Development of Leptin-Sensitive Hypothalamic Pathways

瘦素敏感下丘脑通路的发展

• 批准号: 7998288
• 负责人: RICHARD B SIMERLY
• 金额: $ 9.92万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7998288
• 关键词: Address; Adipocytes; Adult; Architecture; Biological Assay; Body Weight; Brain; Development; Documentation; Eating; Energy Metabolism; Environment; Exposure to; Goals; Growth; Homeostasis; Hormones; Hypothalamic structure; In Vitro; Knowledge; Leptin; Life; Litter Size; Long-Term Effects; Malnutrition; Measures; Mediating; Metabolism; Methods; Mus; Neonatal; Neural Pathways; Neurons; Neurosecretory Systems; Nodal; Nutritional; Nutritional status; Obesity; Overnutrition; Pathway interactions; Pattern; Peripheral; Physiological; Regulation; Research; Research Personnel; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Time; critical developmental period; critical period; energy balance; feeding; gain of function; in vivo; loss of function; mouse model; neural circuit; neurodevelopment; nutrition; paraventricular nucleus; postnatal; programs; relating to nervous system

DESCRIPTION (provided by applicant): The long-range goal of this research is to understand how the adipocyte-derived hormone leptin acts on hypothalamic neurons to regulate development of central neural pathways involved in the regulation of mammalian homeostasis. Central to this goal is determining how leptin influences development of neural projections from the arcuate nucleus of the hypothalamus (ARM) to the paraventricular nucleus (PVH), key sites for integration of information related to peripheral energy stores and neuroendocrine demands. During the past project period we demonstrated that leptin is required for normal development of ARM projections, yet the long-term functional consequences of postnatal leptin remain to be established, and the critical period is not clearly defined. The overall hypothesis addressed in this proposal is that exposure to leptin during a discrete postnatal critical period is sufficient to permanently organize projections from the arcuate nucleus of.the hypothalamus that regulate food intake and key aspects of energy metabolism, and that alterations in neonatal nutrition during this developmental critical period influence growth through accompanying changes in levels of circulating leptin. We will test this hypothesis by using mouse models to address the following specific aims. First, we will evaluate the ability of postnatal leptin exposure to functionally rescue deficits in adult ob/ob mice (Specific Aim 1). Second, we will utilize neuroanatomical techniques to assess the impact of postnatal leptin exposure on identified neural inputs to PVH neurons in adult ob/ob mice (Specific Aim 2). Third, we will utilize the physiological and neuroanatomical assays developed during the first 2 specific aims to define the critical period for the developmental actions of leptin on projections of NPY/AgRP and POMC neurons in the ARM, and to identify associated long term physiological consequences (Specific Aim 3). Finally, we will study the impact of altered nutrition on the postnatal leptin surge and determine whether exogenous postnatal leptin can influence the pattern of catch up growth observed in mice derived from over- and under-nutritional postnatal environments (Specific Aim 4). The results of the proposed research will contribute significantly to our emerging appreciation of leptin as a key developmental factor in the hypothalamus, and may provide clues about how the neonatal nutritional environment imposes enduring consequences on brain architecture and the regulation of energy balance throughout life.

描述（由申请人提供）：这项研究的远距离目标是了解脂肪细胞衍生的激素瘦素如何作用于下丘脑神经元上，以调节参与调节哺乳动物稳态的中心神经途径的发展。这一目标的核心是确定瘦素如何影响从下丘脑（ARM）弧形核（ARM）到室室核（PVH）的神经投影的发展，与周围能量储存和神经内分泌需求相关信息的关键站点。在过去的项目期间，我们证明了瘦素是ARM投影的正常开发所必需的，但是产后瘦素的长期功能后果仍有待确定，并且关键时期尚未明确定义。该提案中解决的总体假设是，在离散产后关键时期内接触瘦素足以从弧形核的核心核永久组织预测。调节食物摄入量和能量代谢的关键方面的下丘脑，以及在这种临界周期内的新生儿营养变化的变化范围内的循环范围。我们将通过使用鼠标模型来解决以下特定目的来检验这一假设。首先，我们将评估产后瘦素暴露于成年OB/OB小鼠功能性挽救缺陷的能力（特定AIM 1）。其次，我们将利用神经解剖技术来评估成年ob/ob小鼠中识别出的神经输入对PVH神经元的神经输入的影响（特定的AIM 2）。第三，我们将利用在前2个特定目的中开发的生理和神经解剖学测定，以定义瘦素对NPY/AGRP和POMC神经元投影的关键时期，并确定相关的长期生理后果（特定的目标3）。最后，我们将研究营养改变对产后瘦素激增的影响，并确定外源后瘦素是否可以影响从过度和下产后环境中衍生的小鼠中观察到的追赶生长的模式（特定目标4）。拟议研究的结果将极大地促进我们对瘦素作为下丘脑的关键发育因素的新兴欣赏，并可能提供有关新生儿营养环境如何对大脑结构和整个生命的能量平衡调节的持久后果的线索。

项目成果

Postnatal dietary fatty acid composition permanently affects the structure of hypothalamic pathways controlling energy balance in mice.

产后膳食脂肪酸组成永久影响控制小鼠能量平衡的下丘脑通路的结构。

• DOI: 10.3945/ajcn.113.069229
• 发表时间: 2013
• 期刊: The American journal of clinical nutrition
• 作者: Schipper,Lidewij;Bouyer,Karine;Oosting,Annemarie;Simerly,RichardB;vanderBeek,ElineM
• 通讯作者: vanderBeek,ElineM