Placenta · 2026
MyD88 signaling in trophoblasts contributes to maternal high fat diet-associated alterations in placental gene expression and lipid profiles.
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Ruebel Meghan L, Zhong Ying, Schall Peter Z, Jambal Purevsuren, Yazza Deaunabah N, Zemski Berry Karin, Chintapalli Sree V, Read Quentin D, Thakali Keshari M, Shankar Kartik
Аннотация
INTRODUCTION: Maternal obesity contributes to programming of offspring obesity. A causal pathway for placental inflammatory changes in utero with 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.
METHODS: 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. Three-way ANOVA and linear mixed models to account for litter effects were used for analyses.
RESULTS: Placenta weight showed an HFD and sex effect, with elevated weight 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 phosphatidylcholines (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 concentrations in both sexes and genotypes. A diet and genotype interaction was identified by ANOVA for lysoglycerophospholipids, as well as a sexual dimorphic effect.
DISCUSSION: These 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.
METHODS: 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. Three-way ANOVA and linear mixed models to account for litter effects were used for analyses.
RESULTS: Placenta weight showed an HFD and sex effect, with elevated weight 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 phosphatidylcholines (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 concentrations in both sexes and genotypes. A diet and genotype interaction was identified by ANOVA for lysoglycerophospholipids, as well as a sexual dimorphic effect.
DISCUSSION: These 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.