Epigenetic Mechanisms and Developmental Actions of Leptin in the Hypothalamus

下丘脑瘦素的表观遗传机制和发育作用

• 批准号: 9889122
• 负责人: RICHARD B SIMERLY
• 金额: $ 59.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889122
• 关键词: Adipocytes; Adult; Affect; Architecture; Body Composition; Body Weight; Brain; Coupling; DNA Methylation; DNA Methylation Regulation; DNMT3a; Data; Development; Developmental Biology; Developmental Process; Eating; Endocrine; Energy Metabolism; Environmental Risk Factor; Epigenetic Process; Event; Gene Expression; Gene Expression Regulation; Genes; Goals; Homeostasis; Hormones; Hypothalamic structure; Individual; Informatics; Leptin; Life; Maps; Measures; Mediating; Metabolic; Methylation; Microdissection; Modification; Molecular; Mus; Neurons; Nucleic Acid Regulatory Sequences; Obese Mice; Obesity; Pathway interactions; Pattern; Physical activity; Physiological; Physiology; Play; Population; Predisposition; Presynaptic Terminals; Process; Regulation; Research; Role; Sensory; Signal Transduction; Site; Specific qualifier value; System; Testing; Transgenic Mice; Wild Type Mouse; Work; base; cell type; critical developmental period; critical period; energy balance; epigenetic regulation; epigenomics; genome-wide; histone modification; loss of function; metabolic phenotype; nerve supply; neurodevelopment; neuron development; neuronal circuitry; obesity risk; paraventricular nucleus; postnatal; postnatal development; postsynaptic neurons; prenatal; relating to nervous system; transcriptomics

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.

项目摘要 累积数据表明产前和早期产后的环境影响 发展会影响个人对肥胖一生的敏感性。这条线的长期目标 研究的是定义介导环境对发展的影响的分子事件 哺乳动物能量稳态调节的神经元电路。下丘脑是 可能将早期环境信号耦合以终身控制体重和神经元的站点 从弧形（ARH）到下丘脑的室核（PVH）核的预测是 在调节能量平衡中必不可少。脂肪细胞衍生的激素瘦素指导形成 从ARH到PVH的神经元投影，体重调节的不同方面是 取决于瘦素的这些发育作用，特别是在产后关键时期。这 将神经元途径限制为离散发育周期的机制在很大程度上是 未知。但是DNA甲基化似乎充当主要的表观遗传标记，可稳定调节 控制各种神经系统中发育的基因的表达是一个极好的候选者。 拟议研究的总体假设是1） 哪种ARH神经元对瘦素的神经营养作用有反应 机理，以及2）基因和其他调节区域的细胞类型特异性甲基化对于 精确靶向功能不同的神经元类别，对正常代谢产生了影响 生理。我们将通过绘制细胞类型特异性表观遗传表达模块来检验这些假设 在这个关键发展窗口的闭合期间和之后的ARH（AIM 1）。此外，我们将 鉴定瘦素介导的表观遗传学变化在ARH神经元的亚群中，显示瘦素 - PVH投影的依赖模式（AIM 2）。我们还将使用针对目标的转基因小鼠 DNA甲基化机制的破坏以确定是否需要DNA甲基化才能闭合 瘦素对ARH投影和相关性的神经营养作用的关键发育阶段 代谢生理学（目标3）。拟议的研究将客观和确定地评估是否是否 表观遗传机制指定了瘦素和其他可能的关键时期 环境因素会影响大脑建筑和整个生命的能量平衡调节。