Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus

项目摘要 越来越多的数据表明，产前和产后早期的环境影响 发育可以影响个体一生中对肥胖的易感性。这一行的长远目标 研究的重点是确定介导环境对发育的影响的分子事件， 参与哺乳动物能量稳态调节的神经元回路。下丘脑是一个 可能的网站耦合早期环境信号终身控制体重，和神经元 从弓状核（ARH）到下丘脑室旁核（PVH）的投射是 调节能量平衡至关重要。脂肪细胞衍生的激素瘦素指导 从ARH到PVH的神经元投射，以及体重调节的不同方面， 依赖于瘦素的这些发育作用，特别是在出生后的关键时期。的 将神经元通路的形成限制在不连续的发育期的机制主要是 未知但DNA甲基化，这似乎是一个主要的表观遗传标记，稳定调节 控制各种神经系统发育的基因的表达，是一个很好的候选者。 本研究的总体假设是：（1）关键的发展窗口， ARH神经元对瘦素的神经营养作用的反应由表观遗传决定， 机制，和2）基因和其他调控区域的细胞类型特异性甲基化是至关重要的， 准确靶向功能不同的神经元类别，对正常代谢产生影响 physiology.我们将通过绘制细胞类型特异性表观遗传表达模块来测试这些假设， 在这一关键的发育窗口期内和关闭后的ARH（目标1）。此外，我们将 确定瘦素介导的ARH神经元亚群内的表观遗传变化， 向PVH投射的依赖性模式（目标2）。我们还将使用转基因小鼠， DNA甲基化机制的破坏，以确定DNA甲基化是否是关闭 瘦素对ARH投射的神经营养作用的关键发育期和相关的 代谢生理学（目标3）。拟议的研究将客观和明确地评估是否 表观遗传机制指定大脑发育的关键时期， 环境因素影响大脑结构和整个生命过程中能量平衡的调节。

PROJECT SUMMARY Accumulating data indicate that environmental influences during prenatal and early postnatal development can affect individual susceptibility to obesity throughout life. The long-term goal of this line of research is to define molecular events that mediate environmental influences on development of neuronal circuitry involved in the regulation of mammalian energy homeostasis. The hypothalamus is a likely site for coupling early environmental signals to lifelong control of body weight, and neuronal projections from the arcuate (ARH) to the paraventricular (PVH) nucleus of the hypothalamus are essential in regulating energy balance. The adipocyte-derived hormone leptin directs formation of neuronal projections from the ARH to the PVH, and distinct aspects of body weight regulation are dependent on these developmental actions of leptin, specifically during a postnatal critical period. The mechanisms that restrict formation of neuronal pathways to discrete developmental periods are largely unknown. But DNA methylation, which appears to function as a major epigenetic mark stably modulating expression of genes that control development in a variety of neural systems, is an excellent candidate. The overall hypotheses of the proposed research are that 1) the critical developmental window during which ARH neurons are responsive to the neurotrophic actions of leptin is dictated by epigenetic mechanisms, and 2) cell type-specific methylation of genic and other regulatory regions is essential for accurate targeting of functionally distinct classes of neurons, with consequences for normal metabolic physiology. We will test these hypotheses by mapping cell type-specific epigenetic expression modules in the ARH during and after closure of this critical developmental window (Aim 1). In addition, we will identify leptin-mediated epigenetic changes within subpopulations of ARH neurons that display leptin- dependent patterns of projections to the PVH (Aim 2). We will also use transgenic mice with targeted disruption of the DNA methylation machinery to determine if DNA methylation is required for closure of the critical developmental period for the neurotrophic action of leptin on ARH projections and associated metabolic physiology (Aim 3). The proposed research will objectively and definitively assess whether epigenetic mechanisms specify critical periods of brain development when leptin and perhaps other environmental factors impact brain architecture and the regulation of energy balance throughout life.