Submitted to: Placenta
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/27/2026
Publication Date: N/A
Citation: N/A

Interpretive Summary: Pregnancy is a critical period when life-long risk of chronic diseases for the child is impacted. Obesity during pregnancy is wellestablished to increase the chances of obesity in the child and is frequently associated with increased signs of inflammation in the placenta. The goal of this research was to understand how placental inflammation affects the weight gain of offspring using a wellestablished mouse model of obesity. The model allows studying the effects of maternal obesity without confounding variables present in human studies. In this study, researchers used a mouse model where they abolished a key pathways of inflammation (TLR/MyD88 signaling) specifically in placenta cells called trophoblasts. Then using high fat diet (HFD) to induce obesity in the animals, researchers studied the effects of maternal HFD at late pregnancy in these animals. The investigators found reduced inflammation, lipid metabolism and adverse effects in male placentas from a HFD dam (female pregnant mouse) where MyD88 signaling was absent. The studies also showed distinct changes in lipid classes with HFD and also showed a genotype and HFD interactive effect. These changes were more pronounced in the female placentas from HFD dam without MyD88 signaling. This data suggest that a combined effect of HFD and lost of MyD88 signaling have an important role in mediating placental inflammation and lipid metabolism and those effects vary depending on fetal sex.

Technical Abstract: Maternal obesity contributes to persistent programming of offspring obesity. A causal pathway for placental inflammatory changes in utero in the context of obesity remains to be established. We examined the role of the toll-like receptor (TLR) pathway in mediating maternal obesity associated changes in placental gene expression using trophoblast-specific deletion of the TLR adapter protein, MyD88. Female MyD88 conditional knockouts (MyD88-CKO) at 5 weeks of age were provided control (17% fat calories, CON) or high-fat diets (HFD, 45% fat calories) for 12 weeks and mated with MyD88 (flox-control) males. At days post coitum (dpc) 17.5, immune cell composition, global gene expression, and target lipidomic changes were investigated in sex-stratified placentas. Placenta weight showed a HFD and sex effect, with elevated placenta weight seen in male flox (p=0.03) and a trending increase in female CKO placentas from HFD compared to CON dams. RNA-seq analyses of male placenta indicate MyD88-dependent changes in immune response and lipid metabolism, and distinct HFD changes in females. HFD increased PC 16:0/22:4, PC 16:0/22:6, PC 18:1/22:6, and PC O-18:1/22:6; and decreased PC 16:0/22:4, PC 16:0/22:6, PC O-18:1/22:5, PC 18:2/18:2, and PC 18:2/20:4 lipid concentrations in both sexes and genotypes. A diet by genotype interaction was identified for lysoglycerophospholipids, as well as a sexual dimorphic effect, driven by female placentas more than males. Combined, our findings suggest that both HFD and placental TLR/MyD88 signaling in trophoblasts play a central role in mediating placental inflammation and lipid metabolism in the context of obesity.