Project 3: Neural mediators in the metabolic effects of Vertical Sleeve Gastrectomy

项目3：垂直袖状胃切除术代谢影响中的神经介质

• 批准号: 10018888
• 负责人: DARLEEN A. SANDOVAL
• 金额: $ 45.71万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018888
• 关键词: Acute; Affect; Afferent Neurons; Anatomy; Behavioral; Body Weight; Body Weight decreased; Brain Stem; Calcitonin Receptor; Cells; Cholecystokinin; Chronic; Communication; Complex; Data; Defect; Diet; Eating; Electrophysiology (science); Feedback; Feeding behaviors; Food Aversion; Gastrectomy; Genetic; Goals; Greater curvature of stomach; High Fat Diet; Hormonal; Impairment; Measures; Mechanics; Mediating; Mediator of activation protein; Metabolic; Metabolic Diseases; Neurons; Nodose Ganglion; Nuclear Pore Complex; Nucleus solitarius; Nutrient; Obesity; Operative Surgical Procedures; Patients; Peptides; Peripheral; Physiological; Physiology; Population; Procedures; Regulation; Role; Satiation; Sensory; Signal Transduction; Stimulus; Stomach; System; Taste aversion; Testing; Toxin; bariatric surgery; effective therapy; feeding; gut-brain axis; neural circuit; neuromechanism; obesity treatment; preclinical study; pressure; programs; relating to nervous system; response; success

Neural mediators of the metabolic effects of vertical sleeve gastrectomy Abstract Decisions about what and how much to eat are regulated by a complex communication network between the CNS and gut and involve a variety of hormonal, metabolite, and neuronal feedback systems. Bariatric surgery, arguably the most effective treatment for obesity and its complications, alters every aspect of these feedback systems and results in substantial weight loss and metabolic improvements. We have demonstrated that nutrient-induced neuronal activation (FOS) is greater within a specific subset of neurons (calcitonin receptor; CALCR) within the nucleus of the solitary tract (NTS), a CNS region that is critical for integrating peripheral signals and initiating changes in feeding behavior, after a particular bariatric surgery, vertical sleeve gastrectomy (VSG). VSG, a procedure where 80% of the stomach along the greater curvature is removed, generates several potential chemo- and mechano-sensing signals that these neurons respond to including the levels of nutrients themselves, greater gastric pressure, or the several-fold increase in many postprandial gut- secreted peptides. The overall aim of this proposal is to determine the identity and function of these activated NTS neurons and the mechanism(s) by which these neuronal populations are activated. In projects 1&2 of this program project, we have generated preliminary data demonstrating that distinct populations of neurons within the NTS (LEPRb, CALCR, and CCK) and PBN (GLP-1R and CGRP) are critical for regulation of feeding and responses to toxins as measured by conditioned taste aversion. Given that our data also demonstrates that CALCR within the NTS are specifically activated by VSG, our over-arching hypothesis is that obesity impairs, and bariatric surgery “fixes” these circuits to reduce feeding and induce weight loss. To test this hypothesis, we will use genetic and chemogenetic strategies in combination with electrophysiology (using the neural physiology core, NPC, Goforth) to determine the relevant circuits within the NTS (Aim 1) responsible for changes in feeding behavior with obesity and after bariatric surgery, and in Aim 2, we will define the mechanisms that underlie the surgery-induced NTS activation.

垂直袖状胃切除术代谢效应的神经介质 摘要 关于吃什么和吃多少的决定由一个复杂的通信网络控制， 中枢和肠道，涉及各种激素、代谢物和神经元反馈系统。减肥手术， 可以说，肥胖及其并发症最有效的治疗方法改变了这些反馈的方方面面 系统和结果大幅减肥和新陈代谢改善。我们已经证明了 营养诱导的神经元激活(FOS)在特定的神经元亚群(降钙素受体； 孤束核(NTS)内的CALCR)，这是一个对整合外周至关重要的CNS区域 在特定的减肥手术后，垂直袖子发出的信号和启动喂养行为的变化 胃切除术(VSG)。VSG是一种沿着大弯切除80%的胃的手术， 产生几个潜在的化学和机械感知信号，这些神经元对这些信号做出反应，包括 营养水平本身，更大的胃压，或者许多餐后肠道的几倍增长- 分泌的多肽。本提案的总体目标是确定被激活的 孤束核神经元及其激活机制(S)。 在这个计划项目的项目1和2中，我们已经生成了初步数据，证明了不同的 NTS(LEPRb、CALCR和CCK)和PBN(GLP-1R和CGRP)内的神经元群体是至关重要的 用于调节摄食和对毒素的反应，通过条件味觉厌恶来衡量。鉴于我们的 数据还表明，NTS内的CALCR是由VSG(我们的最高结构)专门激活的 假说是肥胖会损害身体，而减肥手术“修复”了这些回路，减少了进食和营养。 诱导体重减轻。为了验证这一假设，我们将结合使用遗传和化学发生策略。 用电生理学(使用神经生理学核心、NPC、GOFORTH)确定相关电路 在NTS(目标1)内，负责肥胖和减肥手术后进食行为的变化，以及 在目标2中，我们将定义手术诱导NTS激活的机制。