Hormonal and Nutritional Regulation of Hypothalamic Neurogenesis

描述（由申请人提供）：青少年肥胖症和2型糖尿病的发病率一直很高，但对导致这些疾病的新生儿因素知之甚少。该项目的长期目标是阐明脂肪细胞源性激素瘦素如何影响胚胎期小鼠控制体重和能量平衡的神经内分泌通路的发育。这一目标的核心是确定瘦素如何影响下丘脑核团中的神经发生，下丘脑核团已知在整个生命周期中调节代谢。在这个建议中解决的总体假设是，瘦素直接作用于下丘脑在胚胎生活影响下丘脑神经元的神经发生在体重和能量平衡的调节中发挥作用。我们还认为，母体营养的改变会影响后代下丘脑的神经发生。生理学和体外实验方法将用于通过解决以下具体目标来测试这些假设。具体目标1。我们建议使用组织化学技术和体外试验来测试胚胎中缺乏瘦素（Lepob/Lepob小鼠）的瘦素神经原活性。具体目标2。我们将评估胚胎瘦素暴露在功能上拯救Lepob/Lepob小鼠神经发育和代谢缺陷的能力。具体目标3。最后，我们将探讨母亲过度和营养不足对后代下丘脑神经发生的发育后果，并确定母亲瘦素治疗是否会影响营养不良（低瘦素血症）母鼠后代下丘脑神经发生。拟议的研究结果将扩大我们对瘦素的认识，包括一种深刻的发育活动，促进调节体重和能量平衡的下丘脑神经元的增殖。这些研究也可能为产前营养环境的改变导致后代肥胖和糖尿病的机制提供新的见解，并可能提供新的治疗机会。公共卫生相关性：该项目的长期目标是阐明围产期激素，特别是脂肪衍生激素瘦素如何影响参与食欲调节的发育脑结构，以及在生命的关键时期母体环境的变化如何对后代体重的调节产生长期影响。这些研究可能为了解产前和围产期获得性疾病（特别是肥胖）易感性开辟新的途径，并可能提供新的治疗机会。

DESCRIPTION (provided by applicant): 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.