Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius

孤束核中黑皮质素 4 受体放大饱足感信号

• 批准号: 10389570
• 负责人: Samantha Fortin
• 金额: $ 0.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-15 至 2021-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10389570
• 关键词: Afferent Neurons; Agonist; Amplifiers; Anti-Obesity Agents; Appetite Depressants; Attenuated; Basic Science; Behavior Therapy; Body Weight; Body Weight decreased; Brain; Cell Nucleus; Chemosensitization; Cholecystokinin; Dependovirus; Development; Eating; Endocrine system; FOS gene; Feedback; Feeding behaviors; Fiber; Food Intake Regulation; Immunohistochemistry; Intake; Lead; Mediating; Melanocortin 4 Receptor; Metabolic Pathway; Neurons; Nodose Ganglion; Obesity; Obesity Epidemic; Pancreas; Pattern; Peripheral; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phenotype; Photometry; Population; Positioning Attribute; Prevalence; Public Health; Rattus; Receptor Activation; Receptor Signaling; Regulation; Research; Role; SHU 9119; Satiation; Signal Transduction; System; Testing; United States; Vagus nerve structure; Weight; Weight maintenance regimen; Work; awake; cholecystokinin 8; gastrointestinal; glucagon-like peptide 1; health economics; hindbrain; in vivo; knock-down; melanotan-II; neuroregulation; neurotransmission; novel; obesity treatment; postsynaptic; postsynaptic neurons; presynaptic; reduced food intake; relating to nervous system; response; small hairpin RNA; success; therapeutically effective

Project Summary The astounding prevalence of obesity presents major public health and economic consequences. The development of more effective therapeutics for weight loss is paramount and requires basic science research to characterize the neural control of feeding behavior. Melanocortin signaling, through melanocortin 4 receptors (MC4Rs) in the nucleus tractus solitarius (NTS) contributes to food intake control by reducing meal size via amplification of within-meal gastrointestinally (GI)-derived satiation signals. However, the mechanism of MC4R signaling within the NTS is not clear and the translational significance of the interaction between NTS melanocortin signaling and other hormonal systems at the level of the NTS has not been adequately explored. The proposed research aims to test the hypothesis that endogenous pre- and postsynaptic NTS MC4R activity modulates NTS neural signaling and food intake and body weight suppression evoked by the GI- derived satiation signals cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). Specific Aim I will use in vivo fiber photometry to examine bidirectional modulation of CCK- and GLP-1-evoked NTS neural activity by hindbrain delivery of the MC4R agonist MTII or antagonist Shu9119. We hypothesize that neural activity evoked by either of these satiation signals will be amplified by exogenous MTII and attenuated by Shu9119. As we hypothesize that potentiation of NTS neural activity will result in amplified satiation signaling, we expect NTS delivered MTII to also enhance the food intake and body weight suppressive effects of peripherally administered CCK or GLP-1. Specific Aim II will utilize an adeno-associated virus (AAV)-encoding a validated shRNA construct for the MC4R, delivered to either the nodose ganglion of the vagus nerve or to the NTS, to selectively knockdown MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons, respectively. We will analyze day-to-day meal patterns in each of these groups of rats to dissociate the endogenous contribution of pre- and postsynaptic NTS MC4Rs to food intake and body weight control. We will go on to use this strategy to examine the role of pre- and postsynaptic MC4Rs in mediating the intake-suppressive effects of exogenous NTS MTII delivery and in potentiating the anorectic actions of CCK and GLP-1. Finally, we will begin to characterize the phenotype of MTII-activated neurons within the NTS. By determining the functional relevance and mechanism of MC4R signaling within the NTS, these studies will contribute to identification of a novel NTS MC4R-activated circuit that may be manipulated through pharmacological approaches to reduce food intake and body weight.

项目概要 肥胖症的惊人流行带来了重大的公共卫生和经济后果。这 开发更有效的减肥疗法至关重要，需要基础科学研究 表征进食行为的神经控制。黑皮质素信号传导，通过黑皮质素 4 受体 孤束核（NTS）中的（MC4Rs）通过减少膳食量来控制食物摄入量 放大餐内胃肠道 (GI) 衍生的饱腹感信号。然而，MC4R的机制 NTS 内的信号传导尚不清楚，NTS 之间相互作用的翻译意义 NTS 水平的黑皮质素信号传导和其他激素系统尚未得到充分探索。 拟议的研究旨在检验内源性突触前和突触后 NTS MC4R 的假设 活性调节 NTS 神经信号传导以及胃肠道引起的食物摄入和体重抑制 衍生的饱腹感信号胆囊收缩素 (CCK) 和胰高血糖素样肽-1 (GLP-1)。具体目标我会 使用体内光纤光度测定法检查 CCK 和 GLP-1 诱发的 NTS 神经活动的双向调节 通过后脑递送 MC4R 激动剂 MTII 或拮抗剂 Shu9119。我们假设神经活动 由这些饱足信号中的任何一个引起的饱食信号将被外源 MTII 放大并被 Shu9119 减弱。作为 我们假设 NTS 神经活动的增强将导致饱足感信号放大，我们预计 NTS 提供 MTII 还可以增强外周给药的食物摄入和体重抑制作用 CCK 或 GLP-1。 Specific Aim II 将利用腺相关病毒 (AAV) 编码经过验证的 shRNA 构建体 对于 MC4R，递送至迷走神经的结状神经节或 NTS，以选择性地击倒 MC4R 分别在迷走神经突触前传入神经元或突触后 NTS 神经元上表达。我们将分析 这些组中每一组大鼠的日常膳食模式，以分离前和后的内源性贡献 突触后 NTS MC4R 影响食物摄入和体重控制。我们将继续使用这个策略来检查 突触前和突触后 MC4R 在介导外源性 NTS MTII 摄入抑制作用中的作用 递送并增强 CCK 和 GLP-1 的食欲作用。最后，我们将开始描述 NTS 内 MTII 激活神经元的表型。通过确定功能相关性和机制 NTS 内 MC4R 信号传导的研究，这些研究将有助于鉴定新型 NTS MC4R 激活 可以通过药理学方法操纵回路来减少食物摄入和体重。