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: 10667322
• 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/10667322
• 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; Eating; Electrophysiology (science); Feedback; Feeding behaviors; Food Aversion; Gastrectomy; Genetic; Goals; Greater curvature of stomach; High Fat Diet; Hormonal; Impairment; Maps; Measures; Mechanics; Mediating; Mediator; 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; diet-induced obesity; effective therapy; feeding; genetic approach; gut-brain axis; improved; mechanotransduction; neural; neural circuit; neuromechanism; neurotransmission; obesity treatment; preclinical study; pressure; programs; 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.

垂直套管切除术的代谢作用的神经介体 抽象的 关于饮食的决定，由复杂的通信网络调节 中枢神经系统和肠道涉及各种激素，代谢产物和神经元反馈系统。减肥手术， 可以说是肥胖及其并发症的最有效治疗方法，改变了这些反馈的各个方面 系统和导致体重减轻和代谢改善。我们已经证明了 在特定的神经元（降钙素受体）中，营养素诱导的神经元激活（FOS）更大； calcr）在固体道（NTS）的核内，CNS区域对于整合周围至关重要 特定减肥手术后的信号和喂养行为的变化，垂直袖子 加斯切除术（VSG）。 VSG，该过程，沿着更大的曲率沿着80％的stallch被去除， 产生几种潜在的化学和机械感应信号，这些神经元对包括 养分本身水平，更大的胃压或许多餐后肠道的增加 分泌的肽。该提案的总体目的是确定这些激活的身份和功能 NTS神经元和这些神经元种群被激活的机制。 在该计划项目的项目1和2中，我们生成了初步数据，证明了这一点 NTS（LEPRB，CALCR和CCK）和PBN（GLP-1R和CGRP）内神经元的种群至关重要 用于调节喂养和对毒素的反应，如条件味道厌恶所测量。鉴于我们的 数据还表明，NTS内的CALCR被VSG特别激活 假设是肥胖症会损害，减肥手术“修复”这些电路以减少进食和 诱导体重减轻。为了检验这一假设，我们将使用遗传和化学遗传策略组合 使用电生理学（使用神经生理学核心，NPC，Goforth）来确定相关电路 在NTS内（AIM 1）负责用肥胖症和减肥手术后的喂养行为变化，以及 在AIM 2中，我们将定义手术诱导的NTS激活的机制。