Growth differentiation factor 15 increases in both cerebrospinal fluid and serum during pregnancy.

Ulrika Andersson-Hall,Pernilla Svedin,Agneta Holmäng,Kaj Blennow,Carina Mallard,Henrik Zetterberg,Clive J Petry

doi:10.1371/journal.pone.0248980

Abstract

AimGrowth 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.MethodsWomen 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.ResultsGDF15 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.ConclusionThis, 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.

Highlights

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta family, was first shown to be involved in inflammation and stress pathways but has emerged as a potentially important metabolic regulator [1,2,3]
Serum GDF15 correlated with the homeostatic model assessment for beta-cell function and placental weight, and cerebrospinal fluid (CSF) GDF15 correlated inversely with CSF insulin levels
The GDF15 measurements were supported by the Emil and Wera Cornell Foundation, the Swedish Research Council (VR-2017-01409), Åhlen Foundation, the Swedish state under the agreement between the Swedish government and the country councils, the ALF-agreement (ALFGBG-722491) and Swedish Brain Foundation (FO2019-0270)

Summary

Introduction

Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta family, was first shown to be involved in inflammation and stress pathways but has emerged as a potentially important metabolic regulator [1,2,3]. GDF15 has been shown for example to induce weight loss (probably through appetite suppression and decreased food intake), affect energy expenditure and motivation to exercise, and improve glucose tolerance [4,5,6,7,8,9]. Pregnancy is marked by major metabolic and physiological changes, such as increases in appetite, body weight, insulin resistance and inflammation [13, 14]. GDF15 may play an important role in all these areas and has been found during pregnancy to be linked to altered glucose metabolism [12, 15], and pregnancy-induced nausea [16,17,18]. AP has a highly permeable blood brain barrier (BBB) compared to other brain regions, and can receive signals both from the blood and CSF, whereas NTS is separated from AP with a more solid BBB [24]

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