Pre-conception obesity programs placental inflammation and function

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 DESCRIPTION (provided by applicant): Women with Gestational Diabetes Mellitus (GDM) have the almost invariable development of type 2 diabetes in the years and decades post-partum. Beyond the risk diabetes confers on these with women, with microvascular and macrovasular disease the most common, GDM can also have adverse consequences to the developing fetus, causing macrosomia and complications at delivery, as well as increased lifetime risk of metabolic disorders, obesity, and neurocognitive impairments. The placenta is thought to play a major role in the development of GDM because this tissue synthesizes and secretes pro-inflammatory cytokines, leading to increased systemic inflammation, a hallmark of GDM. The current viewpoint holds that increased placental inflammation is a consequence of the maternal environment, including increased systemic inflammation. However, we now have exciting preliminary data that challenges this dogma by demonstrating that the placenta is already programmed to develop inflammation prior to exposure to the maternal environment during gestation. Using embryo transfer technology we have shown that placentas derived from embryos collected from obese females and implanted into naïve females have increased inflammation compared to placentas derived from embryos of lean females. Because oocytes of obese women and rodents are dysfunctional with increased oxidative stress and altered mitochondria, it is not completely unexpected. Though many of the current practices to improve pregnancy outcomes of obese women and women with GDM are targeted to the pregnant female, our data suggest that the pre-pregnancy environment should be targeted. Based on our preliminary data, our central hypothesis is that pre-conception maternal obesity programs oocytes to give rise to placentas with excessive inflammation and impaired function. We will test our hypothesis with 2 aims. Aim 1. Determine if pre-conception obesity programs placental inflammation and function. In this aim, we will transfer embryos from females in their 1st or 4th pregnancy into naïve females. Activation of inflammatory cascades will be assessed in placentas and maternal tissues, as will maternal insulin resistance. Placental nutrient transport will also be measured. Contributions of aging and pregnancies to placental programming will be dissected out as well. Aim 2. Determine the role of post-conception maternal obesity on placental inflammation and function. Once again using embryo transfer technology, we will determine if pre-conception oocyte environment programs how placentas are affected by post- conception environment. We will examine inflammation and function in placentas derived from embryos of lean or obese females and transferred into MIO surrogate mothers. The rationale for these studies is that they could lead to new targets, i.e. optimal times for interventions, aimed a decreasing the risk of GDM development and adverse pregnancy outcomes due to placental inflammation and dysfunction.