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.

项目摘要 肥胖的惊人患病率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，需要基础科学研究才能 表征喂养行为的神经控制。黑色皮质素信号传导，通过黑色皮质素4受体 （MC4RS）在核Tractus solitarius（NTS）中，通过减小饮食大小来促进食物摄入量 米尔内胃肠道（GI）衍生的饱腹感信号的扩增。但是，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 在NTS水平上，黑色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前和突触后NTS MC4R的假设 活动调节NTS神经信号传导，食物摄入量以及抑制体重。 衍生的饱食信号胆囊化蛋白（CCK）和胰高血糖素样肽-1（GLP-1）。具体目的我会 使用体内纤维光度法检查CCK-和GLP-1诱发的NTS神经活动的双向调制 通过MC4R激动剂MTII或拮抗剂SHU9119的后脑递送。我们假设神经活动 这两个饱满信号中的任何一个都将被外源MTII扩增，并被Shu9119衰减。作为 我们假设NTS神经活动的增强将导致放大的饱腹信号传导，我们预计NTS 交付的MTII还可以增强外周施用的食物摄入量和体重抑制作用 CCK或GLP-1。特定的AIM II将利用与经过验证的shRNA构建的腺相关病毒（AAV） 对于MC4R，交付到迷走神经的淋巴神经节或NTS MC4R在迷走神经前传入剂或突触后NTS神经元上表达。我们将分析 每组大鼠的日常进餐方式，以解离前后的内源性贡献 突触后NTS MC4RS进行食物摄入和体重控制。我们将继续使用此策略检查 突触前和后MC4RS在介导外源性NTS MTII的进气抑制作用中的作用 传递和增强CCK和GLP-1的厌食症作用。最后，我们将开始描述 NTS内的MTII激活神经元的表型。通过确定功能相关性和机制 在NTS中的MC4R信号传导中，这些研究将有助于鉴定新的NTS MC4R激活 可以通过药理方法来操纵的电路，以减少食物摄入和体重。