No abstract

The ligand-dependent nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the differentiation of several tissues and cell types. PPARgamma was recently determined to be essential for murine placental development and differentiation. We therefore assessed the influence of PPARgamma on differentiation of human placental trophoblasts. We initially used immunohistochemistry to examine term human placentas for PPARgamma expression and found that PPARgamma is present in syncytiotrophoblasts and cytotrophoblasts in placental villi. We correlated the expression of PPARgamma with differentiation of primary human trophoblasts and found that 8-bromo-cAMP, a known enhancer of trophoblast differentiation, stimulates PPARgamma activity, but has no effect on PPARgamma expression. We demonstrated that the PPARgamma ligand 15-deoxy-delta12,14-prostaglandin J2 (15deltaPGJ2) and the thiazolidinedione troglitazone stimulate PPARgamma activity in the trophoblast cell line BeWo. Importantly, whereas exposure of cultured primary trophoblasts to troglitazone enhances biochemical and morphological trophoblast differentiation, 15deltaPGJ2 diminishes trophoblast differentiation. Furthermore, 15deltaPGJ2, but not troglitazone, up-regulates p53 expression and promotes trophoblast apoptosis. These data indicate that PPARgamma is expressed in human placental trophoblasts, and that ligand-specific activation of PPARgamma results in opposing effects on trophoblast differentiation. Our results suggest that PPARgamma plays an important role in placental differentiation during human pregnancy.

These data support a role for PPARgamma and RXR in regulation of fatty acid transport and storage in human placental trophoblasts.

Objective-Fatty acids (FA) are essential for fetal development. Cellular FA uptake is modulated by fatty acid binding proteins (FABPs). We hypothesized that hypoxia regulates the expression of FABPs in human trophoblasts.Study design-Primary term human trophoblasts were cultured for 72 h in either standard (O 2 = 20%) or hypoxic (O 2 < 1%) conditions. FABP expression was interrogated using PCR and western immunoblotting. Trophoblast lipid droplets were examined using BODIPY 493/503 staining.Results-We detected the expression of FABP1, 3, 4, 5 and pm, but not FABP2 or FABP6-9 subtypes in trophoblasts. Exposure to hypoxia markedly increased lipid droplet accumulation in trophoblasts. Consistent with this observation, hypoxia enhanced the expression of FABP1, 3 and 4. Lastly, agonists of peroxisome proliferator activated receptor-γ (PPARγ) enhanced the expression of FABP1 and 4 in trophoblasts.Conclusions-Hypoxia enhances the expression of FABP1, 3 and 4 in term human trophoblasts, suggesting that FABPs support fat accumulation in the hypoxic placenta.

The nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) is essential for murine placental development. We previously showed that activation of PPARgamma in primary human trophoblasts enhances the uptake of fatty acids and alters the expression of several proteins associated with fatty acid trafficking. In this study we examined the effect of ligand-activated PPARgamma on placental development and transplacental fatty acid transport in wild-type (wt) and PPARgamma(+/-) embryos. We found that exposure of pregnant mice to the PPARgamma agonist rosiglitazone for 8 d (embryonic d 10.5-18.5) reduced the weights of wt, but not PPARgamma(+/-) placentas and embryos. Exposure to rosiglitazone reduced the thickness of the spongiotrophoblast layer and the surface area of labyrinthine vasculature, and altered expression of proteins implicated in placental development. The expression of fatty acid transport protein 1 (FATP1), FATP4, adipose differentiation related protein, S3-12, and myocardial lipid droplet protein was enhanced in placentas of rosiglitazone-treated wt embryos, whereas the expression of FATP-2, -3, and -6 was decreased. Additionally, rosiglitazone treatment was associated with enhanced accumulation of the fatty acid analog 15-(p-iodophenyl)-3-(R, S)-methyl pentadecanoic acid in the placenta, but not in the embryos. These results demonstrate that in vivo activation of PPARgamma modulates placental morphology and fatty acid accumulation.