The incidence of juvenile obesity and type 2 diabetes is at an all time high, yet neonatal factors that contribute to these diseases are poorly understood. The long-range goal of this project is to clarify how the adipocyte-derived hormone leptin influences, during the embryonic life, the development of neuroendocrine pathways that control body weight and energy balance in mice. Central to this goal is determining how leptin affects neurogenesis in hypothalamic nuclei known to regulate metabolism throughout the lifespan. The overall hypothesis addressed in this proposal is that leptin acts directly on the hypothalamus during the embryonic life to influence neurogenesis of hypothalamic neurons playing a role in the regulation of body weight and energy balance. We also suggest that alteration of maternal nutrition affects neurogenesis in the hypothalamus of the offspring. Both physiological and in vitro experimental approaches will be used to test these hypotheses by addressing the following specific aims. Specific Aim 1. We propose to use histochemical techniques and in vitro assays to test the neurogenic activity of leptin in embryos that lack leptin (Lepob/Lepob mice). Specific Aim 2. We will evaluate the ability of embryonic leptin exposure to functionally rescue neurodevelopmental and metabolic deficits in Lepob/Lepob mice. Specific Aim 3. Finally, we will explore the developmental consequences of maternal over- and undernutrition on hypothalamic neurogenesis in the offspring and determine whether maternal leptin treatment can influence hypothalamic neurogenesis in the offspring of undernourished (hypoleptinemic) dams. The results of the proposed research will expand our appreciation of leptin to include a profound developmental activity that promotes proliferation of hypothalamic neurons that regulate body weight and energy balance. These studies may also provide new insight into the mechanisms by which alteration of prenatal nutritional environment leads to obesity and diabetes in the offspring, and may provide new therapeutic opportunities. PUBLIC HEALTH RELEVANCE: The long-range goal of this project is to clarify how perinatal hormones, particularly the fat- derived hormone leptin, influence development brain structures involved in appetite regulation and how changes in the maternal environment during critical periods of life may have long-term consequences for regulation of body weight in the offspring. These studies may open new avenues for understanding pre- and perinatally acquired predisposition to later disease (particularly obesity), and may provide new therapeutic opportunities.