Examining the role of locus coeruleus glucagon-like peptide-1 receptors in feeding behavior

项目摘要/摘要 肥胖症的惊人流行给公共健康和经济带来了重大后果。有效的抗- 人们迫切需要减肥药来抗击肥胖症的流行，因为行为疗法的效果有限 成功。内源性饱腹感信号胰高血糖素样肽-1(GLP-1)的类似物抑制食物摄取和 并被FDA批准用于肥胖症治疗。然而，GLP-1类似物(例如Semagluide)是 有副作用的，即恶心和呕吐。因此，增加GLP-1的治疗潜力 受体(GLP-1R)激动剂需要表征调节两种食物的中枢机制 GLP-1的摄取抑制和恶心/呕吐作用。在大鼠身上的初步数据表明，GLP-1RS在 蓝斑(LC)是大脑中去甲肾上腺素(NE)的输出来源，在药理上和 在生理上与GLP-1的食物摄取和疾病样作用有关。然而，通过它的电路 LC内源性GLP-1信号参与食物摄取抑制和恶心/呕吐残留 不清楚。此外，LC GLP-1RS与食物摄取抑制和 赛马路德的恶心/呕吐作用尚不清楚。 拟议的5年研究职业发展计划的主要目标是促进申请者的 过渡到拥有独立R01经费的终身教职助理教授。为此，拟议的 研究将对申请者进行各种方法的培训，以识别行为、细胞和电路级别 LC GLP-1R引起厌食和病样行为的机制。目的我将利用药理作用， 化学发生和RNAi介导的GLP-1R基因敲除策略在大鼠和临床前的麝鼠中的作用 具有类似于人类的呕吐轮廓的模型，以揭示内源性GLP-1信号在 LC有助于抑制食物摄入、恶心和呕吐。AIM II将采取翻译方法， 测定LC-NE神经元对半胱氨酸的实时钙信号动力学 LC-GLP-1RS与摄食抑制、恶心呕吐和钙信号转导的药理学关系 由全身性的半乳糖引起。AIM II还将使用尖端的单核RNA测序和 生物信息学分析揭示半胱氨酸诱导的LC-NE神经元转录组的变化 半胱氨酸对LC神经元指纹图谱及对LC NE神经元基因的调控作用来自这些的结果 实验将为开发更有效和更耐受的肥胖治疗方法提供信息，并将提供 申请者拥有一套独特的技能和试点数据，以鼓励她过渡到研究独立。

Project Summary/Abstract The staggering prevalence of obesity presents major public health and economic consequences. Effective anti- obesity drugs are desperately needed to combat the obesity epidemic, as behavioral strategies offer limited success. Analogs of the endogenous satiety signal glucagon-like peptide-1 (GLP-1) suppress food intake and body weight and are FDA-approved for obesity treatment. However, GLP-1 analogs (e.g. semaglutide) are burdened by side effects, namely nausea and emesis. Therefore, increasing the therapeutic potential of GLP-1 receptor (GLP-1R) agonists requires characterization of the central mechanisms that mediate both the food intake-suppressive and nausea/emesis effects of GLP-1. Preliminary data in the rat indicate that GLP-1Rs in the locus coeruleus (LC), a source of norepinephrine (NE) output in the brain, are pharmacologically and physiologically relevant for the food intake and illness-like effects of GLP-1. However, the circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression and nausea/emesis remains unclear. Additionally, the functional relevance of LC GLP-1Rs to the food intake suppressive and nausea/emesis effects of the semaglutide is not known. The main goal of the proposed 5- year research career development plan is to facilitate the applicant’s transition to a tenure-track Assistant Professor with independent R01 funding. To this end, the proposed research will train the applicant in a variety of approaches to identify the behavioral, cellular, and circuit-level mechanisms behind LC GLP-1R induced anorexia and illness-like behaviors. Aim I will utilize pharmacological, chemogenetic and RNAi-mediated GLP-1R knockdown strategies in the rat and musk shrew, a preclinical model that has an emetic profile similar to humans, to reveal a circuit by which endogenous GLP-1 signaling in the LC contributes to food intake suppression, nausea and emesis. Aim II will take a translational approach by determining the real-time calcium signaling dynamics of LC NE neurons to semaglutide as well as the pharmacological relevance of LC GLP-1Rs to the food intake suppression, nausea/emesis and calcium signaling evoked by systemic semaglutide. Aim II will use also cutting-edge single nucleus RNA sequencing and bioinformatic analysis to probe semaglutide-induced changes in the LC NE neuron transcriptome to reveal the fingerprint of LC neurons and regulation of LC NE neuron genes by semaglutide. Results from these experiments will inform the development of more efficacious and tolerated obesity treatments and will provide the applicant with a unique set of skills and pilot data to encourage her transition to research independence.