Mechanisms underlying autonomic innervation plasticity in regulating energy balance

自主神经支配可塑性调节能量平衡的机制

• 批准号: 10675231
• 负责人: Huai Jin Ken Leon Loh
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675231
• 关键词: Acute; Address; Adipose tissue; Adult; Affect; American; Architecture; Automobile Driving; Autonomic nervous system; Axon; Biological Assay; Biotin; Biotinylation; Brain; Brain-Derived Neurotrophic Factor; Brown Fat; Cell Adhesion Molecules; Cells; Chronic; Communication; Defect; Diabetes Mellitus; Disease; Dissection; Eating; Energy Metabolism; Expenditure; Fatty acid glycerol esters; Feedback; Foundations; Functional disorder; Gene Expression Profiling; Glucagon; Grant; Homeostasis; Hormones; Hypothalamic structure; Individual; Insulin; Intake; Islet Cell; Islets of Langerhans; Label; Lead; Leptin; Ligase; Light; Lipolysis; Long-Term Effects; Maintenance; Mass Spectrum Analysis; Mediating; Mentors; Metabolic; Metabolic Diseases; Methods; Microscopy; Molecular; Nature; Nerve; Nervous system structure; Neurons; Nutrient; Obese Mice; Obesity; Organ; Pancreas; Pancreatic Hormones; Pancreatitis; Pattern; Phase; Play; Population; Process; Proteins; Proteomics; Public Health; Regulation; Resistance; Role; Signal Transduction; Surface; Sympathetic Ganglia; Sympathetic Nervous System; Testing; Therapeutic; Thermogenesis; Tissues; Translating; Work; arm; autocrine; blood glucose regulation; cell type; density; diet-induced obesity; differential expression; energy balance; in vivo; in vivo calcium imaging; loss of function; nerve supply; neural circuit; novel therapeutics; prenatal; reinnervation; relating to nervous system; response; restoration; tool; uptake

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.

项目摘要 肥胖是公共卫生的主要挑战 作为糖尿病。由于稳态维持能量平衡的失调而产生，导致 相对于支出过多的摄入/存储。通过将能量存储到白脂中 胰腺胰岛素胰岛素的副交感神经驱动器释放，自主神经系统播放 能量体内稳态中的关键调节作用。它还通过激活脂肪从脂肪中消耗能量 交感神经系统。 脂肪马酮瘦素协调神经系统与能量之间的通信 存储器官，脂肪，这对于维持能量平衡是必需的。瘦素以前是 理解通过与大脑进行负反馈循环作用，以减少脂肪质量，以减少脂肪质量 食物摄入量和交感对脂肪的影响。令人惊讶的是，我们发现瘦素也调节 脂肪组织内部交感神经支配水平的可塑性。这些监管对 交感神经结构支配脂肪对两者都对能量调节具有功能含义 白色脂肪脂解和棕色脂肪的热发生。当我们描述了控制这一点的脑电路时 过程，瘦素用于调节脂肪神经塑性的机制，以及该过程是否 发生在其他代谢器官中，仍然未知。 在这笔赠款的修订阶段，我将追求对瘦素依赖性的机械理解 大脑信号被转化为脂肪交感神经神经塑性。具体来说，我将剖析 自主神经元种群，表达BDNF的神经元的活性 动态调节脂肪中的交感神经神经水平。此外，要识别分子 与交感神经神经支配脂肪中的可塑性相关的变化，我将开发邻近蛋白 标记策略以丰富脂肪内部神经的这些因素以进行定量蛋白质组学。最后，在 独立阶段，我将探讨瘦素对器官自主神经神经可塑性影响的普遍性 超越脂肪组织。在这里，我将研究瘦素对神经可塑性在器官中的作用 储能，胰腺，使用在本提案的指导部分中开发的工具。 总之，这项工作将发现瘦素调节自主神经的机制 脂肪和胰腺内部的神经。了解这些机制将实现识别 下游目标的直接调节自主神经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构成基础。