Requirement of 5-HT2CRs in POMC and SIM1 neurons to Regulate Energy Homeostasis

POMC 和 SIM1 神经元中 5-HT2CR 调节能量稳态的需要

• 批准号: 8265887
• 负责人: Eric Berglund
• 金额: $ 5.39万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265887
• 关键词: Agonist; Body Weight; Brain; Complex; Data; Diet; Eating; Energy Metabolism; Fatty acid glycerol esters; Fenfluramine; Genetically Engineered Mouse; Homeostasis; Hyperphagia; Hypothalamic structure; Knockout Mice; Ligands; Literature; Mediating; Metabolic; Mind; Modeling; Mus; Neurons; Obesity; Pathway interactions; Phenotype; Physical activity; Physiological; Prevalence; Pro-Opiomelanocortin; Process; Protein Isoforms; Reporting; Serotonin; Serotonin Receptor 5-HT2C; Structure of nucleus infundibularis hypothalami; Techniques; Testing; Validation; Work; base; combat; energy balance; feeding; improved; in vivo; insight; loss of function; mouse model; neurodevelopment; new therapeutic target; paraventricular nucleus; phenylpiperazine; receptor; receptor expression; research study

DESCRIPTION (provided by applicant): Serotonin (5-HT) and related agonists are well characterized to act upon the 2C isoform of its receptor (5HT2CR) in the arcuate and paraventricular nuclei of the hypothalamus (ARH and PVH) to suppress food intake and exert anti-obesity effects. The specific neuronal targets of 5-HT and related agonists in the ARH and PVH required for such effects are, in contrast, not well defined. Recent work in which 5HT2CR expression was selectively restored to pro-opiomelanocortin (POMC) neurons within the ARH identifies that this distinct neuronal sub-set is a strong candidate to be a target. This notion is based on evidence that selective re- activation of 5HT2CRs in POMC neurons rescues the hyperphagic and obese phenotype of 5HT2CR-null mice. Preliminary data in this application also highlights that simple-minded 1 (SIM1) neurons in the PVH co-express 5HT2CRs and may be one type of neuron targeted by 5-HT and related agonists. The current proposal aims to test whether 5-HT and related agonists require 5HT2CR expression in POMC and SIM1 neurons in the ARH and PVH, respectively, to maintain normal body weight and to exert anti-obesity effects. This will be accomplished by combining genetically engineered mouse models in which endogenous 5HT2CR are selectively deleted in either POMC or SIM1 neurons with comprehensive analyses of energy homeostasis and administration of 5-HT agonists m-chloro-phenylpiperazine (mCPP) and D-fenfluramine (d-Fen). The proposed mouse models in which 5HT2CRs will be selectively deleted using cre-lox techniques in either POMC or SIM1 neurons provide a powerful and unique model to assess the physiological relevance and requirement for these pathways. The comprehensive approach to analyze the phenotype of these mice will include histological validation of the mouse model as well as assessments of brain development and neural survival. Metabolic cages studies will also be performed in mice fed chow and high-fat diet to assess food intake, energy expenditure, and physical activity. Taken together, these approaches will provide mechanistic insight into the effects of 5-HT and related agonists in the CNS. The expected findings are that 5-HT and related agonist will require POMC and SIM1 neurons to maintain normal body weight homeostasis and to fully mediate the anti- obesity effects of mCPP and d-Fen. These findings would improve our understanding about how the body controls energy homeostasis and potentially offer new therapeutic targets.

描述（由申请人提供）：羟色胺（5-HT）和相关激动剂的特征是在下丘脑（ARH和PVH）的弧形和室室中其受体（5HT2CR）的2C同工型（5HT2CR）作用，以抑制食物的进气口和发挥抗obesity效应。相比之下，ARH和PVH中的5-HT和相关激动剂的特定神经元靶标的定义不当。在ARH中，5HT2CR表达选择性恢复为促蛋白酶皮质素（POMC）神经元的最新工作表明，这种独特的神经元子集是成为目标的有力候选者。该概念基于证据表明，POMC神经元中5HT2CR的选择性激活挽救了5HT2CR-NULL小鼠的肥大和肥胖表型。该应用程序中的初步数据还强调了PVH共表达5HT2CR中的简单1（SIM1）神经元，并且可能是由5-HT和相关激动剂靶向的一种神经元。当前的建议旨在测试5-HT和相关激动剂是否需要在ARH和PVH中分别在POMC和SIM1神经元中表达5HT2CR，以保持正常体重并发挥抗肥胖作用。这将通过结合基因工程的小鼠模型来实现，其中在POMC或SIM1神经元中选择性地删除了内源性5HT2CR与能量稳态的全面分析以及5-HT激动剂M-氯 - 氯苯基吡嗪（MCPP）（MCPP）（MCPP）和二富富胺（D-Fenferramine（D-Fen））的全面分析。在POMC或SIM1神经元中使用CRE-LOX技术选择性删除5HT2CR的提议的小鼠模型提供了一个强大而独特的模型，以评估这些途径的生理相关性和需求。分析这些小鼠表型的综合方法将包括对小鼠模型的组织学验证以及对脑发育和神经存活的评估。还将在喂食食物和高脂饮食的小鼠中进行代谢笼研究，以评估食物摄入，能量消耗和体育锻炼。综上所述，这些方法将提供有关中枢神经系统中5-HT和相关激动剂的影响的机械洞察力。预期的发现是5-HT和相关的激动剂将要求POMC和SIM1神经元保持正常体重稳态，并完全介导MCPP和D-FEN的抗肥胖作用。这些发现将提高我们对人体如何控制能量稳态的理解，并可能提供新的治疗靶标。