Maternal obesity modulates intracellular lipid turnover in the human term placenta.

BACKGROUND: Obesity before pregnancy is associated with impaired metabolic status of the mother and the offspring later in life. These adverse effects have been attributed to epigenetic changes in utero, but little is known about the role of placental metabolism and its contribution to fetal development. OBJECTIVES: We examined the impact of maternal pre-pregnancy obesity on the expression of genes involved in placental lipid metabolism in lean and obese women. SUBJECTS/METHODS: Seventy-three lean and obese women with healthy pregnancy were recruited at term elective cesarean delivery. Metabolic parameters were measured on maternal venous blood samples. Expression of 88 genes involved in lipid metabolism was measured in whole placenta tissue. Proteins of genes differently expressed in response to maternal obesity were quantified, correlated with maternal parameters and immunolocalized in placenta sections. Isolated primary trophoblasts were used for in vitro assays. RESULTS: Triglyceride (TG) content was increased in placental tissue of obese (1.10, CI 1.04-1.24 mg g-1, P<0.05) vs lean (0.84, CI 0.72-1.02 mg g-1) women. Among target genes examined, six showed positive correlation (P<0.05) with maternal pre-pregnancy BMI, namely ATGL (PNPLA2), FATP1 (SLC27A1), FATP3 (SLC27A3), PLIN2, PPARG and CGI-58 (ABHD5). CGI-58 protein abundance was twofold higher (P<0.001) in placentas of obese vs lean women. CGI-58 protein levels correlated positively with maternal insulin levels and pre-pregnancy body mass index (R=0.63, P<0.001 and R=0.64, P<0.001, respectively). CGI-58 and PLIN2 were primarily located in the syncytiotrophoblast and, were upregulated (1.38- and 500-fold, respectively) upon oleic acid and insulin treatment of cultured trophoblast cells. CONCLUSION: Pre-gravid obesity significantly modifies the expression of placental genes related to transport and storage of neutral lipids. We propose that the upregulation of CGI-58, a master regulator of TG hydrolysis, contributes to the turnover of intracellular lipids in placenta of obese women, and is tightly regulated by metabolic factors of the mother.

Computational modelling of fatty acid transport in the human placenta.

Fatty acids are critical for normal fetal growth and development. The placenta mediates the transfer of fatty acids from the maternal to the fetal circulation. Yet, the mechanisms of fatty acid transport are not fully understood. The development of a computational model alongside experiments will test our understanding of the transfer mechanisms. Modelling experimental data suggest the presence of a metabolic pool within placental tissue that could represent the rate-limiting factor for fatty acid transfer. In addition the model suggests a slower flux capacity of the fetal-side of the placenta compared with the maternal-side. The model provides key insights into placental fatty acid transfer which will form the basis for future experimentation.

Selective cholesteryl ester uptake from high density lipoprotein by human first trimester and term villous trophoblast cells.

As villous trophoblast does represent the contact zone between foetal and maternal tissues, the present in vitro study was aimed at investigating cholesterol supply from human high density lipoprotein subclass 3 (HDL(3)) to trophoblast cells isolated from human first trimester and term placenta. Binding of (125)I-HDL(3) was specific and saturable with similar K(d)-values for first trimester (54 microg HDL(3)-protein/ml) and term villous trophoblast cells (29 microg HDL(3)-protein/ml). The cell-association of (125)I-HDL(3) was 3-fold higher for term trophoblast cells while the specific cell-association of [(3)H]cholesterol ester(CE)-labelled HDL(3) was higher for first trimester trophoblast preparations. As a consequence, first trimester trophoblast cells have a pronounced capacity for selective CE-uptake from HDL(3). Competition experiments with native and oxidized low-density lipoprotein as well as cAMP-mediated stimulation of cell-association of [(3)H]CE-HDL(3) in both trophoblast preparations suggested the scavenger receptor class B, type I (SR-BI) as a likely receptor mediating this pathway. SR-BI m RNA could be identified by RT-PCR and Northern blot experiments in both trophoblast preparations. Western blot analysis and immunocytochemistry revealed high expression of SR-BI in first trimester trophoblast. A polyclonal antiserum raised against murine SR-BI significantly decreased cell-association of [(3)H]CE-HDL(3) in trophoblast cells. We conclude that human first trimester and term trophoblast cells express SR-BI which could serve as an efficient route for supplying cholesterol esters from maternal lipoproteins to foetal tissues.