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Ligand-Activated Peroxisome Proliferator Activated Receptor Alters Placental Morphology and Placental Fatty Acid Uptake in Mice

Departments of Obstetrics and Gynecology (W.T.S., T.B.-S., D.M.N., Y.S.), and Cell Biology and Physiology (W.T.S., Y.S.), Washington University School of Medicine, St. Louis, Missouri 63110; Nuclear Medicine Program (F.F.K.), Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831; and The Jackson Laboratory (Y.B.), Bar Harbor, Maine 04609-1500

Address all correspondence and requests for reprints to: Yoel Sadovsky, M.D., Washington University School of Medicine, Department of Obstetrics and Gynecology, Campus Box 8064, 4566 Scott Avenue, St. Louis, Missouri 63110. E-mail: ysadovsky{at}wustl.edu.

The nuclear receptor peroxisome proliferator activated receptor (PPAR) is essential for murine placental development. We previously showed that activation of PPAR 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 PPAR on placental development and transplacental fatty acid transport in wild-type (wt) and PPAR^+/– embryos. We found that exposure of pregnant mice to the PPAR agonist rosiglitazone for 8 d (embryonic d 10.5–18.5) reduced the weights of wt, but not PPAR^+/– 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 PPAR modulates placental morphology and fatty acid accumulation.

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