MyD88 Signaling in Trophoblasts is Necessary for Maternal High Fat Diet-Associated Developmental Programming of Obesity

Maternal obesity contributes to persistent programming of offspring obesity. A causal role for placental inflammatory mechanisms in developmental programming remains to be established. We examined the role of the toll-like receptor (TLR) pathway in mediating maternal obesity associated programming by trophoblast deletion of the TLR adapter protein, MyD88. Female MyD88fl/fl:Cyp19 Cre+ (MyD88-CKO) at 5 wks of age were provided control (17% fat calories, CON) or high-fat diets (HFD, 45% fat calories) for 12 wk and mated with MyD88fl/fl:Cyp19 Cre-(flox-control) males. Placenta were studied at dpc 17.5. In a subset, offspring were randomized to CON or HFD for 16 weeks. Placental weight and gene expression changes associated with HFD showed MyD88-dependence for pro-inflammatory and lipid metabolism related responses. Male MyD88 flox offspring from HFD-dams fed postnatal HFD (HH) showed an increase in body weight, liver steatosis and gene expression. These changes were absent in MyD88 CKO HH offspring, demonstrating a causal link between placental MyD88 mediated changes and long-term changes. Overall, these findings provide the first unequivocal evidence that placental changes due to maternal HFD are causally related to offspring obesity risk.