Activation of Peroxisome Proliferator Activator Receptor Delta in Mouse Impacts Lipid Composition and Placental Development at Early Stage of Gestation1

Abstract

Peroxisome proliferator-activated receptor delta (Ppard) activation has been implicated in regulating a multitude of biological processes in placental development. In this study, we employed the UPLC-ESI-TOFMS approach to investigate the metabolic traits in placenta from GW501516-treated mice at Embryonic Day 10.5. By analyzing the mass spectrum data, ions with the most significant differences between control and GW501516-treated groups were identified. Among these metabolites, the fatty acids, phospholipids, and sterol lipids were dramatically increased. Ingenuity Pathway Analysis (IPA) showed that phosphatidylethanolamine biosynthesis and glycolysis were the top two altered metabolic pathways involved in carbohydrate metabolism, energy production, and lipid metabolism. Subsequent immunoblotting experiments provided evidence for positive correlation of PPARD level and AKT and ERK signaling pathways upon GW501516 treatment. Furthermore, the stimulation of GW501516 increased trophoblast cell fusion gene syncytin-A (Syna), but not syncytin-B (Synb), expression, suggesting a potential role of Ppard activation in promoting cytotrophoblast differentiation. Our results reveal that Ppard activation elicits dramatic changes of the metabolic activities in placenta, which is correlated to AKT and ERK signaling.

Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model

“…GW501516 can also prevent endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells by activating AMPK (43,44). The Akt and ERK signaling pathways have also been shown to be involved in the effects of GW501516 (45). In a previous study, in INS-1E cells treated with GW501516, the expression of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), GLUT-2, and the upregulation of insulin, indicated that the c-Jun N-terminal kinase (JNK)-MafA-GLUT-2 pathway was involved in the enhanced effects of PPARδ on insulin secretion (46).…”

The Role of Peroxisome Proliferator-Activated Receptors in Preeclampsia

“…In terms of trophoblast secretion, PPARγ signaling pathways have been described to promote the energy metabolism of trophoblast cells through the secretion of inflammatory cytokines, including interferon (IFN)-γ and prostaglandin E2 (PGE2) [57]. Both PPARβ and PPARγ are also associated with trophoblast cell fusion and syncytiotrophoblast formation via direct modulation of the target gene syncytin-1 [58,59]. In the context of trophoblast invasion, the molecular mechanism of PPARγ may efficiently decrease pregnancy-associated plasma protein-A (PAPP-A) and avert the secretion of insulin-like growth factor (IFGII) [60].…”