Placental Insulin Signaling and mTOR Nutrient-Sensing Programming of Offspring Metabolic Health

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Abstract Type 2 diabetes (T2D) affects nearly 1 in 10 Americans and is the 7th leading cause of death. It is clear that both genetic and environmental factors contribute to T2D. Epidemiological studies show robust associations between poor fetal environment and infant growth (e.g. fetal growth-restriction or over-growth) and the eventual development of obesity, T2D, and cardiovascular disease later in life. The strong association between birthweight and risk of T2D is U-shaped, thus, both children born small and those born large for gestational age are at risk. We propose that maternal insulin and placental nutrient-sensing by mTORC1 are critical regulators of the metabolic health programming of the offspring. The placenta responds to changes in the maternal environment and integrates maternal signals to placental function in part by growth factor receptors such as the insulin receptor, and the nutrient-sensing protein mTOR kinase. Despite years of research, the roles for maternal insulin and placental mTOR in the metabolic health of the offspring are untested, and we have the model and expertise to address this gap in knowledge. The first goal of this grant is to establish a causal link between maternal insulin and the metabolic health of the offspring. In Aim 1, we will determine the roles of placental insulin signaling in the programming of metabolic health trajectory in the offspring using functional studies with preclinical genetic models of pregnancy complications (gain of maternal hyperinsulinemia during pregnancy or placenta-specific loss of insulin receptor). Second, this proposal aims to identify the mechanisms underlying the developmental programming of peripheral insulin sensitivity by placental nutrient-sensing mTOR. In Aim 2, we will determine mechanisms of insulin sensitivity by placental mTORC1 nutrient-sensing in the offspring using murine models with loss or gain of mTOR signaling in the placenta. Therefore, our studies will determine if maternal hyperinsulinemia is sufficient to drive mal programming of metabolic health in the offspring in multiparous females. Second, we will determine if enhancing placental mTORC1 is a feasible therapeutic strategy for preserving insulin sensitivity in the adult offspring and preventing long-term metabolic dysfunction. Understanding the programming impact of maternal insulin on the metabolic health of the offspring will be significant in illuminating the effects of insulin therapy on the children of women with gestational diabetes, T1D, and T2D during pregnancy, thereby advancing clinical care. The anticipated success of this project will have significant implications in improving women's reproductive health and pregnancy outcomes.