ADA Presidents' Select Abstract: MyD88 Signaling in Trophoblasts Is Necessary for Maternal High-Fat Diet-Associated Developmental Programming of Obesity

Maternal obesity (OB) contributes to 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. We generated MyD88fl/fl:Cyp19 Cre+ (conditional-KO, MyD88-CKO) and MyD88fl/fl:Cyp19 Cre- (flox-control, f/f) mice. Beginning at 5 wk of age, female MyD88-CKO mice were fed ad libitum control (17% fat calories, TD95092) or high-fat diets (HFD, 45% fat calories, TD08811) for 12 wk and then bred with lean MyD88fl/fl:Cyp19 Cre-(flox-control) males (fed control diet). This breeding strategy generated 50% of placenta/offspring with the Myd88-CKO genotype and genetically matched f/f littermate controls. At weaning, offspring (n = 10-12 from distinct litters) were randomized to control or HFD for 16 wk. All offspring have normal TLR signaling, since Cyp19 activity is only present in the placenta. Deletion of placental MyD88 had no effect on offspring growth on control diet. Male f/f offspring from HFD-dams fed HFD showed greater weight gain relative to f/f offspring from control-fed dams fed HFD, indicating an effect of maternal HFD. However, this effect of maternal HFD was not present in MyD88-CKO offspring from HFD-dams fed HFD, revealing a pivotal role for placental TLR signaling in the maternal HFD programming of obesity. Transcriptomic analyses of sex-identified placenta at dpc 17.5 showed that HFD altered more genes in male placenta (864 vs. 580, ±1.5 fold, p<0.05) in a MyD88-dependent manner. Gene ontology analyses showed that alterations in genes related to inflammation, extracellular matrix, and mitochondrial function were absent in placenta lacking MyD88. These findings provide the first unequivocal evidence that placental changes due to maternal HFD are causally related to offspring obesity risk. Disclosure M. L. Ruebel: None. K. M. Thakali: None. S. V. Chintapalli: None. K. Shankar: None. Funding U.S. Department of Agriculture (ARS-CRIS 6026-51000-012-00-D)