Appetite: Serotonin and corticotropin releasing factor

食欲：血清素和促肾上腺皮质激素释放因子

• 批准号: 7545446
• 负责人: SuJean Choi
• 金额: $ 29.8万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 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/7545446
• 关键词: Affect; Anorexia; Appetite Regulation; Back; Body Weight decreased; Brain; Brain region; Caring; Cell Nucleus; Cells; 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; Mediating; Mediator of activation protein; Messenger RNA; Metabolism; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Neuropeptides; Obesity; Pathway interactions; Pharmaceutical Preparations; 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

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）：本提案研究了5-羟色胺（5-HT）及其下丘脑室旁核（PVN）相关神经元对大鼠神经元促肾上腺皮质激素释放因子（CRF）mRNA表达和摄食行为的影响。PVN CRF神经元是控制进食行为的重要介质;例如，外源性应用CRF或刺激CRF神经元导致食物摄入抑制。同样，刺激大脑中突触5-HT传递的药物也被认为可以抑制食物摄入。在解剖学上，还已知在PVN CRF神经元上发现5-HT末端投射;这表明5-HT药剂可以通过迄今为止未表征的对PVN CRF神经元的作用来抑制食欲。5-HT之间的潜在功能联系进一步得到以下数据的支持：证明PVN CRF细胞体中存在与食欲调节相关的5-HT受体亚型的mRNA。值得注意的是，尽管有许多研究的建议，迄今为止还没有明确的研究表明，5-HT相关药物确实可以通过刺激CRF mRNA的产生和CRF蛋白的表达来抑制摄食。在这个建议中，我们假设存在着5-羟色胺（5-HT）和神经肽之间的功能联系，如CRF和黑素细胞刺激激素（α MSH）和它们各自的神经元驻留在PVN（5-HT，CRF）和弓状（ARC）下丘脑核（α MSH），分别。我们的具体目标是（1）确定5-HT释放是否调节PVN中的CRF或α MSH神经元以抑制食物摄入;（2）确定5-HT释放是否通过位于弓状核及其相关神经元中的1-MSH神经元间接调节PVN中的CRF神经元;（3）确定下丘脑CRF及其相关神经元的下游靶点。在我们的实验设计中，我们将利用芬氟拉明（FEN），一种强烈促进5 HT突触传递的药物。将使用中枢和全身FEN施用来评估用5-HT受体拮抗剂预处理的大鼠中的PVN CRF mRNA表达，所述5-HT受体拮抗剂对与食欲相关的PVN CRF神经元（5 HT-1B、2A和2C亚型）具有特异性。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神经元上是刺激性的;因此，FEN可以通过增加1-MSH信号来刺激CRF神经元。RNA干扰将用于消除CRF mRNA，以确定FEN引发的5-HT是否通过其他下游机制影响食欲抑制。这些研究应该提供新的见解，在控制食物摄入量的一个不好的特点5 HT-CRF突触连接的作用，并最终有助于了解这种连接是否以及如何是重要的整体能量平衡的调节，以及肥胖，厌食症的病因，和其他食欲相关的健康问题。本研究旨在探讨下丘脑室旁核（PVN）中5-羟色胺（5-HT）及其相关神经元对大鼠神经元促肾上腺皮质激素释放因子（CRF）mRNA表达和进食行为的影响。这些研究应该提供新的见解，在控制食物摄入量的一个不好的特点5 HT-CRF突触连接的作用，并最终有助于了解这种连接是否以及如何是重要的整体能量平衡的调节，以及肥胖，厌食症的病因，和其他食欲相关的健康问题。