Differentiation of trophoblast giant cells and their metabolic functions are dependent on peroxisome proliferator-activated receptor β/δ

Mutation of the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPARP/8) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPAR beta/delta-null mutant embryos. While very little is known at present about the pathway governed by PPARP/8 in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPAR beta/delta-null embryos is found in the giant cell layer. PPARP/8 activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPAR beta/delta is silenced. Conversely, exposure of Rcho-1 cells to a PPAR beta/delta agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPAR beta/delta activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPAR beta/delta also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPAR beta/delta-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARP/8 in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARP/8 agonist as therapeutic agents of broad application.