Placental PPARγ regulates spatiotemporally diverse genes and a unique metabolic network

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is essential for placental development. For insights into its functions in the placenta, we screened for PPARγ-regulated genes by integrating expression profiles of Pparg-null and Rxra-null placentas with those of WT and Pparg-null trophoblast stem cells differentiated in the presence or absence of a PPARγ agonist. Intersection of these paradigms identified high-probability PPARγ target genes. A few of these genes were previously reported as PPARγ targets in other tissues, but most are new in the context of either PPARγ or placental biology. Transcriptional profiling demonstrated a widespread role for the coactivator NCOA6/AIB3, but not MED1/PBP, in PPARγ-dependent placental gene expression. Spatial and temporal expression analyses revealed that PPARγ impacts genes in diverse trophoblast lineages and during different stages of differentiation. We further validated the Ldhb gene, which encodes the H isoform of lactate dehydrogenase, as a robust PPARγ target in trophoblasts, and propose a hypothetical model that integrates it with a network of PPARγ-regulated genes into a novel pathway of placental fuel metabolism. These findings offer insights not only into the placental functions of PPARγ, but also into unique, previously unsuspected biosynthetic functions of trophoblasts.