Growth Differentiation Factor 15 Increases in Both Cerebrospinal Fluid and Serum During Pregnancy

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2021 May 27

PMID 34043633

Citations 11

Authors

Ulrika Andersson-Hall

Pernilla Svedin

Carina Mallard

Kaj Blennow

Henrik Zetterberg

Agneta Holmang

Affiliations

Soon will be listed here.

Abstract

Aim: Growth differentiation factor 15 (GDF15) increases in serum during pregnancy to levels not seen in any other physiological state and is suggested to be involved in pregnancy-induced nausea, weight regulation and glucose metabolism. The main action of GDF15 is regulated through a receptor of the brainstem, i.e., through exposure of GDF15 in both blood and cerebrospinal fluid (CSF). The aim of the current study was to measure GDF15 in both CSF and serum during pregnancy, and to compare it longitudinally to non-pregnant levels.

Methods: Women were sampled at elective caesarean section (n = 45, BMI = 28.1±5.0) and were followed up 5 years after pregnancy (n = 25). GDF15, insulin and leptin were measured in CSF and serum. Additional measurements included plasma glucose, and serum adiponectin and Hs-CRP.

Results: GDF15 levels were higher during pregnancy compared with follow-up in both CSF (385±128 vs. 115±32 ng/l, P<0.001) and serum (73789±29198 vs. 404±102 ng/l, P<0.001). CSF levels correlated with serum levels during pregnancy (P<0.001), but not in the non-pregnant state (P = 0.98). Both CSF and serum GDF15 were highest in women carrying a female fetus (P<0.001). Serum GDF15 correlated with the homeostatic model assessment for beta-cell function and placental weight, and CSF GDF15 correlated inversely with CSF insulin levels.

Conclusion: This, the first study to measure CSF GDF15 during pregnancy, demonstrated increased GDF15 levels in both serum and CSF during pregnancy. The results suggest that effects of GDF15 during pregnancy can be mediated by increases in both CSF and serum levels.

Citing Articles

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Global Transcriptomic Analysis of Placentas from Women with Gestational SARS-CoV-2 Infection during the Third Trimester of Pregnancy.

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GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

Fejzo M, Rocha N, Cimino I, Lockhart S, Petry C, Kay R Nature. 2023; 625(7996):760-767.

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Gong Y, Shi J, Li J, Liu L Exp Ther Med. 2023; 26(3):427.

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References

Khant Aung Z, Grattan D, Ladyman S . Pregnancy-induced adaptation of central sensitivity to leptin and insulin. Mol Cell Endocrinol. 2020; 516:110933. DOI: 10.1016/j.mce.2020.110933. View

Klein A, Nicolaisen T, Ortenblad N, Gejl K, Jensen R, Fritzen A . Pharmacological but not physiological GDF15 suppresses feeding and the motivation to exercise. Nat Commun. 2021; 12(1):1041. PMC: 7884842. DOI: 10.1038/s41467-021-21309-x. View

Nakayasu E, Syed F, Tersey S, Gritsenko M, Mitchell H, Chan C . Comprehensive Proteomics Analysis of Stressed Human Islets Identifies GDF15 as a Target for Type 1 Diabetes Intervention. Cell Metab. 2020; 31(2):363-374.e6. PMC: 7319177. DOI: 10.1016/j.cmet.2019.12.005. View

Emmerson P, Wang F, Du Y, Liu Q, Pickard R, Gonciarz M . The metabolic effects of GDF15 are mediated by the orphan receptor GFRAL. Nat Med. 2017; 23(10):1215-1219. DOI: 10.1038/nm.4393. View

Worth A, Shoop R, Tye K, Feetham C, DAgostino G, Dodd G . The cytokine GDF15 signals through a population of brainstem cholecystokinin neurons to mediate anorectic signalling. Elife. 2020; 9. PMC: 7410488. DOI: 10.7554/eLife.55164. View

Miller A, Leslie R . The area postrema and vomiting. Front Neuroendocrinol. 1994; 15(4):301-20. DOI: 10.1006/frne.1994.1012. View

Fejzo M, Fasching P, Schneider M, Schwitulla J, Beckmann M, Schwenke E . Analysis of GDF15 and IGFBP7 in Hyperemesis Gravidarum Support Causality. Geburtshilfe Frauenheilkd. 2019; 79(4):382-388. PMC: 6461465. DOI: 10.1055/a-0830-1346. View

Shnaper S, Desbaillets I, Brown D, Murat A, Migliavacca E, Schluep M . Elevated levels of MIC-1/GDF15 in the cerebrospinal fluid of patients are associated with glioblastoma and worse outcome. Int J Cancer. 2009; 125(11):2624-30. DOI: 10.1002/ijc.24639. View

Day E, Ford R, Smith B, Mohammadi-Shemirani P, Morrow M, Gutgesell R . Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss. Nat Metab. 2020; 1(12):1202-1208. DOI: 10.1038/s42255-019-0146-4. View

10.

Andersson-Hall U, Svedin P, Svensson H, Lonn M, Mallard C, Holmang A . Longitudinal changes in adipokines and free leptin index during and after pregnancy in women with obesity. Int J Obes (Lond). 2019; 44(3):675-683. DOI: 10.1038/s41366-019-0452-7. View

11.

Rashid M, Rashid M, Malik F, Herath R . Hyperemesis gravidarum and fetal gender: a retrospective study. J Obstet Gynaecol. 2012; 32(5):475-8. DOI: 10.3109/01443615.2012.666580. View

12.

Maetzler W, Deleersnijder W, Hanssens V, Bernard A, Brockmann K, Marquetand J . GDF15/MIC1 and MMP9 Cerebrospinal Fluid Levels in Parkinson's Disease and Lewy Body Dementia. PLoS One. 2016; 11(3):e0149349. PMC: 4777571. DOI: 10.1371/journal.pone.0149349. View

13.

Kampmann U, Knorr S, Fuglsang J, Ovesen P . Determinants of Maternal Insulin Resistance during Pregnancy: An Updated Overview. J Diabetes Res. 2019; 2019:5320156. PMC: 6885766. DOI: 10.1155/2019/5320156. View

14.

Schiff M, Reed S, Daling J . The sex ratio of pregnancies complicated by hospitalisation for hyperemesis gravidarum. BJOG. 2003; 111(1):27-30. DOI: 10.1046/j.1471-0528.2003.00005.x. View

15.

Rosenfeld C . Sex-Specific Placental Responses in Fetal Development. Endocrinology. 2015; 156(10):3422-34. PMC: 4588817. DOI: 10.1210/en.2015-1227. View

16.

Kosa P, Wu T, Phillips J, Leinonen M, Masvekar R, Komori M . Idebenone does not inhibit disability progression in primary progressive MS. Mult Scler Relat Disord. 2020; 45:102434. PMC: 9386688. DOI: 10.1016/j.msard.2020.102434. View

17.

Moore A, Brown D, Fairlie W, Bauskin A, Brown P, Munier M . The transforming growth factor-ss superfamily cytokine macrophage inhibitory cytokine-1 is present in high concentrations in the serum of pregnant women. J Clin Endocrinol Metab. 2001; 85(12):4781-8. DOI: 10.1210/jcem.85.12.7007. View

18.

Strelau J, Sullivan A, Bottner M, Lingor P, Falkenstein E, Suter-Crazzolara C . Growth/differentiation factor-15/macrophage inhibitory cytokine-1 is a novel trophic factor for midbrain dopaminergic neurons in vivo. J Neurosci. 2000; 20(23):8597-603. PMC: 6773071. View

19.

Tang M, Luo M, Lu W, Wang S, Zhang R, Liang W . Serum growth differentiation factor 15 is associated with glucose metabolism in the third trimester in Chinese pregnant women. Diabetes Res Clin Pract. 2019; 156:107823. DOI: 10.1016/j.diabres.2019.107823. View

20.

Wischhusen J, Melero I, Fridman W . Growth/Differentiation Factor-15 (GDF-15): From Biomarker to Novel Targetable Immune Checkpoint. Front Immunol. 2020; 11:951. PMC: 7248355. DOI: 10.3389/fimmu.2020.00951. View