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.

垂直袖状胃切除术代谢效应的神经介质 抽象的 关于吃什么和吃多少的决定是由大脑之间复杂的通信网络控制的。 中枢神经系统和肠道，涉及多种激素、代谢物和神经反馈系统， 有争议的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 我们已经证明了这一点。 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； CALCR）位于孤束核（NTS）内，这是一个对于整合外周神经系统至关重要的中枢神经系统区域 在特定的减肥手术后，垂直袖子发出信号并开始改变喂养行为 胃切除术 (VSG)，一种沿大弯切除 80% 胃的手术， 产生这些神经元响应的几种潜在的化学和机械感应信号，包括 营养物质本身的水平、更高的胃压或许多餐后肠道的数倍增加 该提案的总体目标是确定这些激活的肽的身份和功能。 NTS 神经元以及这些神经群被激活的机制。 在该计划项目的项目 1 和 2 中，我们生成了初步数据，表明不同的 NTS（LEPRb、CALCR 和 CCK）和 PBN（GLP-1R 和 CGRP）内的神经元群体至关重要 通过条件味觉厌恶来调节进食和对毒素的反应。 数据还表明，NTS 中的 CALCR 是由 VSG（我们的首要任务）专门激活的。 假设肥胖会损害，而减肥手术“修复”这些回路以减少进食和进食 为了验证这一假设，我们将结合使用遗传和化学遗传学策略。 用电生理学（使用神经生理学核心、NPC、Goforth）确定相关电路 NTS（目标 1）内负责肥胖和减肥手术后喂养行为的变化，以及 在目标 2 中，我们将定义手术引起的 NTS 激活的机制。