Effects of obesity and gestational diabetes mellitus on placental phospholipids

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Highlights

Abstract

Gestational diabetes mellitus (GDM) is associated with adverse effects in the offspring. The composition of placental glycerophospholipids (GPL) is known to be altered in GDM and might reflect an aberrant fatty acid transfer across the placenta and thus affect the foetal body composition. The aim of this study was to investigate possible effects of obesity and GDM, respectively, on placental GPL species composition.

We investigated molecular species of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS) in term placentas from controls (lean non-diabetic, body-mass-index [BMI] 18–24.9 kg/m2, n = 31), obese non-diabetics (BMI ≥30 kg/m2, n = 17) and lean diabetics (n = 15), using liquid chromatography – triple quadrupole mass spectrometry.

PE(16:0/22:6) and PE(18:0/20:4) were increased in GDM and decreased species were PC(18:0/20:3), PC(18:1/20:3) and PS(18:0/18:2). A consistent difference between BMI related changes and changes caused by GDM was not observed. Arachidonic acid percentages of cord blood correlated with placental PC(16:0/20:4), whereas foetal docosahexaenoic acid correlated to placental PE species. Furthermore, a positive correlation of placental weight was found to levels of PE containing arachidonic acid.

We demonstrated that obesity and GDM are associated with decreased dihomo-gamma-linolenic acid and increased arachidonic acid and docosahexaenoic acid contents of placental GPL, with unknown consequences for the foetus. PC(16:0/20:4) was identified as the major component for the supply of arachidonic acid to the foetal circulation, whereas PE containing arachidonic acid was found to be associated to the placental and infant growth.

Introduction

Disturbance in normal foetal growth and development induced by gestational diabetes mellitus (GDM) is associated with long-term adverse effects in the offspring, such as later adiposity and type-2 diabetes [1], [2]. GDM is associated with increased foetal weight and the risk for later metabolic and cardiovascular diseases [3], [4]. The metabolic state of pregnant women plays a crucial role in the development of adiposity in the offspring [2]. Altered maternal metabolism, as maternal hyperglycemia, may affect placental metabolism and lead as consequence to an aberrant foetal metabolism [5]. Increased foetal weight is observed in diabetic pregnancies without and with satisfactory glycemic control [6]. Placental transfer of other substrates than glucose, i.e. amino acids and lipids, have been found altered in GDM [7], [8], which may contribute to enhanced foetal weight.

Due to low activities of Δ-5 and Δ-6 desaturases in the placental tissue [8], [9] and limited foetal synthesis [10], foetal needs for long chain polyunsaturated fatty acids (LC-PUFA) must be covered by transfer from the mother. In normal pregnancies there are preferential transfers of docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) from the mother to the foetus [9], as apparent from the observed higher percentages of DHA and AA in foetal plasma phospholipids compared to maternal plasma phospholipids [11], [12]. DHA and AA are required to cover foetal needs for brain tissue incorporation and optimal neurological development. Besides AA and DHA, the LC-PUFA dihomo-gamma-linolenic acid (DGLA, 20:3n-6), which is derived by Δ-6 desaturation and elongation of linoleic acid, has been related to long-term consequences in the offspring [13].

In GDM pregnancies, foetal plasma and red blood cells show an altered lipid pattern compared to controls, with reduced AA and DHA levels [14]. Elevated levels of DHA and AA in placental phospholipids were reported in GDM compared to controls, which leads to the conclusion of an impaired LC-PUFA transport to the foetus [15]. A series of proteins involved in the lipid transfer across the placenta has been described, but their contribution to changes in the placental lipid profile in GDM is uncertain. Fatty acid binding proteins (FABP) are involved in intracellular trafficking of fatty acids [16]. Fatty acid transport proteins (FATP) 1 and 4 were positively correlated to placental DHA uptake and may be important for selective maternal-foetal transfer of DHA [17].

Maternal obesity was shown to modify placental FATP independent of the presence of GDM [18]. Placental mRNA and protein expression of CD36 were increased while FABP1 mRNA and FABP3 protein expression were decreased in GDM [18]. Different availability of carrier proteins and enzymes related to placental fatty acid metabolism may affect placental lipid composition, and thus reflect adaptations of the placenta in response to GDM or obesity.

Considering that placental phospholipids play an important role in maternal transfer of fatty acids to the foetus we investigated possible effects of obesity and GDM, respectively, on placental glycerophospholipid (GPL) species composition.

Section snippets

Subjects and samples collection

Samples were obtained from the participants of the observational PREOBE study [19], which enrolled pregnant women during week 12–20 of gestation at the University of Granada (Spain). Exclusion criteria were participation in another study, drug treatment, other accompanying disorders such as hypertension, pre-eclampsia, foetal IUGR, infection during pregnancy, hypo- or hyperthyroidism, hepatic renal diseases, or supplementation with DHA or folate for more than the first 3 months of pregnancy. To

Results

Samples from placentas of 63 women were analyzed for GPL species. Thirty-one subjects were classified as controls (lean, non-diabetic), 17 women were obese and 15 samples were obtained from lean women with GDM (Table 1). Extracted lipids were analyzed for a total of 157 phospholipid species. The limit of quantification was used as criteria for inclusion of molecular species into statistical analyses. The metabolites were discarded in all subjects, if the concentration in more than 6 subjects

Discussion

GDM is one of the most frequent complications during pregnancy. GDM usually resolves after birth, with glucose metabolism returning to normal conditions. Obesity is one of the known risk factors, however GDM can also appear without any known risk factors. Thus, it is suggested that more than one factor may trigger GDM. A common characteristic of all GDM cases is disturbed glucose metabolism and the majority of women have ß cell dysfunction as a result of insulin resistance. A linear

Conclusions

In conclusion, an increased BMI and GDM are associated with decreased DGLA and subtle increased AA and DHA contents of placental GPL. This agrees with the hypothesis that GDM leads to a change in the placental transfer of fatty acids with unknown consequences for the foetus. The identification at which point of pregnancy alterations take place will be very important for predicting the consequences of aberrant fatty acid transfer for the offspring late in life. A species specific relation of

Conflict of interest statement

Ricardo Rueda work for Abbott Laboratories. Other authors declared to have no conflict of interests.

Acknowledgments

The work reported here was carried out with partial financial support from Abbott Laboratories, contract Project PREOBE Follow up, the Andalucian Ministry of Innovation, Technology and Science. Excellence Research Project. Ref. n°: P06-CTS-02341, the Commission of the European Communities, the 7th Framework Programme, contract FP7-289346-EARLY NUTRITION, the European Research Council Advanced Grant ERC-2012-AdG–no.322605 META-GROWTH. This manuscript does not necessarily reflect the views of the

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