Leptin and Developmental Programming of Hypothalamic Autonomic Outflow

项目总结 尽管越来越多的人一致认为代谢调节的发展规划有助于 目前肥胖的流行，我们对影响这一过程的发育机制的理解仍然 很初级的。这项研究的长期目标是确定中枢神经系统的发育神经生物学 有助于代谢表型的发育规划的途径。母体高脂饮食 接触MHFD是一种发育风险因素，可导致代谢失调和 影响瘦素敏感性。MHFD似乎也影响瘦素的分泌，但目前尚不清楚是否 影响瘦素的发育行为。对于提议的研究，我们将重点关注神经通路， 下丘脑室旁核(PVH)与迷走神经背侧核的联系 复合体(DVC)：迷走神经背侧运动核(DMX)和孤束核(NTS)； 它们调节自主神经功能，如产热、能量消耗和胃运动。输入到 来自NTS的PVH传递内脏感觉信息，并从弓状核传入。 下丘脑(ARH)和NTS传递荷尔蒙信号。此信息在PVH中的集成 通过从PVH向DMX和NTS的下行投射影响自主调节。然而，它 目前尚不清楚这些连接的发展是否受到编程新陈代谢的因素的影响 表型，如MHFD和Leptin。拟议研究的总体假设是，MHFD-L 在出生后发育的关键时期引起高瘦素血症，从而扰乱正常的靶向 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和自主神经功能的不同方面的信号。 瘦素信号的分子遗传操作、神经解剖学方法和生理图谱将被 用于解决以下具体目标：1)确定MHFD对形成连接的影响 子代PVH和DVC之间的关系，以及出生后瘦素分泌的相应变化 和自主神经生理学；2)确定瘦素是否是发展双向连接所必需的 在PVH和DVC之间；3)确定作用部位(S)和生理后果， 瘦素在下丘脑-下丘脑-下丘脑室旁核连接形成中的发育作用完成这些工作 AIMS将促进我们对环境信号如何编程神经的基本组成部分的理解 维持正常代谢生理所需的系统，并可能确定新的治疗靶点。

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.