Leptin Promotes Inflammation at the Fetal-Maternal Interface in BPH5 Mice

Maternal obesity is a significant contributor to adverse outcomes such as preeclampsia (PE). Increased levels of adipose tissue in mothers with obesity elevates circulating leptin, a hormone critical for regulating food intake and energy balance, and inflammation. Recent studies suggest that leptin administered during gestation can induce PE-like conditions in mice. BPH/5, a spontaneous genetic mouse model of superimposed PE, has mild hypertension and obesity with hyperleptinemia prior to pregnancy. Our lab has previously shown that BPH/5 implantation sites in early pregnancy have increased pro-inflammatory cytokines and angiogenic factors, presumably due to hypoxia at the fetal-maternal interface prior to placental formation. When maternal obesity is attenuated with weight loss, inflammation is resolved and angiogenic balance is restored in the BPH/5 placenta. This study aimed to investigate exogenous leptin effects on the fetal-maternal interface, decidua, during early pregnancy in BPH/5 compared to lean normotensive control C57 mice. We tested the hypothesis that exogenous leptin increases pro-inflammatory cytokines in vitro from control pregnant C57 and BPH/5 embryonic day (e) 7.5 decidua. Furthermore, angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) would be perturbed in the decidua with exogenous leptin exposure. Intra-strain timed matings were performed with day of copulatory plug denoted as e0.5 followed by harvest of implantations sites at e7.5, and dissection of decidua tissue only. C57 and BPH/5 decidual tissues (n=3-6) were cultured with or without leptin, and mRNA expression levels of inflammatory markers, interleukin (IL)- 6, prostaglandin synthase 2 (Ptgs2), and tumor necrosis factor (TNF) alpha, were measured by quantitative real time PCR. "The analysis was performed using a one-way ANOVA to compare all groups, followed by paired and unpaired t-tests to determine significance. In vitro leptin exposure increased IL-6 mRNA (p=0.002) in BPH/5 but not C57 decidua (p>0.05), decreased TNF alpha mRNA in BPH/5 (p,0.001) without an effect on C57 decidua (p>0.05), and Ptgs2 mRNA was unchanged by leptin in both BPH/5 and C57 decidua. Finally, VEGF and PlGF mRNA were increased in only BPH/5 decidua (p>0.05) in response to exogenous leptin exposure. These findings suggest that leptin plays a crucial role in regulating inflammation at the fetal-maternal interface in e7.5 mice, particularly in the context of maternal obesity-associated hyperleptinemia. Elevated cytokine levels and disrupted angiogenic factors in the disease model, but not in the control group, highlight leptin's synergistic interaction with obesity. These results emphasize the detrimental impact of elevated leptin on pregnancy outcomes in obese mice and suggest that reducing leptin levels at the fetal-maternal interface could improve both pregnancy outcomes and offspring health. Funding: National Institutes of Health This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.