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: 9344621
• 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/9344621
• 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; Image Analysis; Immunohistochemistry; Impairment; 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; 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.

项目概要 尽管越来越多的人认为代谢调节的发育编程有助于 当前肥胖流行，我们对影响这一过程的发育机制的理解仍然存在 简陋的。这一系列研究的长期目标是定义中枢神经系统的发育神经生物学。 有助于代谢表型发育编程的途径。产妇高脂肪饮食 (MHFD) 暴露是一种发育风险因素，会导致代谢失调和 影响瘦素敏感性。 MHFD 似乎也会影响瘦素分泌，但仍不清楚是否会影响瘦素分泌。 影响瘦素的发育作用。对于拟议的研究，我们将重点关注神经元通路 连接下丘脑室旁核（PVH）与背侧迷走神经的两个重要组成部分 复合体（DVC）：迷走神经背运动核（DMX）和孤束核（NTS）， 调节自主神经功能，如产热、能量消耗和胃蠕动。输入到 来自 NTS 的 PVH 传递内脏感觉信息，以及来自神经弓状核的输入 下丘脑 (ARH) 和 NTS 传递激素信号。将此信息集成到 PVH 中 通过从 PVH 到 DMX 和 NTS 的下降投影来影响自主调节。然而，它 目前尚不清楚这些连接的发展是否受到代谢程序因素的影响 表型，例如 MHFD 和瘦素。本研究的总体假设是 MHFD-L 在出生后发育的关键时期引起高瘦素血症，破坏正常的目标 PVH 和 DVC 之间的连接，这些连接的完整性对于 传递调节神经内分泌生理学和自主神经功能不同方面的信号。 瘦素信号传导的分子遗传学操作、神经解剖学方法和生理学分析将是 用于实现以下具体目标： 1) 定义 MHFD 对连接形成的影响 后代的 PVH 和 DVC 之间的关系，并记录出生后瘦素分泌的相应变化 和自主生理学； 2) 确定双向连接的发展是否需要瘦素 PVH 和 DVC 之间； 3) 确定作用部位和生理后果， 瘦素对 PVH 和 DVC 之间连接形成的发育影响。完成这些 目标将增进我们对环境信号如何编程神经元基本组成部分的理解 维持正常代谢生理学所需的系统，并可能确定新的治疗靶点。