1932

Abstract

GDF15 is a cell activation and stress response cytokine of the glial cell line–derived neurotrophic factor family within the TGF-β superfamily. It acts through a recently identified orphan member of the GFRα family called GFRAL and signals through the Ret coreceptor. Cell stress and disease lead to elevated GDF15 serum levels, causing anorexia, weight loss, and alterations to metabolism, largely by actions on regions of the hindbrain. These changes restore homeostasis and, in the case of obesity, cause a reduction in adiposity. In some diseases, such as advanced cancer, serum GDF15 levels can rise by as much as 10–100-fold, leading to an anorexia-cachexia syndrome, which is often fatal. This review discusses how GDF15 regulates appetite and metabolism, the role it plays in resistance to obesity, and how this impacts diseases such as diabetes, nonalcoholic fatty liver disease, and anorexia-cachexia syndrome. It also discusses potential therapeutic applications of targeting the GDF15-GFRAL pathway and lastly suggests some potential unifying hypotheses for its biological role.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-physiol-022020-045449
2021-02-10
2024-06-23
Loading full text...

Full text loading...

/deliver/fulltext/physiol/83/1/annurev-physiol-022020-045449.html?itemId=/content/journals/10.1146/annurev-physiol-022020-045449&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M et al. 1997. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-β superfamily. PNAS 94:11514–19
    [Google Scholar]
  2. 2. 
    Breit SN, Tsai VW, Brown DA 2017. Targeting obesity and cachexia: identification of the GFRAL receptor-MIC-1/GDF15 pathway. Trends Mol. Med. 23:1065–67
    [Google Scholar]
  3. 3. 
    Tsai VWW, Husaini Y, Sainsbury A, Brown DA, Breit SN 2018. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab 28:353–68
    [Google Scholar]
  4. 4. 
    Olsen OE, Skjærvik A, Størdal BF, Sundan A, Holien T 2017. TGF-β contamination of purified recombinant GDF15. PLOS ONE 12:e0187349
    [Google Scholar]
  5. 5. 
    Okamura H. 2015. Lack of canonical SMAD2 pathway activation by recombinant GDF15 in vitro. J. Cachexia Sarcopenia Muscle 6:25
    [Google Scholar]
  6. 6. 
    Bauskin AR, Brown DA, Junankar S, Rasiah KK, Eggleton S et al. 2005. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res 65:2330–36
    [Google Scholar]
  7. 7. 
    Bauskin AR, Jiang L, Luo XW, Wu L, Brown DA et al. 2010. The TGF-β superfamily cytokine MIC-1/GDF15: secretory mechanisms facilitate creation of latent stromal stores. J. Interferon Cytokine Res. 30:389–97
    [Google Scholar]
  8. 8. 
    Johnen H, Lin S, Kuffner T, Brown DA, Tsai VW et al. 2007. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat. Med. 13:1333–40
    [Google Scholar]
  9. 9. 
    Brown DA, Bauskin AR, Fairlie WD, Smith MD, Liu T et al. 2002. Antibody-based approach to high-volume genotyping for MIC-1 polymorphism. Biotechniques 33:118–26
    [Google Scholar]
  10. 10. 
    Yang L, Chang CC, Sun Z, Madsen D, Zhu H et al. 2017. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23:1158–66
    [Google Scholar]
  11. 11. 
    Mullican SE, Lin-Schmidt X, Chin CN, Chavez JA, Furman JL et al. 2017. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23:1150–57
    [Google Scholar]
  12. 12. 
    Emmerson PJ, Wang F, Du Y, Liu Q, Pickard RT et al. 2017. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23:1215–19
    [Google Scholar]
  13. 13. 
    Hsu JY, Crawley S, Chen M, Ayupova DA, Lindhout DA et al. 2017. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550:255–59
    [Google Scholar]
  14. 14. 
    Li Z, Wang B, Wu X, Cheng SY, Paraoan L et al. 2005. Identification, expression and functional characterization of the GRAL gene. J. Neurochem. 95:361–76
    [Google Scholar]
  15. 15. 
    Mullican SE, Rangwala SM. 2018. Uniting GDF15 and GFRAL: therapeutic opportunities in obesity and beyond. Trends Endocrinol. Metab. 29:560–70
    [Google Scholar]
  16. 16. 
    Bloch SA, Lee JY, Syburra T, Rosendahl U, Griffiths MJ et al. 2015. Increased expression of GDF-15 may mediate ICU-acquired weakness by down-regulating muscle microRNAs. Thorax 70:219–28
    [Google Scholar]
  17. 17. 
    Kannan K, Amariglio N, Rechavi G, Givol D 2000. Profile of gene expression regulated by induced p53: connection to the TGF-β family. FEBS Lett 470:77–82
    [Google Scholar]
  18. 18. 
    Li PX, Wong J, Ayed A, Ngo D, Brade AM et al. 2000. Placental transforming growth factor-β is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression. J. Biol. Chem. 275:20127–35
    [Google Scholar]
  19. 19. 
    Tan M, Wang Y, Guan K, Sun Y 2000. PTGF-β, a type β transforming growth factor (TGF-β) superfamily member, is a p53 target gene that inhibits tumor cell growth via TGF-β signaling pathway. PNAS 97:109–14
    [Google Scholar]
  20. 20. 
    Baek SJ, Kim JS, Nixon JB, DiAugustine RP, Eling TE 2004. Expression of NAG-1, a transforming growth factor-β superfamily member, by troglitazone requires the early growth response gene EGR-1. J. Biol. . Chem 279:6883–92
    [Google Scholar]
  21. 21. 
    Baek SJ, Kim JS, Moore SM, Lee SH, Martinez J et al. 2005. Cyclooxygenase inhibitors induce the expression of the tumor suppressor gene EGR-1, which results in the up-regulation of NAG-1, an antitumorigenic protein. Mol. Pharmacol. 67:356–64
    [Google Scholar]
  22. 22. 
    Chung HK, Ryu D, Kim KS, Chang JY, Kim YK et al. 2017. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216:149–65
    [Google Scholar]
  23. 23. 
    Li D, Zhang H, Zhong Y 2018. Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice. Biochem. Biophys. Res. Commun. 498:388–94
    [Google Scholar]
  24. 24. 
    Patel S, Alvarez-Guaita A, Melvin A, Rimmington D, Dattilo A et al. 2019. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab 29:707–18.e8
    [Google Scholar]
  25. 25. 
    Conte M, Ostan R, Fabbri C, Santoro A, Guidarelli G et al. 2019. Human aging and longevity are characterized by high levels of mitokines. J. Gerontol. A Biol. Sci. Med. Sci. 74:600–7
    [Google Scholar]
  26. 26. 
    Wollert KC, Kempf T, Wallentin L 2017. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin. Chem. 63:140–51
    [Google Scholar]
  27. 27. 
    Luan HH, Wang A, Hilliard BK, Carvalho F, Rosen CE et al. 2019. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178:1231–44.e11
    [Google Scholar]
  28. 28. 
    Wiklund FE, Bennet AM, Magnusson PK, Eriksson UK, Lindmark F et al. 2010. Macrophage inhibitory cytokine-1 (MIC-1/GDF15): a new marker of all-cause mortality. Aging Cell 9:1057–64
    [Google Scholar]
  29. 29. 
    Lajer M, Jorsal A, Tarnow L, Parving HH, Rossing P 2010. Plasma growth differentiation factor-15 independently predicts all-cause and cardiovascular mortality as well as deterioration of kidney function in type 1 diabetic patients with nephropathy. Diabetes Care 33:1567–72
    [Google Scholar]
  30. 30. 
    Daniels LB, Clopton P, Laughlin GA, Maisel AS, Barrett-Connor E 2011. Growth-differentiation factor-15 is a robust, independent predictor of 11-year mortality risk in community-dwelling older adults: the Rancho Bernardo Study. Circulation 123:2101–10
    [Google Scholar]
  31. 31. 
    Eggers KM, Kempf T, Wallentin L, Wollert KC, Lind L 2013. Change in growth differentiation factor 15 concentrations over time independently predicts mortality in community-dwelling elderly individuals. Clin. Chem. 59:1091–98
    [Google Scholar]
  32. 32. 
    Gerstein HC, Pare G, Hess S, Ford RJ, Sjaarda J et al. 2017. Growth differentiation factor 15 as a novel biomarker for metformin. Diabetes Care 40:280–83
    [Google Scholar]
  33. 33. 
    Kis E, Szatmári T, Keszei M, Farkas R, Esik O et al. 2006. Microarray analysis of radiation response genes in primary human fibroblasts. Int. J. Radiat. Oncol. Biol. Phys. 66:1506–14
    [Google Scholar]
  34. 34. 
    Okazaki R, Moon Y, Norimura T, Eling T 2006. Ionizing radiation enhances the expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG1) by increasing the expression of TP53 in human colon cancer cells. Radiat. Res. 165:125–30
    [Google Scholar]
  35. 35. 
    Moritake T, Fujita H, Yanagisawa M, Nakawatari M, Imadome K et al. 2012. Strain-dependent damage in mouse lung after carbon ion irradiation. Int. J. Radiat. Oncol. Biol. Phys. 84:e95–102
    [Google Scholar]
  36. 36. 
    Tucker JD, Joiner MC, Thomas RA, Grever WE, Bakhmutsky MV et al. 2014. Accurate gene expression-based biodosimetry using a minimal set of human gene transcripts. Int. J. Radiat. Oncol. Biol. Phys. 88:933–39
    [Google Scholar]
  37. 37. 
    Schober A, Böttner M, Strelau J, Kinscherf R, Bonaterra GA et al. 2001. Expression of growth differentiation factor-15/ macrophage inhibitory cytokine-1 (GDF-15/MIC-1) in the perinatal, adult, and injured rat brain. J. Comp. Neurol. 439:32–45
    [Google Scholar]
  38. 38. 
    Hsiao EC, Koniaris LG, Zimmers-Koniaris T, Sebald SM, Huynh TV et al. 2000. Characterization of growth-differentiation factor 15, a transforming growth factor β superfamily member induced following liver injury. Mol. Cell. Biol. 20:3742–51
    [Google Scholar]
  39. 39. 
    Koniaris LG. 2003. Induction of MIC-1/growth differentiation factor-15 following bile duct injury. J. Gastrointest. Surg. 7:901–5
    [Google Scholar]
  40. 40. 
    Hassanpour Golakani M, Mohammad MG, Li H, Gamble J, Breit SN et al. 2019. MIC-1/GDF15 overexpression is associated with increased functional recovery in traumatic spinal cord injury. J. Neurotrauma 36:3410–21
    [Google Scholar]
  41. 41. 
    Welsh JB, Sapinoso LM, Kern SG, Brown DA, Liu T et al. 2003. Large-scale delineation of secreted protein biomarkers overexpressed in cancer tissue and serum. PNAS 100:3410–15
    [Google Scholar]
  42. 42. 
    Lawton LN, Bonaldo MF, Jelenc PC, Qiu L, Baumes SA et al. 1997. Identification of a novel member of the TGF-β superfamily highly expressed in human placenta. Gene 203:17–26
    [Google Scholar]
  43. 43. 
    Moore AG, Brown DA, Fairlie WD, Bauskin AR, Brown PK et al. 2000. The transforming growth factor-β superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J. Clin. Endocrinol. Metab. 85:4781–88
    [Google Scholar]
  44. 44. 
    Marjono AB, Brown DA, Horton KE, Wallace EM, Breit SN et al. 2003. Macrophage inhibitory cytokine-1 in gestational tissues and maternal serum in normal and pre-eclamptic pregnancy. Placenta 24:100–6
    [Google Scholar]
  45. 45. 
    Fejzo MS, Fasching PA, Schneider MO, Schwitulla J, Beckmann MW et al. 2019. Analysis of GDF15 and IGFBP7 in hyperemesis gravidarum support causality. Geburtshilfe Frauenheilkd 79:382–88
    [Google Scholar]
  46. 46. 
    Petry CJ, Ong KK, Burling KA, Barker P, Goodburn SF et al. 2018. Associations of vomiting and antiemetic use in pregnancy with levels of circulating GDF15 early in the second trimester: a nested case-control study. Wellcome Open Res 3:123
    [Google Scholar]
  47. 47. 
    Michelsen TM, Henriksen T, Reinhold D, Powell TL, Jansson T 2019. The human placental proteome secreted into the maternal and fetal circulations in normal pregnancy based on 4-vessel sampling. FASEB J 33:2944–56
    [Google Scholar]
  48. 48. 
    Díaz M, Campderrós L, Guimaraes MP, López-Bermejo A, de Zegher F et al. 2020. Circulating growth-and-differentiation factor-15 in early life: relation to prenatal and postnatal growth and adiposity measurements. Pediatr. Res. 87:897–902
    [Google Scholar]
  49. 49. 
    Fejzo MS, Sazonova OV, Sathirapongsasuti JF, Hallgrímsdóttir IB, Vacic V et al. 2018. Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat. Commun. 9:1178
    [Google Scholar]
  50. 50. 
    Tong S, Marjono B, Brown DA, Mulvey S, Breit SN et al. 2004. Serum concentrations of macrophage inhibitory cytokine 1 (MIC 1) as a predictor of miscarriage. Lancet 363:129–30
    [Google Scholar]
  51. 51. 
    Kaitu'u-Lino TJ, Bambang K, Onwude J, Hiscock R, Konje J et al. 2013. Plasma MIC-1 and PAPP-A levels are decreased among women presenting to an early pregnancy assessment unit, have fetal viability confirmed but later miscarry. PLOS ONE 8:e72437
    [Google Scholar]
  52. 52. 
    Chen Q, Wang Y, Zhao M, Hyett J, da Silva Costa F et al. 2016. Serum levels of GDF15 are reduced in preeclampsia and the reduction is more profound in late-onset than early-onset cases. Cytokine 83:226–30
    [Google Scholar]
  53. 53. 
    Yuksel IT, Mathyk BA, Aslan Cetin B, Turhan U, Okumus ZG et al. 2018. Maternal levels of growth differentiation factor-15 in patients with preeclampsia. Hypertens. Pregnancy 37:192–96
    [Google Scholar]
  54. 54. 
    Binder AK, Kosak JP, Janardhan KS, Moser G, Eling TE, Korach KS 2016. Expression of human NSAID activated gene 1 in mice leads to altered mammary gland differentiation and impaired lactation. PLOS ONE 11:e0146518
    [Google Scholar]
  55. 55. 
    Tsai VW, Manandhar R, Jørgensen SB, Lee-Ng KK, Zhang HP et al. 2014. The anorectic actions of the TGFβ cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLOS ONE 9:e100370
    [Google Scholar]
  56. 56. 
    Tsai VW, Macia L, Johnen H, Kuffner T, Manadhar R et al. 2013. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLOS ONE 8:e55174
    [Google Scholar]
  57. 57. 
    Tsai VW, Macia L, Feinle-Bisset C, Manandhar R, Astrup A et al. 2015. Serum levels of human MIC-1/GDF15 vary in a diurnal pattern, do not display a profile suggestive of a satiety factor and are related to BMI. PLOS ONE 10:e0133362
    [Google Scholar]
  58. 58. 
    Xiong Y, Walker K, Min X, Hale C, Tran T et al. 2017. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl. Med. 9:eaan8732
    [Google Scholar]
  59. 59. 
    Frikke-Schmidt H, Hultman K, Galaske JW, Jørgensen SB, Myers MG et al. 2019. GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice. Mol. Metab. 21:13–21
    [Google Scholar]
  60. 60. 
    Tsai VW, Zhang HP, Manandhar R, Schofield P, Christ D et al. 2019. GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS. Int. J. Obes. 43:2370–80
    [Google Scholar]
  61. 61. 
    Wu Q, Clark MS, Palmiter RD 2012. Deciphering a neuronal circuit that mediates appetite. Nature 483:594–97
    [Google Scholar]
  62. 62. 
    Anesten F, Mishra D, Dalmau Gasull A, Engström-Ruud L, Bellman J et al. 2019. Glucagon-like peptide-1-, but not growth and differentiation factor 15-, receptor activation increases the number of interleukin-6-expressing cells in the external lateral parabrachial nucleus. Neuroendocrinology 109:310–21
    [Google Scholar]
  63. 63. 
    Macia L, Tsai VW, Nguyen AD, Johnen H, Kuffner T et al. 2012. Macrophage inhibitory cytokine 1 (MIC-1/GDF15) decreases food intake, body weight and improves glucose tolerance in mice on normal & obesogenic diets. PLOS ONE 7:e34868
    [Google Scholar]
  64. 64. 
    Tran T, Yang J, Gardner J, Xiong Y 2018. GDF15 deficiency promotes high fat diet-induced obesity in mice. PLOS ONE 13:e0201584
    [Google Scholar]
  65. 65. 
    Vila G, Riedl M, Anderwald C, Resl M, Handisurya A et al. 2011. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin. Chem. 57:309–16
    [Google Scholar]
  66. 66. 
    Kleinert M, Bojsen-Møller KN, Jørgensen NB, Svane MS, Martinussen C et al. 2019. Effect of bariatric surgery on plasma GDF15 in humans. Am. J. Physiol. Endocrinol. Metab. 316:E615–21
    [Google Scholar]
  67. 67. 
    Kleinert M, Clemmensen C, Sjøberg KA, Carl CS, Jeppesen JF et al. 2018. Exercise increases circulating GDF15 in humans. Mol. Metab. 9:187–91
    [Google Scholar]
  68. 68. 
    Zhang H, Fealy CE, Kirwan JP 2019. Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity. Am. J. Physiol. Endocrinol. Metab. 316:E829–36
    [Google Scholar]
  69. 69. 
    Day EA, Ford RJ, Smith BK, Mohammadi-Shemirani P, Morrow MR et al. 2019. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1:1202–8
    [Google Scholar]
  70. 70. 
    Coll AP, Chen M, Taskar P, Rimmington D, Patel S et al. 2020. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578:444–48
    [Google Scholar]
  71. 71. 
    Tsai VW, Zhang HP, Manandhar R, Lee-Ng KKM, Lebhar H et al. 2018. Treatment with the TGF-b superfamily cytokine MIC-1/GDF15 reduces the adiposity and corrects the metabolic dysfunction of mice with diet-induced obesity. Int. J. Obes. 42:561–71
    [Google Scholar]
  72. 72. 
    Dostálová I, Roubícek T, Bártlová M, Mráz M, Lacinová Z et al. 2009. Increased serum concentrations of macrophage inhibitory cytokine-1 in patients with obesity and type 2 diabetes mellitus: the influence of very low calorie diet. Eur. J. Endocrinol. 161:397–404
    [Google Scholar]
  73. 73. 
    Shin MY, Kim JM, Kang YE, Kim MK, Joung KH et al. 2016. Association between growth differentiation factor 15 (GDF15) and cardiovascular risk in patients with newly diagnosed type 2 diabetes mellitus. J. Korean Med. Sci. 31:1413–18
    [Google Scholar]
  74. 74. 
    Schindler K, Vila G, Hoppichler F, Lechleitner M, Luger A et al. 2012. The impact of type 2 diabetes on circulating adipokines in patients with metabolic syndrome. Obes. Facts 5:270–76
    [Google Scholar]
  75. 75. 
    Schernthaner-Reiter MH, Itariu BK, Krebs M, Promintzer-Schifferl M, Stulnig TM et al. 2019. GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism. Nutr. Metab. Cardiovasc. Dis. 29:334–42
    [Google Scholar]
  76. 76. 
    Kempf T, Guba-Quint A, Torgerson J, Magnone MC, Haefliger C et al. 2012. Growth differentiation factor 15 predicts future insulin resistance and impaired glucose control in obese nondiabetic individuals: results from the XENDOS trial. Eur. J. Endocrinol. 167:671–78
    [Google Scholar]
  77. 77. 
    Bao X, Borné Y, Muhammad IF, Nilsson J, Lind L et al. 2019. Growth differentiation factor 15 is positively associated with incidence of diabetes mellitus: the Malmö Diet and Cancer-Cardiovascular Cohort. Diabetologia 62:78–86
    [Google Scholar]
  78. 78. 
    Yalcin MM, Altinova AE, Akturk M, Gulbahar O, Arslan E et al. 2016. GDF-15 and hepcidin levels in nonanemic patients with impaired glucose tolerance. J. Diabetes Res. 2016:1240843
    [Google Scholar]
  79. 79. 
    Hong JH, Chung HK, Park HY, Joung KH, Lee JH et al. 2014. GDF15 is a novel biomarker for impaired fasting glucose. Diabetes Metab. J. 38:472–79
    [Google Scholar]
  80. 80. 
    Bozkurt L, Göbl CS, Rami-Merhar B, Winhofer Y, Baumgartner-Parzer S et al. 2016. The cross-link between adipokines, insulin resistance and obesity in offspring of diabetic pregnancies. Horm. Res. Paediatr. 86:300–8
    [Google Scholar]
  81. 81. 
    Tang M, Luo M, Lu W, Wang S, Zhang R et al. 2019. Serum growth differentiation factor 15 is associated with glucose metabolism in the third trimester in Chinese pregnant women. Diabetes Res. Clin. Pract. 156:107823
    [Google Scholar]
  82. 82. 
    Schernthaner-Reiter MH, Kasses D, Tugendsam C, Riedl M, Peric S et al. 2016. Growth differentiation factor 15 increases following oral glucose ingestion: effect of meal composition and obesity. Eur. J. Endocrinol. 175:623–31
    [Google Scholar]
  83. 83. 
    Karczewska-Kupczewska M, Kowalska I, Nikolajuk A, Adamska A, Otziomek E et al. 2012. Hyperinsulinemia acutely increases serum macrophage inhibitory cytokine-1 concentration in anorexia nervosa and obesity. Clin. Endocrinol. 76:46–50
    [Google Scholar]
  84. 84. 
    Resl M, Clodi M, Vila G, Luger A, Neuhold S et al. 2016. Targeted multiple biomarker approach in predicting cardiovascular events in patients with diabetes. Heart 102:1963–68
    [Google Scholar]
  85. 85. 
    Dominguez-Rodriguez A, Abreu-Gonzalez P, Avanzas P 2014. Usefulness of growth differentiation factor-15 levels to predict diabetic cardiomyopathy in asymptomatic patients with type 2 diabetes mellitus. Am. J. Cardiol. 114:890–94
    [Google Scholar]
  86. 86. 
    Pavo N, Wurm R, Neuhold S, Adlbrecht C, Vila G et al. 2016. GDF-15 is associated with cancer incidence in patients with type 2 diabetes. Clin. Chem. 62:1612–20
    [Google Scholar]
  87. 87. 
    Hellemons ME, Mazagova M, Gansevoort RT, Henning RH, de Zeeuw D et al. 2012. Growth-differentiation factor 15 predicts worsening of albuminuria in patients with type 2 diabetes. Diabetes Care 35:2340–46
    [Google Scholar]
  88. 88. 
    Frimodt-Møller M, von Scholten BJ, Reinhard H, Jacobsen PK, Hansen TW et al. 2018. Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes—an observational follow-up study. PLOS ONE 13:e0196634
    [Google Scholar]
  89. 89. 
    Mazagova M, Buikema H, van Buiten A, Duin M, Goris M et al. 2013. Genetic deletion of growth differentiation factor 15 augments renal damage in both type 1 and type 2 models of diabetes. Am. J. Physiol. Ren. Physiol. 305:F1249–64
    [Google Scholar]
  90. 90. 
    Liu J, Kumar S, Heinzel A, Gao M, Guo J et al. 2020. Renoprotective and immunomodulatory effects of GDF15 following AKI invoked by ischemia-reperfusion injury. J. Am. Soc. Nephrol. 31:701–15
    [Google Scholar]
  91. 91. 
    Wang X, Chrysovergis K, Kosak J, Kissling G, Streicker M et al. 2014. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging 6:690–704
    [Google Scholar]
  92. 92. 
    Husaini Y, Qiu MR, Lockwood GP, Luo XW, Shang P et al. 2012. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice. PLOS ONE 7:e43833
    [Google Scholar]
  93. 93. 
    Yeung SLA, Luo S, Schooling CM 2019. The impact of GDF-15, a biomarker for metformin, on the risk of coronary artery disease, breast and colorectal cancer, and type 2 diabetes and metabolic traits: a Mendelian randomisation study. Diabetologia 62:1638–46
    [Google Scholar]
  94. 94. 
    Liu X, Chi X, Gong Q, Gao L, Niu Y et al. 2015. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLOS ONE 10:e0127518
    [Google Scholar]
  95. 95. 
    Krawczyk M, Zimmermann S, Hess G, Holz R, Dauer M et al. 2017. Panel of three novel serum markers predicts liver stiffness and fibrosis stages in patients with chronic liver disease. PLOS ONE 12:e0173506
    [Google Scholar]
  96. 96. 
    Lee ES, Kim SH, Kim HJ, Kim KH, Lee BS et al. 2017. Growth differentiation factor 15 predicts chronic liver disease severity. Gut Liver 11:276–82
    [Google Scholar]
  97. 97. 
    Koo BK, Um SH, Seo DS, Joo SK, Bae JM et al. 2018. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int 38:695–705
    [Google Scholar]
  98. 98. 
    Kim KH, Kim SH, Han DH, Jo YS, Lee YH et al. 2018. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci. Rep. 8:6789
    [Google Scholar]
  99. 99. 
    Zhang M, Sun W, Qian J, Tang Y 2018. Fasting exacerbates hepatic growth differentiation factor 15 to promote fatty acid β-oxidation and ketogenesis via activating XBP1 signaling in liver. Redox Biol 16:87–96
    [Google Scholar]
  100. 100. 
    Kalko SG, Paco S, Jou C, Rodríguez MA, Meznaric M et al. 2014. Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor-15 as a potential novel biomarker for mitochondrial myopathies. BMC Genom 15:91
    [Google Scholar]
  101. 101. 
    Yatsuga S, Fujita Y, Ishii A, Fukumoto Y, Arahata H et al. 2015. Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders. Ann. Neurol. 78:814–23
    [Google Scholar]
  102. 102. 
    Koene S, de Laat P, van Tienoven DH, Weijers G, Vriens D et al. 2015. Serum GDF15 levels correlate to mitochondrial disease severity and myocardial strain, but not to disease progression in adult m.3243A>G carriers. JIMD Rep 24:69–81
    [Google Scholar]
  103. 103. 
    Montero R, Yubero D, Villarroya J, Henares D, Jou C et al. 2016. GDF-15 is elevated in children with mitochondrial diseases and is induced by mitochondrial dysfunction. PLOS ONE 11:e0148709
    [Google Scholar]
  104. 104. 
    Davis RL, Liang C, Sue CM 2016. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology 86:2010–15
    [Google Scholar]
  105. 105. 
    Lehtonen JM, Forsström S, Bottani E, Viscomi C, Baris OR et al. 2016. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 87:2290–99
    [Google Scholar]
  106. 106. 
    Tsygankova PG, Itkis YS, Krylova TD, Kurkina MV, Bychkov IO et al. 2019. Plasma FGF-21 and GDF-15 are elevated in different inherited metabolic diseases and are not diagnostic for mitochondrial disorders. J. Inherit Metab. Dis. 42:918–33
    [Google Scholar]
  107. 107. 
    Choi MJ, Jung SB, Lee SE, Kang SG, Lee JH et al. 2020. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia 63:837–52
    [Google Scholar]
  108. 108. 
    Forsström S, Jackson CB, Carroll CJ, Kuronen M, Pirinen E et al. 2019. Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metab 30:1040–54.e7
    [Google Scholar]
  109. 109. 
    Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E et al. 2011. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 12:489–95
    [Google Scholar]
  110. 110. 
    Fearon K, Arends J, Baracos V 2013. Understanding the mechanisms and treatment options in cancer cachexia. Nat. Rev. Clin. Oncol. 10:90–99
    [Google Scholar]
  111. 111. 
    Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH 2018. Cancer-associated cachexia. Nat. Rev. Dis. Primers 4:17105
    [Google Scholar]
  112. 112. 
    Tsai VW, Brown DA, Breit SN 2018. Targeting the divergent TGFβ superfamily cytokine MIC-1/GDF15 for therapy of anorexia/cachexia syndromes. Curr. Opin. Support Palliat. Care 12:404–9
    [Google Scholar]
  113. 113. 
    Selander KS, Brown DA, Sequeiros GB, Hunter M, Desmond R et al. 2007. Serum macrophage inhibitory cytokine-1 concentrations correlate with the presence of prostate cancer bone metastases. Cancer Epidemiol. Biomarkers Prev. 16:532–37
    [Google Scholar]
  114. 114. 
    Lerner L, Hayes TG, Tao N, Krieger B, Feng B et al. 2015. Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J. Cachexia Sarcopenia Muscle 6:317–24
    [Google Scholar]
  115. 115. 
    Lerner L, Gyuris J, Nicoletti R, Gifford J, Krieger B et al. 2016. Growth differentiating factor-15 (GDF-15): a potential biomarker and therapeutic target for cancer-associated weight loss. Oncol. Lett. 12:4219–23
    [Google Scholar]
  116. 116. 
    Breit SN, Carrero JJ, Tsai VWW, Yagoutifam N, Luo W et al. 2012. Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrol. Dial. Transplant. 27:70–75
    [Google Scholar]
  117. 117. 
    You AS, Kalantar-Zadeh K, Lerner L, Nakata T, Lopez N et al. 2017. Association of growth differentiation factor 15 with mortality in a prospective hemodialysis cohort. Cardiorenal Med 7:158–68
    [Google Scholar]
  118. 118. 
    Kempf T, von Haehling S, Peter T, Allhoff T, Cicoira M et al. 2007. Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J. Am. Coll. Cardiol. 50:1054–60
    [Google Scholar]
  119. 119. 
    Husebø GR, Grønseth R, Lerner L, Gyuris J, Hardie JA et al. 2017. Growth differentiation factor-15 is a predictor of important disease outcomes in patients with COPD. Eur. Respir. J. 49:1601298
    [Google Scholar]
  120. 120. 
    Patel MS, Lee J, Baz M, Wells CE, Bloch S et al. 2016. Growth differentiation factor-15 is associated with muscle mass in chronic obstructive pulmonary disease and promotes muscle wasting in vivo. J. Cachexia Sarcopenia Muscle 7:436–48
    [Google Scholar]
  121. 121. 
    Modlich O, Prisack HB, Munnes M, Audretsch W, Bojar H 2004. Immediate gene expression changes after the first course of neoadjuvant chemotherapy in patients with primary breast cancer disease. Clin. Cancer Res. 10:6418–31
    [Google Scholar]
  122. 122. 
    Yang H, Filipovic Z, Brown D, Breit SN, Vassilev LT 2003. Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation. Mol. Cancer Ther. 2:1023–29
    [Google Scholar]
  123. 123. 
    Bloechl-Daum B, Deuson RR, Mavros P, Hansen M, Herrstedt J 2006. Delayed nausea and vomiting continue to reduce patients’ quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J. Clin. Oncol. 24:4472–78
    [Google Scholar]
  124. 124. 
    Davidson W, Teleni L, Muller J, Ferguson M, McCarthy AL et al. 2012. Malnutrition and chemotherapy-induced nausea and vomiting: implications for practice. Oncol. Nurs. Forum 39:E340–45
    [Google Scholar]
  125. 125. 
    Caillet P, Liuu E, Raynaud Simon A, Bonnefoy M, Guerin O et al. 2017. Association between cachexia, chemotherapy and outcomes in older cancer patients: a systematic review. Clin. Nutr. 36:1473–82
    [Google Scholar]
  126. 126. 
    Lerner L, Tao J, Liu Q, Nicoletti R, Feng B et al. 2016. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J. Cachexia Sarcopenia Muscle 7:467–82
    [Google Scholar]
  127. 127. 
    Lu ZH, Yang L, Yu JW, Lu M, Li J et al. 2014. Weight loss correlates with macrophage inhibitory cytokine-1 expression and might influence outcome in patients with advanced esophageal squamous cell carcinoma. Asian Pac. J. Cancer Prev. 15:6047–52
    [Google Scholar]
  128. 128. 
    Borner T, Arnold M, Ruud J, Breit SN, Langhans W et al. 2017. Anorexia-cachexia syndrome in hepatoma tumour-bearing rats requires the area postrema but not vagal afferents and is paralleled by increased MIC-1/GDF15. J. Cachexia Sarcopenia Muscle 8:417–27
    [Google Scholar]
  129. 129. 
    Dostálová I, Kaválková P, Papežová H, Domluvilová D, Zikán V et al. 2010. Association of macrophage inhibitory cytokine-1 with nutritional status, body composition and bone mineral density in patients with anorexia nervosa: the influence of partial realimentation. Nutr. Metab. 7:34
    [Google Scholar]
  130. 130. 
    Lee J, Choi J, Scafidi S, Wolfgang MJ 2016. Hepatic fatty acid oxidation restrains systemic catabolism during starvation. Cell Rep 16:201–12
    [Google Scholar]
  131. 131. 
    Smati S, Régnier M, Fougeray T, Polizzi A, Fougerat A et al. 2020. Regulation of hepatokine gene expression in response to fasting and feeding: influence of PPAR-α and insulin-dependent signalling in hepatocytes. Diabetes Metab 46:129–36
    [Google Scholar]
  132. 132. 
    Abulizi P, Loganathan N, Zhao D, Mele T, Zhang Y et al. 2017. Growth differentiation factor-15 deficiency augments inflammatory response and exacerbates septic heart and renal injury induced by lipopolysaccharide. Sci. Rep. 7:1037
    [Google Scholar]
  133. 133. 
    Wang A, Huen SC, Luan HH, Yu S, Zhang C et al. 2016. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166:1512–25.e12
    [Google Scholar]
  134. 134. 
    Chrysovergis K, Wang X, Kosak J, Lee SH, Kim JS et al. 2014. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int. J. Obes. 38:1555–64
    [Google Scholar]
  135. 135. 
    Wang X, Chrysovergis K, Kosak J, Eling TE 2014. Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity. Obesity 22:1256–63
    [Google Scholar]
  136. 136. 
    Borner T, Shaulson ED, Ghidewon MY, Barnett AB, Horn CC et al. 2020. GDF15 induces anorexia through nausea and emesis. Cell Metab 31:351–62.e5
    [Google Scholar]
  137. 137. 
    Jones MF, Li XL, Subramanian M, Shabalina SA, Hara T et al. 2015. Growth differentiation factor-15 encodes a novel microRNA 3189 that functions as a potent regulator of cell death. Cell Death Differ 22:1641–53
    [Google Scholar]
  138. 138. 
    Teng MS, Hsu LA, Juan SH, Lin WC, Lee MC et al. 2017. A GDF15 3′ UTR variant, rs1054564, results in allele-specific translational repression of GDF15 by hsa-miR-1233–3p. PLOS ONE 12:e0183187
    [Google Scholar]
  139. 139. 
    Ajona D, Ortiz-Espinosa S, Lozano T, Exposito F, Calvo A et al. 2020. Short-term starvation reduces IGF-1 levels to sensitize lung tumors to PD-1 immune checkpoint blockade. Nat. Cancer 1:75–85
    [Google Scholar]
  140. 140. 
    Nencioni A, Caffa I, Cortellino S, Longo VD 2018. Fasting and cancer: molecular mechanisms and clinical application. Nat. Rev. Cancer 18:707–19
    [Google Scholar]
  141. 141. 
    Goodpaster BH, Sparks LM. 2017. Metabolic flexibility in health and disease. Cell Metab 25:1027–36
    [Google Scholar]
/content/journals/10.1146/annurev-physiol-022020-045449
Loading
/content/journals/10.1146/annurev-physiol-022020-045449
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error