Leptin and Developmental Programming of Hypothalamic Autonomic Outflow

瘦素与下丘脑自主神经流出的发育编程

• 批准号: 9185840
• 负责人: RICHARD B SIMERLY
• 金额: $ 44.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-03 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9185840
• 关键词: Address; Affect; Body Weight; Brain region; Complex; Consensus; Data; Development; Dorsal; Energy Metabolism; Environmental Risk Factor; Epidemic; Fatty acid glycerol esters; Goals; High Fat Diet; Hormonal; Hormones; Hypothalamic structure; Immunohistochemistry; Individual; Lactation; Leptin; Life; Link; Metabolic; Methods; Modification; Molecular Genetics; Mus; Neonatal; Neurons; Neurosecretory Systems; Nucleus solitarius; Nutritional; Obesity; Pathway interactions; Pattern; Peripheral; Physiological; Physiology; Play; Predisposition; Process; Regulation; Research; Risk Factors; Role; Sensory; Signal Transduction; Site; Specific qualifier value; Spinal Cord; Stomach; Structure; Structure of nucleus infundibularis hypothalami; System; Testing; Thermogenesis; Three-Dimensional Image; Time; To specify; Tracer; Vagus nerve structure; Visceral; base; cell motility; critical period; density; developmental neurobiology; dorsal motor nucleus; energy balance; gain of function; genetic manipulation; glucose metabolism; loss of function; metabolic phenotype; mother nutrition; nerve supply; neuron development; neuronal circuitry; new therapeutic target; nutrition; offspring; paraventricular nucleus; postnatal; programs; relating to nervous system; sensory input

PROJECT SUMMARY Despite a growing consensus that developmental programming of metabolic regulation contributes to the current obesity epidemic, our understanding of developmental mechanisms impacting this process remains rudimentary. The long range goal of this line of research is to define the developmental neurobiology of central pathways that contribute to developmental programming of metabolic phenotype. Maternal high fat diet (MHFD) exposure represents a developmental risk factor that contributes to metabolic dysregulation and impacts leptin sensitivity. MHFD also appears to impact leptin secretion, but it remains unknown whether it affects the developmental actions of leptin. For the proposed studies we will focus on neuronal pathways that connect the paraventricular hypothalamic nucleus (PVH) with two important components of the dorsal vagal complex (DVC): the dorsal motor nucleus of the vagus nerve (DMX) and the nucleus of the solitary tract (NTS), which regulate autonomic functions such as thermogenesis, energy expenditure and gastric motility. Inputs to the PVH from the NTS convey visceral sensory information, and inputs from the arcuate nucleus of the hypothalamus (ARH) and from the NTS convey hormonal signals. Integration of this information in the PVH impacts autonomic regulation through descending projections from the PVH to the DMX and NTS. However, it remains unknown if development of these connections is influenced by factors that program metabolic phenotype, such as MHFD and leptin. The overall hypothesis of the proposed research is that MHFD-L causes hyperleptinemia during a critical period of postnatal development that disrupts normal targeting of connections between the PVH and the DVC, and that the integrity of these connections is important for conveying signals that regulate distinct aspects of neuroendocrine physiology and autonomic function. Molecular genetic manipulation of leptin signaling, neuroanatomical methods, and physiological profiling will be used to address the following Specific Aims: 1) Define the impact of MHFD on formation of connections between the PVH and DVC in offspring, and document corresponding changes in postnatal leptin secretion and autonomic physiology; 2) Determine if leptin is required for development of bidirectional connections between the PVH and DVC; 3) Identify the site(s) of action, and physiological consequences, for developmental effects of leptin on formation of connections between the PVH and DVC. Completion of these aims will advance our understanding of how environmental signals program essential components of neural systems required to maintain normal metabolic physiology, and may identify novel therapeutic targets.

项目摘要 尽管人们越来越共识，即代谢法规的发展计划有助于 当前的肥胖流行，我们对影响这一过程的发展机制的理解仍然存在 基本。这一研究的远距离目标是定义中央的发育神经生物学 有助于代谢表型的发展编程的途径。产妇高脂饮食 （MHFD）暴露是一个发育风险因素，导致代谢失调和 影响瘦素敏感性。 MHFD似乎也会影响瘦素的分泌，但尚不清楚它是否 影响瘦素的发育作用。对于拟议的研究，我们将重点介绍 将旁丘脑下丘脑核（PVH）与背面迷走神经的两个重要组成部分连接 复合物（DVC）：迷走神经的背运动核（DMX）和孤立道的核（NTS）， 调节自主神经功能，例如生热，能量消耗和胃运动。输入到 来自NTS的PVH传达内脏的感觉信息，并输入来自 下丘脑（ARH）和NTS传达荷尔蒙信号。将此信息集成在PVH中 通过从PVH到DMX和NTS的下降预测来影响自主神经调节。但是，它 这些连接的发展是否受到代谢程序的因素的影响仍然不知道 表型，例如MHFD和瘦素。拟议研究的总体假设是MHFD-L 在产后发育的关键时期引起高血治血症，这破坏了正常的靶向 PVH与DVC之间的联系，这些连接的完整性对于 传达信号，这些信号调节神经内分泌生理和自主功能的不同方面。 瘦素信号传导，神经解剖学方法和生理分析的分子遗传操纵将是 用于解决以下特定目的：1）定义MHFD对建立连接的影响 在后代的PVH和DVC之间，以及文档的产后瘦素分泌的相应变化 和自主生理学； 2）确定开发双向连接是否需要瘦素 在PVH和DVC之间； 3）确定动作的部位和生理后果 瘦素对PVH和DVC之间联系形成的发育影响。这些完成 目标将促进我们对环境信号计划如何神经的重要组成部分的理解 维持正常的代谢生理所需的系统，并可能识别新的治疗靶点。