The focus of our research is placental differentiation and function. These processes are essential for intact embryonic development. We seek to elucidate the impact of the intra-uterine environment on placental function, and consequently fetal growth. An adequate supply of proteins, carbohydrates and fat is obligatory for fetal development Transfer of these nutrients is regulated by a set of well-orchestrated signals, programmed by genetic and environmental cues. Whereas our understanding of placental import of proteins and carbohydrates has markedly advanced in recent years, the mechanisms that govern transport of fatty acids in placental trophoblasts are largely unknown. Recent data implicate the nuclear receptor PPARy in regulation of fatty acid transport. This conclusion is supported by the following observations: (1) PPARy is an essential determinant of adipose tissue differentiation. (2) PPARy regulates the transcription of several genes that encode fatty acid transporters. (3) PPARy -I- embryos exhibit intrauterine growth restriction and subsequently fetal death, associated with diminished size of fat globules within the labyrinthine placenta. In addition, we have recently found that PPARy is expressed in the human placenta, where it influences trophoblast differentiation in a ligand- specific manner. Correspondingly, human trophoblasts express several fatty acid transporters. We therefore hypothesize that PPARy is a pivotal regulator of fatty acid uptake by placental trophoblast. To test our hypothesis, we address the following questions: Does PPARy regulate the expression of placental fatty acid transporters? Does this regulation translate into a different degree of fatty acid import into trophoblasts? What mechanisms underlie the effect of ligandactivated PPARy on trophoblast differentiation and fatty acid transporter expression? Our studies are likely to unveil previously unrecognized pathways to placental dysfunction and sub-optimal intrauterine growth, which have direct implications for development and behavior in early childhood. Furthermore, fetal growth restriction is associated with metabolic disorders in the adult, including atherosclerosis, hypertension, diabetes and hyperlipidemia. Hence, insight into fetal disease may shed light on novel approaches designed to improve adult health.
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