At the Cutting EdgeThe pleiotropic function of PPARγ in the placenta
Introduction
Proper growth and differentiation of the placenta is essential for mammalian fetal development and the maintenance of pregnancy. During pregnancy the placenta must attach to and invade the uterine wall, and differentiate into structures that facilitate exchange of gas, nutrient and waste products between the maternal and fetal circulation. The placenta also imparts an anatomical and immunological barrier between the two systems, and provides hormonal signals for the maintenance of pregnancy. Many aspects of these processes are regulated by the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), which functions as a heterodimer along with its partner, RXR. This review summarizes the central role of PPARγ in supporting mammalian feto-placental development. A detailed description of the molecular mechanisms PPARγ activity can be found elsewhere in excellent reviews, some of which are cited here.
Section snippets
The transcriptional activation function of PPARγ
PPARγ is one of three PPAR proteins (α, β/δ and γ, also termed NR1C1, NR1C2 or NR1C3, respectively) that belong to a family of ligand-activated nuclear hormone receptors (Desvergne and Wahli, 1999, Tan et al., 2005). PPARs regulate development and differentiation, and govern cellular bioenergetics by modulating fat and glucose metabolism and inflammatory response (reviewed in Kota et al., 2005, Lazar, 2005). Alternative promoters give rise to two major PPARγ isoforms, which differ in their AF1
Placental expression of PPARγ
PPARγ is expressed in the mouse placenta as early as embryonic day 8.5 (E8.5) (Barak et al., 1999) and in rats by E11 (Asami-Miyagishi et al., 2004). Murine PPARγ is expressed both in the spongiotrophoblast and in the labyrinth, which forms an interface between the maternal and fetal blood (Asami-Miyagishi et al., 2004, Barak et al., 1999, Kubota et al., 1999, Wang et al., 2004). Within the human placenta PPARγ is expressed predominantly in trophoblasts (Rodie et al., 2005, Schaiff et al., 2000
PPARγ pathways in placental development
In the absence of information on PPARγ deficiency in humans, the unexpected essential functions of PPARγ in placental development were gleaned from studies of gene-targeted mice. Ablation of PPARγ in mice leads to embryonic lethality at E10, a time when nutritional support to the developing embryo switches from the primary yolk sac to the placenta (Barak et al., 1999, Kubota et al., 1999). PPARγ-null placentas exhibit malformed labyrinth zone, with no permeation of fetal blood vessels and
Exposure to PPARγ ligands during pregnancy
Although the natural ligand for placental PPARγ is presently unknown, it could originate in the placenta, maternal serum, fetus or the amniotic fluid (Fig. 1). Waite et al. (2000) provided evidence for the presence of a PPARγ agonist in the serum of pregnant women. This agonist is heat stable, suggesting that it is not a protein but possibly a naturally occurring prostanoid or fatty acid, which are known to stimulate PPARγ activity (reviewed in Kota et al., 2005). Administration of the
Conclusion
PPARγ is essential for multiple functions of the placenta, including trophoblast differentiation, invasion and uptake of lipids that are important for fetal intrauterine development and as precursors for steroid hormone biosynthesis by trophoblasts. In addition, PPARγ agonists may decrease the risk of preterm delivery by suppressing the inflammatory response within the fetal membranes. Additional research that focuses on the mechanism of action, molecular targets, and functions of placental
Acknowledgements
This work was supported by NIH R01 HD044103 (to YB) and R01 ES11597 (to YS). We thank Lori Rideout for assistance with manuscript and figure preparation. While we are grateful to all researchers who contributed to this field, we are cognizant that not all manuscripts related to PPARγ and its role in the placenta could be cited here. We apologize for any relevant paper that was excluded from this review.
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