Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Nature Reviews Endocrinology volume 17, pages 592–607 (2021)Cite this article

Subjects

Abstract

Growth differentiation factor 15 (GDF15) is a member of the TGFβ superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. 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. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15–GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings 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. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases.

Key points

  • Growth differentiation factor 15 (GDF15) is expressed in multiple cell types and can be increased by cellular stressors, including hypoxia, mitochondrial dysfunction, metformin and endurance exercise.

  • Increases in GDF15 secretion are mediated through mitochondrial stress and by activation of the integrated stress response pathway as well as, potentially, via AMPK.

  • GDF15 reduces the intake of high-fat diets 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 and this event is required for weight loss and improved glycaemic control.

  • Evidence suggests that GDF15 might alleviate non-alcoholic fatty liver disease and non-alcoholic steatohepatitis but the mechanisms mediating the anti-inflammatory effects and whether these are independent of reductions in body weight remain to be determined.

  • GDF15 might have cardioprotective effects by reducing atherosclerosis, cardiac hypertrophy and ischaemia–reperfusion injury; however, the mechanisms mediating these effects are still unclear.

  • Clinical testing of long-acting analogues of GDF15 is under way and will be important to determine whether the beneficial effects observed in animal models are translated to humans in a safe and efficacious manner.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: GDF15 regulation, maturation and secretion.
Fig. 2: A model of the formation of the GDF15–GFRAL–RET signalling complex.
Fig. 3: Proposed mechanisms by which GDF15 suppresses energy intake and obesity.
Fig. 4: Potential effects of GDF15 in cardiometabolic diseases beyond obesity.

References

  1. Lyall, D. M. et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. 2, 882–889 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fabbrini, E., Sullivan, S. & Klein, S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 51, 679–689 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Liu, Z. et al. Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J. Hepatol. 73, 263–276 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Friedman, S. L., Neuschwander-Tetri, B. A., Rinella, M. & Sanyal, A. J. Mechanisms of NAFLD development and therapeutic strategies. Nat. Med. 24, 908–922 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cai, J. et al. Nonalcoholic fatty liver disease pandemic fuels the upsurge in cardiovascular diseases. Circ. Res. 126, 679–704 (2020).

    Article  CAS  PubMed  Google Scholar 

  6. Kumanyika, S. K. et al. Population-based prevention of obesity: the need for comprehensive promotion of healthful eating, physical activity, and energy balance: a scientific statement from American Heart Association Council on Epidemiology and Prevention, Interdisciplinary Committee for Prevention (formerly the expert panel on population and prevention science). Circulation 118, 428–464 (2008).

    Article  PubMed  Google Scholar 

  7. Gadde, K. M., Martin, C. K., Berthoud, H. R. & Heymsfield, S. B. Obesity: pathophysiology and management. J. Am. Coll. Cardiol. 71, 69–84 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Lockhart, S. M., Saudek, V. & O’Rahilly, S. GDF15: a hormone conveying somatic distress to the brain. Endocr. Rev. 41, 610–642 (2020).

    Article  Google Scholar 

  9. Hsiao, E. C. et al. Characterization of growth-differentiation factor 15, a transforming growth factor beta superfamily member induced following liver injury. Mol. Cell Biol. 20, 3742–3751 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Coll, A. P. et al. GDF15 mediates the effects of metformin on body weight and energy balance. Nature 578, 444–448 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Paralkar, V. M. et al. Cloning and characterization of a novel member of the transforming growth factor-beta/bone morphogenetic protein family. J. Biol. Chem. 273, 13760–13767 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. Yokoyama-Kobayashi, M., Saeki, M., Sekine, S. & Kato, S. Human cDNA encoding a novel TGF-beta superfamily protein highly expressed in placenta. J. Biochem. 122, 622–626 (1997).

    Article  CAS  PubMed  Google Scholar 

  13. Tsai, V. W. et al. 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, 561–571 (2018).

    Article  CAS  Google Scholar 

  14. Tsai, V. W. et al. Anorexia/cachexia of chronic diseases: a role for the TGF-beta family cytokine MIC-1/GDF15. J. Cachexia Sarcopenia Muscle 3, 239–243 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tsai, V. W. W., Husaini, Y., Sainsbury, A., Brown, D. A. & Breit, S. N. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 28, 353–368 (2018).

    Article  CAS  PubMed  Google Scholar 

  16. Dostálová, I. et al. 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 (2009).

    Article  PubMed  CAS  Google Scholar 

  17. Vila, G. et al. The relationship between insulin resistance and the cardiovascular biomarker growth differentiation factor-15 in obese patients. Clin. Chem. 57, 309–316 (2011).

    Article  CAS  PubMed  Google Scholar 

  18. Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: Evidence from mice to monkeys. Sci. Transl. Med. 9, eaan8732 (2017).

    Article  PubMed  CAS  Google Scholar 

  19. Gil, C. I. et al. Role of GDF15 in active lifestyle induced metabolic adaptations and acute exercise response in mice. Sci. Rep. 9, 20120 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Tsai, V. W. et al. 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 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Gerstein, H. C. et al. Growth differentiation factor 15 as a novel biomarker for metformin. Diabetes Care 40, 280–283 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. Altena, R. et al. Growth differentiation factor 15 (GDF-15) plasma levels increase during bleomycin- and cisplatin-based treatment of testicular cancer patients and relate to endothelial damage. PLoS One 10, e0115372 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Petry, C. J. et al. 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, 123–123 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Tsai, V. W.-W. et al. TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS One 8, e55174 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Patel, S. et al. GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 29, 707–718.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Campderros, L. et al. Brown adipocytes secrete GDF15 in response to thermogenic activation. Obesity 27, 1606–1616 (2019).

    Article  CAS  PubMed  Google Scholar 

  27. Bootcov, M. R. et al. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta superfamily. Proc. Natl Acad. Sci. USA 94, 11514–11519 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bottner, M., Suter-Crazzolara, C., Schober, A. & Unsicker, K. Expression of a novel member of the TGF-beta superfamily, growth/differentiation factor-15/macrophage-inhibiting cytokine-1 (GDF-15/MIC-1) in adult rat tissues. Cell Tissue Res. 297, 103–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Liu, R. & Nikolajczyk, B. S. Tissue immune cells fuel obesity-associated inflammation in adipose tissue and beyond. Front. Immunol. 10, 1587 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ramachandran, P. et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature 575, 512–518 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Govaere, O. et al. Transcriptomic profiling across the nonalcoholic fatty liver disease spectrum reveals gene signatures for steatohepatitis and fibrosis. Sci. Transl. Med. 12, eaba4448 (2020).

    Article  CAS  PubMed  Google Scholar 

  32. Nohara, S. et al. GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis. J. Neurol. Sci. 405, 116429 (2019).

    Article  CAS  PubMed  Google Scholar 

  33. Wollert, K. C., Kempf, T. & Wallentin, L. Growth differentiation factor 15 as a biomarker in cardiovascular disease. Clin. Chem. 63, 140–151 (2017).

    Article  CAS  PubMed  Google Scholar 

  34. Lindholm, D. et al. Association of multiple biomarkers with risk of all-cause and cause-specific mortality after acute coronary syndromes: a secondary analysis of the PLATO biomarker study. JAMA Cardiol. 3, 1160–1166 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wallentin, L. et al. GDF-15 for prognostication of cardiovascular and cancer morbidity and mortality in men. PLoS One 8, e78797 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Brown, D. A. et al. Macrophage inhibitory cytokine 1: a new prognostic marker in prostate cancer. Clin. Cancer Res. 15, 6658–6664 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tsui, K. H. et al. Growth differentiation factor-15: a p53- and demethylation-upregulating gene represses cell proliferation, invasion, and tumorigenesis in bladder carcinoma cells. Sci. Rep. 5, 12870 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tan, M., Wang, Y., Guan, K. & Sun, Y. 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. Proc. Natl Acad. Sci. USA 97, 109–114 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Baek, S. J., Kim, J. S., Nixon, J. B., DiAugustine, R. P. & Eling, T. E. Expression of NAG-1, a transforming growth factor-beta superfamily member, by troglitazone requires the early growth response gene EGR-1. J. Biol. Chem. 279, 6883–6892 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Li, D., Zhang, H. & Zhong, Y. Hepatic GDF15 is regulated by CHOP of the unfolded protein response and alleviates NAFLD progression in obese mice. Biochem. Biophys. Res. Commun. 498, 388–394 (2018).

    Article  CAS  PubMed  Google Scholar 

  41. Day, E. A. et al. Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat. Metab. 1, 1202–1208 (2019).

    Article  CAS  PubMed  Google Scholar 

  42. Quiros, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 216, 2027–2045 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Anderson, N. S. & Haynes, C. M. Folding the mitochondrial UPR into the integrated stress response. Trends Cell Biol. 30, 428–439 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chung, H. K. et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216, 149–165 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Choi, M. J. et al. An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models. Diabetologia 63, 837–852 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Zechner, C. et al. Total skeletal muscle PGC-1 deficiency uncouples mitochondrial derangements from fiber type determination and insulin sensitivity. Cell Metab. 12, 633–642 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. O’Neill, H. M. et al. AMP-activated protein kinase (AMPK) β1β2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc. Natl Acad. Sci. USA 108, 16092–16097 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Wredenberg, A. et al. Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochem. Biophys. Res. Commun. 350, 202–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Pospisilik, J. A. et al. Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell 131, 476–491 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Conte, M. et al. Human aging and longevity are characterized by high levels of mitokines. J. Gerontol. A Biol. Sci. Med. Sci. 74, 600–607 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Moon, J. S. et al. Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice. Aging Cell 19, e13195 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 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. 16, 17–29 (2016).

    Article  PubMed  Google Scholar 

  53. Townsend, L. K. et al. AMPK mediates energetic stress-induced liver GDF15. FASEB J. 35, e21218 (2021).

    Article  CAS  PubMed  Google Scholar 

  54. Baek, S. J. & Eling, T. Growth differentiation factor 15 (GDF15): a survival protein with therapeutic potential in metabolic diseases. Pharmacol. Ther. 198, 46–58 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li, J. J. et al. Growth differentiation factor 15 maturation requires proteolytic cleavage by PCSK3, -5, and -6. Mol. Cell Biol. 38, e00249-18 (2018).

    PubMed  PubMed Central  Google Scholar 

  56. Zhang, Z. et al. ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation. J. Hepatol. 72, 976–989 (2020).

    Article  CAS  PubMed  Google Scholar 

  57. Bauskin, A. R. et al. The propeptide mediates formation of stromal stores of PROMIC-1: role in determining prostate cancer outcome. Cancer Res. 65, 2330–2336 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Bauskin, A. R. et al. 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. 19, 2212–2220 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Li, S. et al. Maturation of growth differentiation factor 15 in human placental trophoblast cells depends on the interaction with matrix metalloproteinase-26. J. Clin. Endocrinol. Metab. 99, E2277–E2287 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Abd El-Aziz, S. H., Endo, Y., Miyamaori, H., Takino, T. & Sato, H. Cleavage of growth differentiation factor 15 (GDF15) by membrane type 1-matrix metalloproteinase abrogates GDF15-mediated suppression of tumor cell growth. Cancer Sci. 98, 1330–1335 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).

    Article  PubMed  CAS  Google Scholar 

  62. Yang, L. et al. GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat. Med. 23, 1158–1166 (2017).

    Article  CAS  PubMed  Google Scholar 

  63. Mullican, S. E. et al. GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat. Med. 23, 1150–1157 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Emmerson, P. J. et al. The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat. Med. 23, 1215–1219 (2017).

    Article  CAS  PubMed  Google Scholar 

  65. Wong, A. et al. Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol. Cell. Biol. 25, 9661–9673 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Tsai, V. W. et al. The anorectic actions of the TGFbeta cytokine MIC-1/GDF15 require an intact brainstem area postrema and nucleus of the solitary tract. PLoS One 9, e100370 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Codo, P. et al. Control of glioma cell migration and invasiveness by GDF-15. Oncotarget 7, 7732–7746 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Olsen, O. E., Skjaervik, A., Stordal, B. F., Sundan, A. & Holien, T. TGF-beta contamination of purified recombinant GDF15. PLoS One 12, e0187349 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Johnen, H. et al. Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat. Med. 13, 1333–1340 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Tsai, V. W.-W. et al. GDF15 mediates adiposity resistance through actions on GFRAL neurons in the hindbrain AP/NTS. Int. J. Obes. 43, 2370–2380 (2019).

    Article  CAS  Google Scholar 

  71. Frikke-Schmidt, H. et al. GDF15 acts synergistically with liraglutide but is not necessary for the weight loss induced by bariatric surgery in mice. Mol. Metab. 21, 13–21 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Murphy, K. G. & Bloom, S. R. Gut hormones and the regulation of energy homeostasis. Nature 444, 854–859 (2006).

    Article  CAS  PubMed  Google Scholar 

  73. Banno, R. et al. Central administration of melanocortin agonist increased insulin sensitivity in diet-induced obese rats. FEBS Lett. 581, 1131–1136 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Zarjevski, N., Cusin, I., Vettor, R., Rohner-Jeanrenaud, F. & Jeanrenaud, B. Intracerebroventricular administration of neuropeptide Y to normal rats has divergent effects on glucose utilization by adipose tissue and skeletal muscle. Diabetes 43, 764–769 (1994).

    Article  CAS  PubMed  Google Scholar 

  75. Worth, A. A. et al. The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling. eLife 9, e55164 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Camilleri, M. Peripheral mechanisms in the control of appetite and related experimental therapies in obesity. Regul. Pept. 156, 24–27 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Borner, T. et al. GDF15 induces anorexia through nausea and emesis. Cell Metab. 31, 351–362.e355 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Endo, T. et al. Neurochemistry and neuropharmacology of emesis - the role of serotonin. Toxicology 153, 189–201 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Herrstedt, J. The latest consensus on antiemetics. Curr. Opin. Oncol. 30, 233–239 (2018).

    Article  PubMed  Google Scholar 

  80. Hayes, M. R. & Covasa, M. Gastric distension enhances CCK-induced Fos-like immunoreactivity in the dorsal hindbrain by activating 5-HT3 receptors. Brain Res. 1088, 120–130 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Borner, T. et al. GDF15 induces an aversive visceral malaise state that drives anorexia and weight loss. Cell Rep. 31, 107543 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Palmiter, R. D. The parabrachial nucleus: CGRP neurons function as a general alarm. Trends Neurosci. 41, 280–293 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Morton, G. J., Meek, T. H. & Schwartz, M. W. Neurobiology of food intake in health and disease. Nat. Rev. Neurosci. 15, 367–378 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Carter, M. E., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chrysovergis, K. et al. NAG-1/GDF-15 prevents obesity by increasing thermogenesis, lipolysis and oxidative metabolism. Int. J. Obes. 38, 1555–1564 (2014).

    Article  CAS  Google Scholar 

  86. Suriben, R. et al. Antibody-mediated inhibition of GDF15–GFRAL activity reverses cancer cachexia in mice. Nat. Med. 26, 1264–1270 (2020).

    Article  PubMed  CAS  Google Scholar 

  87. Beiroa, D. et al. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63, 3346–3358 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Tomas, E. et al. GLP-1(32-36)amide pentapeptide increases basal energy expenditure and inhibits weight gain in obese mice. Diabetes 64, 2409–2419 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Heppner, K. M. et al. Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice. Diabetologia 58, 2124–2132 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Harder, H., Nielsen, L., Tu, D. T. & Astrup, A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes Care 27, 1915–1921 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Müller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Yengo, L. et al. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum. Mol. Genet. 27, 3641–3649 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Pulit, S. L. et al. Meta-analysis of genome-wide association studies for body fat distribution in 694 649 individuals of European ancestry. Hum. Mol. Genet. 28, 166–174 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Võsa, U. et al. Unraveling the polygenic architecture of complex traits using blood eQTL metaanalysis. bioRxiv https://doi.org/10.1101/447367 (2018).

    Article  Google Scholar 

  95. Sun, B. B. et al. Genomic atlas of the human plasma proteome. Nature 558, 73–79 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Lonsdale, J. et al. The genotype-tissue expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

    Article  CAS  Google Scholar 

  97. Machiela, M. J. & Chanock, S. J. LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants. Bioinformatics 31, 3555–3557 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Turcot, V. et al. Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat. Genet. 50, 26–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  99. Li, J. et al. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. eLife 8, e47650 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cheung, C. L., Tan, K. C. B., Au, P. C. M., Li, G. H. Y. & Cheung, B. M. Y. Evaluation of GDF15 as a therapeutic target of cardiometabolic diseases in human: A Mendelian randomization study. EBioMedicine 41, 85–90 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Macia, L. et al. 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 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, X. et al. hNAG-1 increases lifespan by regulating energy metabolism and insulin/IGF-1/mTOR signaling. Aging 6, 690–704 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Wang, X., Chrysovergis, K., Kosak, J. & Eling, T. E. Lower NLRP3 inflammasome activity in NAG-1 transgenic mice is linked to a resistance to obesity and increased insulin sensitivity. Obesity 22, 1256–1263 (2014).

    Article  CAS  PubMed  Google Scholar 

  104. Hong, J. H. et al. GDF15 is a novel biomarker for impaired fasting glucose. Diabetes Metab. J. 38, 472–479 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kempf, T. et al. 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, 671–678 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Carstensen, M. et al. Macrophage inhibitory cytokine-1 is increased in individuals before type 2 diabetes diagnosis but is not an independent predictor of type 2 diabetes: the Whitehall II study. Eur. J. Endocrinol. 162, 913–917 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Schernthaner-Reiter, M. H. et al. GDF15 reflects beta cell function in obese patients independently of the grade of impairment of glucose metabolism. Nutr. Metab. Cardiovasc. Dis. 29, 334–342 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Nakayasu, E. S. et al. Comprehensive proteomics analysis of stressed human islets identifies GDF15 as a target for type 1 diabetes intervention. Cell Metab. 31, 363–374.e6 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Yi, H. S. et al. T-cell senescence contributes to abnormal glucose homeostasis in humans and mice. Cell Death Dis. 10, 249 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Jung, S. B. et al. Reduced oxidative capacity in macrophages results in systemic insulin resistance. Nat. Commun. 9, 1551 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Lee, S. E. et al. Growth differentiation factor 15 mediates systemic glucose regulatory action of T-helper type 2 cytokines. Diabetes 66, 2774–2788 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Foretz, M., Guigas, B. & Viollet, B. Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus. Nat. Rev. Endocrinol. 15, 569–589 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Steinberg, G. R. Cellular energy sensing and metabolism—implications for treating diabetes: the 2017 outstanding scientific achievement award lecture. Diabetes 67, 169–179 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Natali, A. et al. Metformin is the key factor in elevated plasma growth differentiation factor-15 levels in type 2 diabetes: a nested, case-control study. Diabetes Obes. Metab. 21, 412–416 (2019).

    Article  CAS  PubMed  Google Scholar 

  115. Colberg, S. R. et al. Physical activity/exercise and diabetes: a position statement of the American Diabetes Association. Diabetes Care 39, 2065–2079 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kleinert, M. et al. Exercise increases circulating GDF15 in humans. Mol. Metab. 9, 187–191 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tchou, I. et al. Growth-differentiation factor-15, endoglin and N-terminal pro-brain natriuretic peptide induction in athletes participating in an ultramarathon foot race. Biomarkers 14, 418–422 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, H., Fealy, C. E. & Kirwan, J. P. Exercise training promotes a GDF15-associated reduction in fat mass in older adults with obesity. Am. J. Physiol. Endocrinol. Metab. 316, E829–E836 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Laurens, C. et al. Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans. JCI insight 5, e131870 (2020).

    Article  PubMed Central  Google Scholar 

  120. Klein, A. B. et al. Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nat. Commun. 12, 1041 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Yardley, M. et al. Immediate response in markers of inflammation and angiogenesis during exercise: a randomised cross-over study in heart transplant recipients. Open Heart 4, e000635 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. Murphy, R. M., Watt, M. J. & Febbraio, M. A. Metabolic communication during exercise. Nat. Metab. 2, 805–816 (2020).

    Article  PubMed  Google Scholar 

  123. Camacho, R. C., Donahue, E. P., James, F. D., Berglund, E. D. & Wasserman, D. H. Energy state of the liver during short-term and exhaustive exercise in C57BL/6J mice. Am. J. Physiol. Endocrinol. Metab. 290, E405–E408 (2006).

    Article  CAS  PubMed  Google Scholar 

  124. Kim, K. H. et al. Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. Sci. Rep. 8, 6789 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Koo, B. K. et al. Growth differentiation factor 15 predicts advanced fibrosis in biopsy-proven non-alcoholic fatty liver disease. Liver Int. 38, 695–705 (2018).

    Article  CAS  PubMed  Google Scholar 

  126. Chung, H. K. et al. GDF15 deficiency exacerbates chronic alcohol- and carbon tetrachloride-induced liver injury. Sci. Rep. 7, 17238 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Luan, H. H. et al. GDF15 is an inflammation-induced central mediator of tissue tolerance. Cell 178, 1231–1244.e11 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Adela, R. & Banerjee, S. K. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J. Diabetes Res. 2015, 490842 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Xu, J. et al. GDF15/MIC-1 functions as a protective and antihypertrophic factor released from the myocardium in association with SMAD protein activation. Circ. Res. 98, 342–350 (2006).

    Article  CAS  PubMed  Google Scholar 

  130. Kempf, T. et al. The transforming growth factor-beta superfamily member growth-differentiation factor-15 protects the heart from ischemia/reperfusion injury. Circ. Res. 98, 351–360 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Kempf, T. & Wollert, K. C. Growth differentiation factor-15: a new biomarker in cardiovascular disease. Herz 34, 594–599 (2009).

    Article  PubMed  Google Scholar 

  132. Lusis, A. J. Atherosclerosis. Nature 407, 233–241 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Wang, D. et al. Targeting foam cell formation in atherosclerosis: therapeutic potential of natural products. Pharmacol. Rev. 71, 596–670 (2019).

    Article  CAS  PubMed  Google Scholar 

  134. Bentzon, J. F., Otsuka, F., Virmani, R. & Falk, E. Mechanisms of plaque formation and rupture. Circ. Res. 114, 1852–1866 (2014).

    Article  CAS  PubMed  Google Scholar 

  135. Bonaterra, G. A. et al. Growth differentiation factor-15 deficiency inhibits atherosclerosis progression by regulating interleukin-6-dependent inflammatory response to vascular injury. J. Am. Heart Assoc. 1, e002550 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. de Jager, S. C. et al. Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. J. Exp. Med. 208, 217–225 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Preusch, M. R. et al. GDF-15 protects from macrophage accumulation in a mousemodel of advanced atherosclerosis. Eur. J. Med. Res. 18, 19 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Johnen, H. et al. Increased expression of the TGF-b superfamily cytokine MIC-1/GDF15 protects ApoE(-/-) mice from the development of atherosclerosis. Cardiovasc. Pathol. 21, 499–505 (2012).

    Article  CAS  PubMed  Google Scholar 

  139. Tian, X. Y. et al. Thermoneutral housing accelerates metabolic inflammation to potentiate atherosclerosis but not insulin resistance. Cell Metab. 23, 165–178 (2016).

    Article  CAS  PubMed  Google Scholar 

  140. Skop, V. et al. Mouse thermoregulation: introducing the concept of the thermoneutral point. Cell Rep. 31, 107501 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Silvestre-Roig, C., Braster, Q., Ortega-Gomez, A. & Soehnlein, O. Neutrophils as regulators of cardiovascular inflammation. Nat. Rev. Cardiol. 17, 327–340 (2020).

    Article  PubMed  Google Scholar 

  142. Thygesen, K. et al. Third universal definition of myocardial infarction. Nat. Rev. Cardiol. 9, 620–633 (2012).

    Article  PubMed  Google Scholar 

  143. Saver, J. L. Proposal for a universal definition of cerebral infarction. Stroke 39, 3110–3115 (2008).

    Article  PubMed  Google Scholar 

  144. Kempf, T. et al. GDF-15 is an inhibitor of leukocyte integrin activation required for survival after myocardial infarction in mice. Nat. Med. 17, 581–588 (2011).

    Article  CAS  PubMed  Google Scholar 

  145. Zhang, Y. et al. Over-expression of growth differentiation factor 15 (GDF15) preventing cold ischemia reperfusion (I/R) injury in heart transplantation through Foxo3a signaling. Oncotarget 8, 36531–36544 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Rossaint, J., Vestweber, D. & Zarbock, A. GDF-15 prevents platelet integrin activation and thrombus formation. J. Thromb. Haemost. 11, 335–344 (2013).

    Article  CAS  PubMed  Google Scholar 

  147. Sen-Chowdhry, S., Jacoby, D., Moon, J. C. & McKenna, W. J. Update on hypertrophic cardiomyopathy and a guide to the guidelines. Nat. Rev. Cardiol. 13, 651–675 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Xu, X. Y. et al. Growth differentiation factor (GDF)-15 blocks norepinephrine-induced myocardial hypertrophy via a novel pathway involving inhibition of epidermal growth factor receptor transactivation. J. Biol. Chem. 289, 10084–10094 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Tisdale, M. J. Molecular pathways leading to cancer cachexia. Physiology 20, 340–348 (2005).

    Article  CAS  PubMed  Google Scholar 

  150. Lerner, L. et al. MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J. Cachexia, Sarcopenia Muscle 7, 467–482 (2016).

    Article  Google Scholar 

  151. Breen, D. M. et al. GDF-15 neutralization alleviates platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and nonhuman primates. Cell Metab. 32, 938–950.e6 (2020).

    Article  CAS  PubMed  Google Scholar 

  152. Tran, T., Yang, J., Gardner, J. & Xiong, Y. GDF15 deficiency promotes high fat diet-induced obesity in mice. PLoS One 13, e0201584 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

G.R.S. acknowledges the support of a Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Canadian Institutes of Health Research Foundation Grant (201709FDN-CEBA-116200), a Tier 1 Canada Research Chair in Metabolic Diseases and a J. Bruce Duncan Endowed Chair in Metabolic Diseases. L.K.T. acknowledges the support of a CIHR Post-Doctoral Fellowship Award and Michael DeGroote Fellowship Award in Basic Biomedical Science.

Author information

Authors and Affiliations

  1. Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada

    Dongdong Wang, Emily A. Day, Logan K. Townsend & Gregory R. Steinberg

  2. Global Obesity and Liver Disease Research, Novo Nordisk A/S, Maaloev, Denmark

    Djordje Djordjevic & Sebastian Beck Jørgensen

Authors
  1. Dongdong Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily A. Day
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Logan K. Townsend
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Djordje Djordjevic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sebastian Beck Jørgensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gregory R. Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.W. researched data for the article. All authors made substantial contributions to the discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Gregory R. Steinberg.

Ethics declarations

Competing interests

D.D. and S.B.J. are employees of Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. G.R.S. is a co-founder and shareholder of Espervita Therapeutics, a company developing new medications for liver cancer. McMaster University has received funding from Espervita Therapeutics, Esperion Therapeutics, Poxel Pharmaceuticals and Novo Nordisk for research conducted in the laboratory of G.R.S. G.R.S. has received consulting/speaking fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Merck, Poxel Pharmaceuticals and Takeda. The other authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Endocrinology thanks S. Breit, S. O’Rahilly and M. Shong for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Common Metabolic Diseases Knowledge Portal: https://t2d.hugeamp.org/region.html?chr=19&end=18549986&phenotype=WHRadjBMI&start=18435541

The Blood Atlas: https://www.proteinatlas.org/humanproteome/blood

the Human Protein Atlas GFRAL expression: https://www.proteinatlas.org/ENSG00000187871-GFRAL/blood

Glossary

Non-alcoholic fatty liver disease

(NAFLD). A spectrum of liver pathology ranging from liver steatosis (>5% lipids) to inflammation and fibrosis, known as non-alcoholic steatohepatitis, that is an important risk factor for type 2 diabetes mellitus, cardiovascular disease, liver cirrhosis and hepatocellular carcinoma.

Integrated stress response

A eukaryotic cellular stress response to restore cellular homeostasis by phosphorylation of eIF2 by four specialized kinases (PERK, GCN2, PKR and HRI), leading to a decrease in global protein synthesis and an increase in the expression of specific genes, including ATF4.

Mitochondrial unfolded protein response

(UPR). This cellular stress response is triggered when unfolded or misfolded proteins accumulate in mitochondria beyond the protective capacity of chaperone proteins.

Cancer cachexia

This state is characterized by reductions in appetite and increases in energy expenditure, which leads to involuntary loss of adipose and lean mass that is associated with poor quality of life and reduced survival.

Foam cells

Macrophages or vascular smooth muscle cells with a foamy appearance, which are over-laden with lipids and are a key cell type contributing to the development of atherosclerotic cardiovascular disease (coronary artery disease).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, D., Day, E.A., Townsend, L.K. et al. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol 17, 592–607 (2021). https://doi.org/10.1038/s41574-021-00529-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-021-00529-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing