; 39:649–655. PMID: 17129398.

34. Cekanova M, Lee SH, Donnell RL, Sukhthankar M, Eling TE, Fischer SM, Baek SJ. Nonsteroidal anti-inflammatory drug-activated gene-1 expression inhibits urethane-induced pulmonary tumorigenesis in transgenic mice. Cancer Prev Res (Phila). 2009; 2:450–458. PMID: 19401523.

35. Zhang Z, Wu L, Wang J, Li G, Feng D, Zhang B, Li L, Yang J, Ma L, Qin H. Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis. PLoS One. 2014; 9:e96283. PMID: 24759784.

36. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013; 153:1194–1217. PMID: 23746838.

37. Conte M, Ostan R, Fabbri C, Santoro A, Guidarelli G, Vitale G, Mari D, Sevini F, Capri M, Sandri M, Monti D, Franceschi C, Salvioli S. Human aging and longevity are characterized by high levels of mitokines. J Gerontol A Biol Sci Med Sci. 2019; 74:600–607. PMID: 29955888.

38. Fujita Y, Taniguchi Y, Shinkai S, Tanaka M, Ito M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr Gerontol Int. 2016; 16 Suppl 1:17–29. PMID: 27018280.

39. Lehallier B, Gate D, Schaum N, Nanasi T, Lee SE, Yousef H, Moran Losada P, Berdnik D, Keller A, Verghese J, Sathyan S, Franceschi C, Milman S, Barzilai N, Wyss-Coray T. Undulating changes in human plasma proteome profiles across the lifespan. Nat Med. 2019; 25:1843–1850. PMID: 31806903.

40. Osawa Y, Semba RD, Fantoni G, Candia J, Biancotto A, Tanaka T, Bandinelli S, Ferrucci L. Plasma proteomic signature of the risk of developing mobility disability: a 9-year follow-up. Aging Cell. 2020; 19:e13132. PMID: 32157804.

41. Jang JY, Blum A, Liu J, Finkel T. The role of mitochondria in aging. J Clin Invest. 2018; 128:3662–3670. PMID: 30059016.

42. Moro L. Mitochondrial dysfunction in aging and cancer. J Clin Med. 2019; 8:1983.

43. Durieux J, Wolff S, Dillin A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell. 2011; 144:79–91. PMID: 21215371.

44. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim DH, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013; 19:83–92. PMID: 23202295.

45. Morrow RM, Picard M, Derbeneva O, Leipzig J, McManus MJ, Gouspillou G, Barbat-Artigas S, Dos Santos C, Hepple RT, Murdock DG, Wallace DC. Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity. Proc Natl Acad Sci U S A. 2017; 114:2705–2710. PMID: 28223503.

46. Wang X, Chrysovergis K, Kosak J, Kissling G, Streicker M, Moser G, Li R, Eling TE. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging (Albany NY). 2014; 6:690–704. PMID: 25239873.

47. Zhang Y, Xie Y, Berglund ED, Coate KC, He TT, Katafuchi T, Xiao G, Potthoff MJ, Wei W, Wan Y, Yu RT, Evans RM, Kliewer SA, Mangelsdorf DJ. The starvation hormone, fibroblast growth factor-21, extends lifespan in mice. Elife. 2012; 1:e00065. PMID: 23066506.

48. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 2013; 18:333–340. PMID: 24011069.

49. Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW, Bauskin AR, Wu L, Pankhurst G, Jiang L, Junankar S, Hunter M, Fairlie WD, Lee NJ, Enriquez RF, Baldock PA, Corey E, Apple FS, Murakami MM, Lin EJ, Wang C, During MJ, Sainsbury A, Herzog H, Breit SN. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1. Nat Med. 2007; 13:1333–1340. PMID: 17982462.

50. Kim KK, Lee JJ, Yang Y, You KH, Lee JH. Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells. Carcinogenesis. 2008; 29:704–712. PMID: 18258606.

51. de Jager SC, Bermudez B, Bot I, Koenen RR, Bot M, Kavelaars A, de Waard V, Heijnen CJ, Muriana FJ, Weber C, van Berkel TJ, Kuiper J, Lee SJ, Abia R, Biessen EA. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J Exp Med. 2011; 208:217–225. PMID: 21242297.

52. Li C, Wang J, Kong J, Tang J, Wu Y, Xu E, Zhang H, Lai M. GDF15 promotes EMT and metastasis in colorectal cancer. Oncotarget. 2016; 7:860–872. PMID: 26497212.

53. Li S, Ma YM, Zheng PS, Zhang P. GDF15 promotes the proliferation of cervical cancer cells by phosphorylating AKT1 and Erk1/2 through the receptor ErbB2. J Exp Clin Cancer Res. 2018; 37:80. PMID: 29636108.

54. Tarfiei GA, Shadboorestan A, Montazeri H, Rahmanian N, Tavosi G, Ghahremani MH. GDF15 induced apoptosis and cytotoxicity in A549 cells depends on TGFBR2 expression. Cell Biochem Funct. 2019; 37:320–330. PMID: 31172564.

55. Olsen OE, Skjaervik A, Stordal BF, Sundan A, Holien T. TGF-β contamination of purified recombinant GDF15. PLoS One. 2017; 12:e0187349. PMID: 29161287.

56. Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT, Gonciarz MD, Coskun T, Hamang MJ, Sindelar DK, Ballman KK, Foltz LA, Muppidi A, Alsina-Fernandez J, Barnard GC, Tang JX, Liu X, Mao X, Siegel R, Sloan JH, Mitchell PJ, Zhang BB, Gimeno RE, Shan B, Wu X. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017; 23:1215–1219. PMID: 28846098.

57. Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL, Armstrong AA, Beck SC, South VJ, Dinh TQ, Cash-Mason TD, Cavanaugh CR, Nelson S, Huang C, Hunter MJ, Rangwala SM. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017; 23:1150–1157. PMID: 28846097.

58. Yang L, Chang CC, Sun Z, Madsen D, Zhu H, Padkjaer SB, Wu X, Huang T, Hultman K, Paulsen SJ, Wang J, Bugge A, Frantzen JB, Norgaard P, Jeppesen JF, Yang Z, Secher A, Chen H, Li X, John LM, Shan B, He Z, Gao X, Su J, Hansen KT, Yang W, Jorgensen SB. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017; 23:1158–1166. PMID: 28846099.

59. Li J, Shang G, Chen YJ, Brautigam CA, Liou J, Zhang X, Bai XC. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Elife. 2019; 8:e47650. PMID: 31535977.

60. Tsai VW, Manandhar R, Jorgensen SB, Lee-Ng KK, Zhang HP, Marquis CP, Jiang L, Husaini Y, Lin S, Sainsbury A, Sawchenko PE, Brown DA, Breit SN. The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One. 2014; 9:e100370. PMID: 24971956.

61. Chung HK, Kim JT, Kim HW, Kwon M, Kim SY, Shong M, Kim KS, Yi HS. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci Rep. 2017; 7:17238. PMID: 29222479.

62. Kim KH, Kim SH, Han DH, Jo YS, Lee YH, Lee MS. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci Rep. 2018; 8:6789. PMID: 29717162.

63. Bauskin AR, Brown DA, Junankar S, Rasiah KK, Eggleton S, Hunter M, Liu T, Smith D, Kuffner T, Pankhurst GJ, Johnen H, Russell PJ, Barret W, Stricker PD, Grygiel JJ, Kench JG, Henshall SM, Sutherland RL, Breit SN. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res. 2005; 65:2330–2336. PMID: 15781647.

64. Bauskin AR, Zhang HP, Fairlie WD, He XY, Russell PK, Moore AG, Brown DA, Stanley KK, Breit SN. The propeptide of macrophage inhibitory cytokine (MIC-1), a TGF-beta superfamily member, acts as a quality control determinant for correctly folded MIC-1. EMBO J. 2000; 19:2212–2220. PMID: 10811612.

65. Bauskin AR, Jiang L, Luo XW, Wu L, Brown DA, Breit SN. The TGF-beta superfamily cytokine MIC-1/GDF15: secretory mechanisms facilitate creation of latent stromal stores. J Interferon Cytokine Res. 2010; 30:389–397. PMID: 20187768.

66. 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 YCL, Rodriguez-Cuenca S, Tomaz RA, Harding HP, Melvin A, Yeo GSH, 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. 2020; 578:444–448. PMID: 31875646.