Mechanisms underlying autonomic innervation plasticity in regulating energy balance

项目概要 肥胖是公共卫生的一个重大挑战，它使个人容易患代谢性疾病，例如 如糖尿病。它的出现是由于能量平衡的稳态维持失调，导致 相对于支出而言过量的摄入/储存。通过将能量储存驱动到白色脂肪中 副交感神经驱动胰腺激素胰岛素的释放，自主神经系统发挥作用 在能量稳态中发挥关键的调节作用。它还通过激活脂肪来驱动能量的消耗 交感神经系统。 脂肪激素瘦素协调神经系统和能量之间的沟通 储存器官，脂肪，是维持能量平衡的稳态所必需的。瘦素以前是 据了解，这是通过与大脑形成负反馈循环来减少脂肪量来实现这一点的。 食物摄入和对脂肪的交感神经兴奋作用。令人惊讶的是，我们发现瘦素还调节 脂肪组织内部交感神经支配水平的可塑性。这些监管影响 支配脂肪的交感神经结构对能量调节具有功能性影响 白色脂肪脂肪分解和棕色脂肪产热。虽然我们已经描绘了控制这个的大脑回路 过程，瘦素用于调节脂肪神经支配可塑性的机制，以及该过程是否 是否发生在其他代谢器官中，目前尚不清楚。 在这笔资助的指导阶段，我将寻求对瘦素依赖性如何产生机械性的理解 大脑信号被转化为脂肪交感神经支配的可塑性。具体来说，我会剖析如何 前自主神经群的活动，室旁下丘脑中表达 BDNF 的神经元， 动态调节脂肪中的交感神经支配水平。此外，为了鉴定分子 与支配脂肪的交感神经节可塑性相关的变化，我将开发一种邻近蛋白 标记策略从脂肪内的神经中丰富这些因子，用于定量蛋白质组学。最后，在 独立阶段，我将探讨瘦素对器官自主神经支配可塑性影响的一般性 超出脂肪组织。在这里，我将研究瘦素对一个重要器官的神经支配可塑性的作用。 能量存储，胰腺，使用在本提案的指导部分中开发的工具。 总而言之，这项工作将揭示瘦素调节自主神经可塑性的机制 脂肪和胰腺内部的神经支配。了解这些机制将有助于识别 直接调节自主神经支配的下游靶标及其在调节中的功能作用 能量平衡，为治疗肥胖和糖尿病的新疗法奠定了基础。

Project Summary Obesity is a major challenge for public health that predisposes individuals for metabolic diseases such as diabetes. It arises because of a dysregulation in homeostatic maintenance of energy balance, resulting in excess intake/storage relative to expenditure. By driving the storage of energy into white fat via parasympathetic nerve driven release of the pancreatic hormone insulin, the autonomic nervous system plays a key regulatory role in energy homeostasis. It also drives the expending of energy from fat by activation of the sympathetic nervous system. The adipose hormone leptin orchestrates the communication between the nervous system and energy storage organ, fat, that is necessary for homeostatic maintenance of energy balance. Leptin was previously understood to do this by acting in a negative feedback loop with the brain to reduce fat mass via reduction of food intake and sympatho-excitatory effects on adipose. Surprisingly, we discovered that leptin also regulates plasticity in levels of sympathetic innervation inside of adipose tissue. These regulatory effects on the sympathetic nerve architecture innervating adipose has functional implications for energy regulation by both white fat lipolysis and brown fat thermogenesis. While we have delineated the brain circuit controlling this process, the mechanisms that leptin uses to regulate adipose innervation plasticity, and whether this process occurs in other metabolic organs, is still unknown. In the mentored phase of this grant, I will pursue a mechanistic understanding of how leptin-dependent brain signals are translated into adipose sympathetic innervation plasticity. Specifically, I will dissect how activity of a pre-autonomic neural population, BDNF-expressing neurons in the paraventricular hypothalamus, dynamically regulates sympathetic innervation levels in adipose. Furthermore, to identify the molecular changes associated with plasticity in sympathetic ganglia innervating fat, I will develop a proximity protein tagging strategy to enrich these factors from nerves inside fat for quantitative proteomics. Finally, in the independent phase, I will explore the generality of leptin’s effects on autonomic innervation plasticity in organs beyond adipose tissue. Here, I will study the role of leptin on innervation plasticity in an organ important for energy storage, the pancreas, using the tools developed during the mentored part of this proposal. Altogether, this work will uncover the mechanisms by which leptin regulates the plasticity of autonomic innervation inside of adipose and the pancreas. Understanding these mechanisms will enable the identification of downstream targets which directly modulate autonomic innervation and their functional role in regulating energy balance, forming a foundation for new therapies to treat obesity and diabetes.