Contribution of adipocyte inflammation to parturition timing

PROJECT SUMMARY Abnormal timing of labor, especially preterm birth (PTB), is a major threat to maternal and infant health. Mothers with pre-pregnancy obesity have increased risk for pregnancy complications including PTB. However, cellular and molecular mechanisms underlying the induction of such adverse health outcomes in pregnancy remain unknown. Induction of labor is associated with hormone release (e.g., oxytocin), increase in systemic inflammatory mediators (e.g., fetal DNA, LPS) and proinflammatory cytokines (e.g., IL-6, TNF), and sympathetic nervous system (SNS) activation. Here, we aim to define non-dogmatic sources of pro-inflammatory cytokine production throughout pregnancy that may affect the timing of labor. Specifically, due to its expanded status in pregnancy and known role in various inflammatory diseases, we propose to study how white adipose tissue (WAT) inflammation is induced in pregnancy and how such inflammation contributes to the overall inflammatory balance. Using a mouse pregnancy model, we show that WAT temporally expands in pregnancy, and that such expansion positively correlates with higher pro-inflammatory cytokine production by WAT at baseline and uniquely in adipocytes after LPS sensing. However, whether and how hormonal and inflammatory signals unite to instruct the timing of labor in WAT remains unknown. Dogmatically, oxytocin is known as the major hormone responsible for uterine contraction during labor. Recent findings show the ability of oxytocin to induce lipolysis and change metabolic characteristics of adipocytes via direct SNS stimulation. We now show that oxytocin and LPS have a synergistic effect on adipocyte IL-6 production, and that oxytocin-expressing neurons are present in WAT of female mice. Thus, our preliminary data and published reports support the overarching hypothesis that SNS-derived oxytocin secretion in pregnancy amplifies WAT inflammation via adipocyte oxytocin receptor signaling. In this proposal, we aim define how oxytocinergic innervation of WAT affects tissue and cellular inflammation in pregnancy (Aim 1), and to examine the role of adipocyte oxytocin sensing for amplified inflammation in pregnancy (Aim 2). Together, these studies will lay novel groundwork for exploration of peripheral tissue neuro-inflammation in initiation of labor – a timely need given the increasing prevalence of preterm labor and pre-pregnancy obesity in this country. Further, the associated training plan will establish a foundation for a successful career as a physician scientist with a focus on academic obstetrics & gynecology research.