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Selected Publication:
Hirschmugl, B.
Maternal-to-fetal transfer of fatty acids across the human placenta
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp. 105
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- Authors Med Uni Graz:
- Advisor:
- Desoye Gernot
- Wadsack Christian
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- Abstract:
- Infant and childhood obesity is known to be a risk factor for obesity and related diseases later in life. Obese women are prone to deliver more likely infants with elevated adipose tissue mass. The underlying mechanisms and the functional role of the placenta during late pregnancy are not well understood yet. The main objective of this thesis was to investigate whether maternal pre-pregnancy obesity impacts fatty acid (FA) transfer across the human placenta and to understand the distribution of exogenously provided FAs between placental and fetal compartment. This study aimed also to examine the effect of maternal pre-pregnancy obesity on placental genes and proteins, which are involved in lipid and FA uptake, metabolism, and transport. Maternal-to-fetal free FA (FFA) transfer was examined in placentas of lean (pre-pregnancy body mass index (BMI) =25 kg/m²) and obese women (BMI =30 kg/m²) by ex-vivo perfusion approach. 13C-labelled FFAs bound to albumin were offered to the maternal compartment and transfer of 13C FFAs to the fetal compartment was followed by gas chromatography (GC) – mass spectrometry. Distribution of FAs to different lipid classes of maternal and fetal perfusates was measured by thin-layer chromatography and GC. Target specific gene expression, determined by nCounter technology, as well as protein expression and localization were performed in placental tissue of lean and obese women. Results from perfusion experiments showed that transferred palmitic, oleic, and linoleic acid are mainly restored in phospholipids (PL) and as FFAs in fetal perfusates. Minor amounts of palmitic acid were also detectable in cholesterol esters and triglycerides (TG). Maternal-to-fetal transfer of palmitic, oleic, and linoleic acid is slightly higher in obese compared to lean placentas. In placentas of obese women the transfer of docosahexaenoic acid (DHA) is significantly (P=0.040) elevated by 44% compared to lean placentas. By stratifying the cohort according to fetal sex, comparable absolute transfer of all FFAs was observed in obese male and lean female placentas. Again, DHA transfer was significantly (P<0.05) increased in obese compared to lean female placentas. Maternal-to-fetal DHA transfer correlated positively (R=0.697; P<0.003) with maternally offered DHA concentrations, independently of maternal BMI. Additionally, endogenously stored FAs were mobilized from intracellular lipid pools and were released to the fetal compartment, which was 1.7 to 58.6-fold higher than direct FFA transfer. In this study 73 placental target genes were examined and six showed positive correlation (P<0.05) with maternal BMI, which were ATGL, FATP1, FATP3, PLIN2, PPARG and CGI-58. CGI-58 protein level was 2-fold higher (P<0.001) in placentas of obese compared to lean women. Furthermore, CGI-58 protein amounts correlated positively with maternal plasma insulin levels at the time of delivery (R=0.63; P<0.001). In conclusion, the results of my thesis suggest that FFA transport across the placenta is a complex process including more than one distinct route. To guarantee sufficient FFA supply to the fetus at least three related mechanisms are proposed. Direct efficient transfer of maternally derived FFAs takes place and is corroborated by mobilization of FFAs from placental lipid pools, if required. In addition the placenta releases phospholipids to the fetal compartment, which provides a second lipid species for fetal requirements. Maternal pre-pregnancy obesity leads to significantly elevated expression of placental genes and proteins related to transport and storage of neutral lipids. In particular CGI-58, important for initiation and regulation of TG hydrolysis, may contribute to elevated intracellular lipid turnover in placentas of obese women. Taken together the increased direct transfer of maternally derived FFAs and the enhanced lipid turnover may lead to elevated FFA supply to fetus and subsequently accretion in adipose tissue