Appetite: Serotonin and corticotropin releasing factor

食欲：血清素和促肾上腺皮质激素释放因子

基本信息

批准号：
7364444
负责人：
SuJean Choi
金额：
$ 29.8万
依托单位：
MARQUETTE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7364444
关键词：
Affect Anorexia Appetite Regulation Back Body Weight decreased Brain Brain region Caring Cell Nucleus Cells Chromosome Pairing Clinical Corticotropin-Releasing Hormone Data Desire for food Development Disease Eating Effectiveness Endocannabinoids Etiology Experimental Designs Feeding behaviors Fenfluramine Funding Future Grant Health Hypothalamic structure Individual Laboratories Lead Link Literature MeSH Thesaurus Mediating Mediator of activation protein Melanocyte stimulating hormone Messenger RNA Metabolism Molecular National Institute of Diabetes and Digestive and Kidney Diseases Neurons Neuropeptides Numbers Obesity POMC gene Pathway interactions Pharmaceutical Preparations Pro-Opiomelanocortin Production RNA Interference Rattus Regulation Role Serotonin Serotonin Agonists Signal Transduction Suggestion Synapses Synaptic Transmission Tachyphylaxis Testing alpha-Melanocyte stimulating hormone base design energy balance feeding insight mRNA Expression monoamine neuronal cell body paraventricular nucleus protein expression receptor research study serotonin receptor transmission process

项目摘要

DESCRIPTION (provided by applicant): This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. PVN CRF neurons are important mediators in the control of feeding behavior; e.g. exogenous application of CRF or stimulation of CRF neurons result in the inhibition of food intake. Similarly, drugs that stimulate synaptic 5-HT transmission in the brain are also well known to inhibit food intake. Anatomically, it is also known that 5-HT terminal projections are found on PVN CRF neurons; this suggests that 5HT agents may suppress appetite through heretofore uncharacterized actions on PVN CRF neurons. A potential functional link between 5-HT is further supported by data demonstrating the presence of mRNAs for 5-HT receptor subtypes linked to appetite regulation in PVN CRF cell bodies. Remarkably, despite the suggestion of a number of studies, there have been no definitive studies to date demonstrating that 5-HT-associated drugs may indeed suppress feeding by stimulating CRF mRNA production and CRF protein expression. In this proposal, we hypothesize that there exists a functional link between serotonin (5-HT) and neuropeptides, such as CRF and melanocyte stimulating hormone (alpha MSH) and their respective neurons residing within the PVN (5-HT, CRF) and the arcuate (ARC) hypothalamic nuclei (alpha MSH), respectfully. Our Specific Aims are to (1) determine if 5-HT release regulates CRF or alpha MSH neurons in the PVN to suppress food intake; (2) Determine if 5-HT release indirectly regulates CRF neurons in the PVN via 1-MSH neurons residing in the arcuate and its associated neurons; and (3) determine downstream targets of hypothalamic CRF and its associated neurons. In our experimental design, we will utilize fenfluramine (FEN), a drug that strongly promotes 5HT synaptic transmission. Central and systemic FEN administration will be used to assess PVN CRF mRNA expression in rats pre-treated with 5-HT receptor antagonists specific to PVN CRF neurons that are appetite-linked (the 5HT-1B, 2A, & 2C subtypes). FEN will also be used to test whether 5-HT affects PVN CRF mRNA expression indirectly; 1-MSH release onto CRF neurons is stimulatory; hence, FEN could stimulate CRF neurons by increasing 1-MSH signaling. RNA interference will be used to eliminate CRF mRNA, to determine if FEN-initiated 5-HT influences appetite suppression by additional downstream mechanisms. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems. This proposal investigates the influence of serotonin (5-HT) and its associated neurons in the hypothalamic paraventricular nuclei (PVN) on neuronal corticotropin releasing factor (CRF) mRNA expression and feeding behavior in rats. These studies should provide new insight into the role of a poorly characterized 5HT-CRF synaptic connection in the control of food intake, and ultimately contribute to understanding if and how this connectivity is important to the regulation of overall energy balance, and the etiology of obesity, anorexia, and other appetite-related health problems.

描述（由申请人提供）：该提案研究了羟色胺（5-HT）及其在下丘脑旁脑室核（PVN）对神经元皮质性释放因子（CRF）mRNA表达和大鼠中喂养行为的影响。 PVN CRF神经元是控制喂养行为的重要介体。例如CRF的外源应用或CRF神经元的刺激导致食物摄入的抑制。同样，刺激大脑突触5-HT传播的药物也众所周知可以抑制食物摄入量。从解剖学上讲，还知道在PVN CRF神经元上发现了5-HT末端投影。这表明5HT代理可以通过对PVN CRF神经元的迄今未表征的作用来抑制食欲。数据在5-HT之间的潜在功能联系进一步支持，该数据证明了与PVN CRF细胞体中食欲调节相关的5-HT受体亚型的mRNA。值得注意的是，尽管有许多研究的建议，但迄今为止尚无确切的研究表明，与5-HT相关的药物确实可以通过刺激CRF mRNA的产生和CRF蛋白表达来抑制喂养。在该提议中，我们假设存在血清素（5-HT）与神经肽之间存在功能联系，例如CRF和黑色素细胞刺激激素（Alpha MSH）及其在PVN（5-HT，CRF）和ARCURE（ARC）（ARC）（ARC）下丘脑核中的PVN（5-HT，CRF）中的各自神经元（Alpha）（Alphamic）（Alpha）（Alpha）（Alpha）（Alpha）（Alpha）我们的具体目的是（1）确定5-HT释放是否调节PVN中的CRF或Alpha MSH神经元以抑制食物摄入；（2）确定5-HT释放是否通过位于弧形及其相关神经元中的1-MSH神经元中的PVN中间接调节CRF神经元；（3）确定下丘脑CRF及其相关神经元的下游靶标。在我们的实验设计中，我们将利用Fenfluramine（FEN），这是一种强烈促进5HT突触传播的药物。中央和全身FEN给药将用于评估与食欲相关的PVN CRF神经元预先治疗的大鼠PVN CRF mRNA表达（5HT-1B，2A，2A和2C亚型）。 FEN还将用于测试5-HT是否间接影响PVN CRF mRNA表达。 1-MSH释放到CRF神经元是刺激性的。因此，FEN可以通过增加1-MSH信号传导来刺激CRF神经元。 RNA干扰将用于消除CRF mRNA，以确定FEN发射的5-HT是否通过其他下游机制影响食欲抑制。这些研究应提供有关5HT-CRF突触连接在控制食物摄入量中的作用的新见解，并最终有助于理解这种连通性是否以及该连通性是否对调节整体能量平衡以及肥胖，厌食症和其他与食欲相关的健康问题的病因该提案研究了羟色胺（5-HT）及其相关神经元在下丘脑旁脑室核（PVN）对大鼠神经元皮质激素释放因子（CRF）mRNA表达和大鼠喂养行为的影响。这些研究应提供有关5HT-CRF突触连接在控制食物摄入量中的作用的新见解，并最终有助于理解这种连通性是否以及该连通性是否对调节整体能量平衡以及肥胖，厌食症和其他与食欲相关的健康问题的病因