GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement

Audrey Melvin, Dimitrios Chantzichristos, Catriona J Kyle, Scott D Mackenzie, Brian R Walker, Gudmundur Johannsson, Roland H Stimson, Stephen O'Rahilly, Audrey Melvin, Dimitrios Chantzichristos, Catriona J Kyle, Scott D Mackenzie, Brian R Walker, Gudmundur Johannsson, Roland H Stimson, Stephen O'Rahilly

Abstract

Context: GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15.

Objective: To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels.

Methods and results: We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison's disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison's cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison's disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001.

Conclusions: GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.

Keywords: GDF15; adrenal insufficiency; glucocorticoids.

© Endocrine Society 2019.

Figures

Figure 1.
Figure 1.
Circulating GDF15 is increased in primary adrenal insufficiency. (A) Early morning serum cortisol levels are significantly lower in 10 patients with Addison’s disease (AD) following withdrawal of maintenance glucocorticoid therapy when compared to a cohort of healthy matched control participants (n = 10). (B) Serum GDF15 measured in parallel with cortisol sampling was significantly higher within the steroid deficient Addison’s disease cohort than in the control group. Data presented as mean ± standard deviation and compared using an unpaired t-test. *P < .05 and ****P < .0001.
Figure 2.
Figure 2.
Hydrocortisone replacement reduces GDF15 in primary adrenal insufficiency. (A) Ten adult volunteers with Addison’s disease who had glucocorticoid therapy withdrawn demonstrated significantly lower GDF15 levels following a 22-h intravenous infusion of hydrocortisone (red circles) compared to the equivalent infusion of normal saline (black circles). (B) GDF15 levels reduced significantly from baseline measurements following infusion of hydrocortisone in 8 participants with Addison’s disease following withdrawal of glucocorticoid therapy. (C) Among 9 participants with CAH whose glucocorticoid therapy was withdrawn, baseline GDF15 levels did not differ significantly between placebo (black circles) and hydrocortisone (black squares) visits. GDF15 levels were significantly lower in participants (n = 8) who received the hydrocortisone infusion (red squares) when compared to those receiving placebo (red circles). Data expressed as mean ± standard deviation and compared using a paired t-test, *P < .05 and **P < .01.
Figure 3.
Figure 3.
Dose effect of hydrocortisone replacement on circulating GDF15. Serum GDF15 was measured in n = 20 healthy male volunteers with metyrapone inhibited endogenous cortisol synthesis who received low, medium, and high dose hydrocortisone replacement on three separate occasions. Exposure to increasing doses of hydrocortisone was associated with significantly lower GDF15 levels. Data expressed as mean ± standard deviation and compared using a one-way analysis of variance and post-hoc Tukey test, **P < .01, ***P < .001, ****P < .0001.

References

    1. Bootcov MR, Bauskin AR, Valenzuela SM, et al. . MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF- superfamily. Proceedings of the National Academy of Sciences. 1997;94(21):11514–11519. doi:10.1073/pnas.94.21.11514.
    1. GTex Portal. . Accessed November 17, 2019.
    1. Tsai VW, Husaini Y, Sainsbury A, Brown DA, Breit SN. The MIC-1/GDF15-GFRAL pathway in energy homeostasis: implications for obesity, cachexia, and other associated diseases. Cell Metab. 2018;28(3):353–368. doi:10.1016/j.cmet.2018.07.018.
    1. Patel S, Alvarez-Guaita A, Melvin A, et al. . GDF15 provides an endocrine signal of nutritional stress in mice and humans. Cell Metab. 2019;29(3):707–718.e8. doi:10.1016/j.cmet.2018.12.016.
    1. Yang H, Park SH, Choi HJ, Moon Y. The integrated stress response-associated signals modulates intestinal tumor cell growth by NSAID-activated gene 1 (NAG-1/MIC-1/PTGF-β). Carcinogenesis. 2010;31(4):703–711. doi:10.1093/carcin/bgq008.
    1. Chung HK, Ryu D, Kim KS, et al. . Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J Cell Biol. 2016;216(1):149–165. doi:10.1083/jcb.201607110.
    1. Johnen H, Lin S, Kuffner T, et al. . Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1. Nat Med. 2007;13(11):1333–1340. doi:10.1038/nm1677.
    1. Tsai VW, Macia L, Johnen H, et al. . TGF-b superfamily cytokine MIC-1/GDF15 is a physiological appetite and body weight regulator. PLoS ONE. 2013;8(2):e55174. doi:10.1371/journal.pone.0055174.
    1. Tsai VW, Manandhar R, Jørgensen SB, et al. . 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(6):e100370. doi:10.1371/journal.pone.0100370.
    1. Emmerson PJ, Wang F, Du Y, et al. . The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017;23(10):1215–1219. doi:10.1038/nm.4393.
    1. Hsu J, Crawley S, Chen M, et al. . Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature. 2017;550(7675):255–259. doi:10.1038/nature24042
    1. Mullican SE, Lin-Schmidt X, Chin C, et al. . GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Nat Med. 2017;23(10):1150–1157. doi:10.1038/nm.4392.
    1. Yang L, Chang C, Sun Z, et al. . GFRAL is the receptor for GDF15 and is required for the anti-obesity effects of the ligand. Nat Med. 2017;23(10):1158–1166. doi:10.1038/nm.4394.
    1. Lu Z, Yang L, Yu J, et al. . 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 P. 2014;15(15):6047–6052. doi:10.7314/apjcp.2014.15.15.6047.
    1. Lerner L, Hayes TG, Tao N, et al. . Plasma growth differentiation factor 15 is associated with weight loss and mortality in cancer patients. J Cachexia Sarcopenia Muscle. 2015;6(4):317–324. doi:10.1002/jcsm.12033.
    1. Lerner L, Tao J, Liu Q, et al. . MAP3K11/GDF15 axis is a critical driver of cancer cachexia. J Cachexia Sarcopenia Muscle. 2015;7(4):467–482. doi:10.1002/jcsm.12077.
    1. Kempf T, von Haehling S, Peter T, et al. . Prognostic utility of growth differentiation factor-15 in patients with chronic heart failure. J Am Coll Cardiol. 2007;50(11):1054–1060. doi:10.1016/j.jacc.2007.04.091.
    1. Breit SN, Carrero JJ, Tsai VW, et al. . Macrophage inhibitory cytokine-1 (MIC-1/GDF15) and mortality in end-stage renal disease. Nephrol Dial Transpl. 2011;27(1):70–75. doi:10.1093/ndt/gfr575.
    1. You AS, Kalantar-Zadeh K, Lerner L, et al. . Association of growth differentiation factor 15 with mortality in a prospective hemodialysis cohort. Cardiorenal Med. 2017;7(2):158–168. doi:10.1159/000455907.
    1. Breit SN, Tsai VW, Brown DA. Targeting obesity and cachexia: identification of the GFRAL Receptor–MIC-1/GDF15 pathway. Trends Mol Med. 2017;23(12):1065–1067. doi:10.1016/j.molmed.2017.10.005.
    1. O’rahilly S. GDF15—From Biomarker to Allostatic Hormone. Cell Metab. 2017;26(6):807–808. doi:10.1016/j.cmet.2017.10.017.
    1. Fejzo MS, Sazonova OV, Sathirapongsasuti JF, et al. . Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum. Nat Commun. 2018;9(1). doi:10.1038/s41467-018-03258-0.
    1. Petry CJ, Ong KK, Burling KA, 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 2018;3:123. doi:10.12688/wellcomeopenres.14818.1.
    1. Borner T, Shaulson ED, Stein LM, Fortin SM, Hayes MR, De Jonge BC. GDF15 induced anorexia in rats and shrews is driven by malaise. Program of the 27th Annual Meeting of the Society for the Study of Ingestive Behavior Utrecht, Netherlands, July 2019. (Abstract P29).
    1. Bornstein SR, Allolio B, Arlt W, et al. . Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(2):364–389. doi:10.1210/jc.2015-1710.
    1. Munck A, Guyre P, Holbrook N. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984;5(1):25–44. doi:10.1210/edrv-5-1-25.
    1. Sapolsky R, Romero L, Munck A. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21(1):55–89. doi:10.1210/edrv.21.1.0389.
    1. Fuller P, Young M. Mechanisms of mineralocorticoid action. Hypertension. 2005;46(6):1227–1235. doi:10.1161/01.hyp.0000193502.77417.17.
    1. Erichsen MM, LøvåS K, Skinningsrud B, et al. . Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a norwegian registry. J Clin Endocrinol Metab. 2009;94(12):4882–4890. doi:10.1210/jc.2009-1368.
    1. Feeney C, Buell KA. Case of Addison’s disease nearly mistaken for anorexia nervosa. Am J Med. 2018;131(11):e457–e458. doi:10.1016/j.amjmed.2018.06.027.
    1. Mandadi S, Sattar S, Towfiq B, Bachuwa G. A case of nausea and vomiting to remember. Case Reports. 2015;2015:bcr2014207251. doi:10.1136/bcr-2014-207251.
    1. Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab. 1993;76(6):1505–1510. doi:10.1210/jcem.76.6.8501158.
    1. Nixon M, Mackenzie SD, Taylor AI. ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: a rationale for safer glucocorticoid replacement therapy. Sci Transl Med. 2016;8(352):352ra109–352ra109. doi:10.1126/scitranslmed.aaf9074.
    1. Stimson RH, Anderson AJ, Ramage LE, et al. . Acute physiological effects of glucocorticoids on fuel metabolism in humans are permissive but not direct. Diabetes Obes Metab. 2017;19(6):883–891. doi:10.1111/dom.12899.
    1. Engel K, Yamamoto K. The glucocorticoid receptor and the coregulator BRM selectively modulate each other’s occupancy and activity in a gene-specific manner. Mol Cell Biol. 2011;31(16):3267–3276. doi:10.1128/mcb.05351-11.
    1. Varadarajan S, Breda C, Smalley JL, et al. . The transrepression arm of glucocorticoid receptor signaling is protective in mutant huntingtin-mediated neurodegeneration. Cell Death Differ. 2015;22(8):1388–1396. doi:10.1038/cdd.2015.1.
    1. Chu C, Hsing C, Shieh J, Chien C, Ho C, Wang J. The cellular mechanisms of the antiemetic action of dexamethasone and related glucocorticoids against vomiting. Eur J Pharmacol. 2014;722:48–54. doi:10.1016/j.ejphar.2013.10.008.
    1. Kis E, Szatmári T, Keszei M, et al. . Microarray analysis of radiation response genes in primary human fibroblasts. Int J Radiat Oncol Biol Phys. 2006;66(5):1506–1514. doi:10.1016/j.ijrobp.2006.08.004.
    1. Tsai VW, Macia L, Feinle-Bisset C, 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. 2015;10(7):e0133362. doi:10.1371/journal.pone.0133362.
    1. Dallman MF, La Fleur SE, Pecoraro NC, Gomez F, Houshyar H, Akana SF. Minireview: glucocorticoids—food intake, abdominal obesity, and wealthy nations in 2004. Endocrinology. 2004;145(6):2633–2638. doi:10.1210/en.2004-0037.
    1. Andrioli M, Giraldi FP, Cavagnini F. Isolated corticotrophin deficiency. Pituitary. 2006;9(4):289–295. doi:10.1007/s11102-006-0408-5.
    1. Bensing S, Hulting A, Husebye ES, Kämpe O, Løvås K. Management of endocrine disease: Epidemiology, quality of life and complications of primary adrenal insufficiency: a review. Eur J Endocrinol. 2016;175(3):R107–R116. doi:10.1530/eje-15-1242.
    1. Murray RD, Ekman B, Uddin S, Marelli C, Quinkler M, Zelissen PM; the EU-AIR investigators Management of glucocorticoid replacement in adrenal insufficiency shows notable heterogeneity: data from the EU-AIR. Clin Endocrinol. 2016;86(3):340–346. doi:10.1111/cen.13267.
    1. Esposito D, Pasquali D, Johannsson G. Primary adrenal insufficiency: managing mineralocorticoid replacement therapy. J Clin Endocrinol Metab. 2017;103(2):376–387. doi:10.1210/jc.2017-01928.
    1. Øksnes M, Ross R, Løvås K. Optimal glucocorticoid replacement in adrenal insufficiency. Best Pract Res Clin Endocrinol Metab. 2015;29(1):3–15. doi:10.1016/j.beem.2014.09.009.
    1. Melvin A, Chantzichristos D, Kyle CJ, et al. . Supplementary data: GDF15 is elevated in conditions of glucocorticoid deficiency and is modulated by glucocorticoid replacement. Cambridge Research Repository; 10.17863/CAM.46534. Deposited November 2019.

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