Understanding the role of vagal FFAR3 in regulating glucose homeostasis

了解迷走神经 FFAR3 在调节葡萄糖稳态中的作用

• 批准号: 10207515
• 负责人: Tyler Cook
• 金额: $ 3.69万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207515
• 关键词: Acetates; Acute; Afferent Neurons; Attention; Automobile Driving; Behavior; Behavioral; Binding; Blood Glucose; Butyrates; Cells; Cues; Data; Diabetes Mellitus; Diet; Dietary Fiber; Dietary Supplementation; Eating; Energy Metabolism; Exhibits; FFAR2 gene; FFAR3 gene; Fasting; Female; Fiber; G-Protein-Coupled Receptors; GLP-I receptor; Ganglia; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Gluconeogenesis; Glucose; Glucose Intolerance; Glucose tolerance test; Goals; Hand; Hormonal; Hormone Receptor; Hormones; Hour; Immediate-Early Genes; In Vitro; Intake; Intervention; Knock-out; Knockout Mice; Life Style; Ligands; Liver; Longitudinal Studies; LoxP-flanked allele; Measures; Mediating; Messenger RNA; Modeling; Molecular; Mus; Nervous System control; Neuraxis; Neurobiology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Obese Mice; Obesity; Oral; Pathway interactions; Phosphoenolpyruvate Carboxylase; Physiological; Plasma; Prevalence; Propionates; Regulation; Reverse Transcription; RiboTag; Rodent Model; Role; Saline; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Thinness; Translating; Translations; Vagus nerve structure; Volatile Fatty Acids; Water; Work; blood glucose regulation; cell motility; comorbidity; detection of nutrient; diet-induced obesity; dietary; drinking water; energy balance; experimental study; fasting glucose; fecal transplantation; glucose metabolism; glucose tolerance; gut bacteria; gut microbiome; improved; in vivo; innovation; insulin tolerance; male; metabolic phenotype; microbiome; mind control; mouse model; novel; obesity treatment; receptor; receptor expression; receptor function; relating to nervous system; response; western diet

PROJECT SUMMARY/ABSRACT The goal of this F31 application is to elucidate the roles and mechanisms of FFAR3 signaling in the vagus nerve in regulating glucose homeostasis. Proper regulation of energy metabolism requires sensing of nutrient and hormonal cues to coordinate an appropriate behavioral and physiological response. Vagus nerve sensing of dietary nutrients or nutrient-stimulated hormones has been demonstrated to regulate food intake, glucose homeostasis, and gut motility. The gut microbiome ferments soluble non-digestible fiber to release short-chain fatty acids (SCFA’s) which can serve as signaling molecules through G-protein coupled receptors. The SCFA’s, including acetate, propionate, and butyrate can bind free fatty acid receptor 2 (FFAR2) and 3 (FFAR3). Increasing dietary fiber intake or directly supplementing SCFA’s has been shown to improve host glucose homeostasis, but the molecular mechanisms mediating these effects are unclear. Direct vagal sensing of gut microbiome produced SCFA’s via FFAR3 could contribute to regulation of glucose metabolism. We found that propionate was decreased in the plasma of western diet (WD)-fed mice compared to normal chow (NC)-fed controls. When obese mice received oral gavages of fecal microbiome transplantations (FMT) from lean NC-fed donors, their plasma propionate levels increased, and fasting blood glucose decreased. Directly supplementing propionate in the water of WD- fed mice lowered fasting glucose and improved glucose tolerance. Propionate is the most potent known endogenous ligand for FFAR3, and FFAR3 KO mice exhibit disrupted glucose tolerance, so we hypothesized that FFAR3 expressed on the vagus nerve connects microbiome-produced propionate and central nervous system control of glucose homeostasis. Indeed, we found Ffar3 to be actively translated in vagal sensory neurons. Treatment of vagal cultures with the FFAR3 ligand, propionate, activated the neurons and increased neuronal translation of Glp1r. Vagal GLP1R function and expression is dysregulated in rodent models of obesity, but the molecular mechanisms are not well understood. We hypothesize that propionate signals through FFAR3 in the vagus nerve to increase Glp1r expression and improve glucose homeostasis. We will test this hypothesis through the following aims. Aim 1 will assess if propionate activates vagal neurons and increases Glp1r translation via FFAR3 in vagal organotypic cultures. We will accomplish this by utilizing the ribotag genetic mouse model which allows for cell-specific assessment of genes in translation. We will assess translation of glucoregulatory genes after propionate stimulation in vagal ganglia expressing FFAR3, and ganglia from FFAR3KO mice. Aim 2 will assess whether vagal FFAR3 is required for propionate to improve glucose intolerance in vivo in WD-fed male and female mice. To accomplish this, we will utilize a novel FFAR3 floxed mouse model and genetically ablate FFAR3 only from vagal neurons. We will challenge control and vagal FFAR3KO mice with a western diet, supplemented with either saline or propionate, to determine if propionate improves WD-induced glucose intolerance via FFAR3. Overall, we expect this study to improve the understanding of how propionate and FFAR3 contribute to autonomic control of glucose homeostasis and energy balance. The proposed study will elucidate new signaling pathways for the treatment of type 2 diabetes.

项目概要/摘要 该 F31 应用的目标是阐明 FFAR3 信号在迷走神经调节中的作用和机制 葡萄糖稳态。能量代谢的正确调节需要感知营养和激素信号来协调 适当的行为和生理反应。迷走神经感知饮食营养或营养刺激 激素已被证明可以调节食物摄入、葡萄糖稳态和肠道蠕动。肠道微生物组 发酵可溶性不可消化纤维，释放短链脂肪酸 (SCFA)，可作为信号分子 通过G蛋白偶联受体。 SCFA，包括乙酸盐、丙酸盐和丁酸盐，可以结合游离脂肪酸 受体 2 (FFAR2) 和 3 (FFAR3)。增加膳食纤维摄入量或直接补充 SCFA 已被证明可以 改善宿主葡萄糖稳态，但介导这些作用的分子机制尚不清楚。直接迷走神经感应 肠道微生物组通过 FFAR3 产生 SCFA 可能有助于调节葡萄糖代谢。我们发现 与正常饲料（NC）喂养的对照组相比，西方饮食（WD）喂养的小鼠血浆中丙酸盐含量降低。什么时候 肥胖小鼠接受来自瘦 NC 喂养供体的粪便微生物组移植 (FMT) 的口服强饲，其血浆 丙酸水平升高，空腹血糖降低。直接在WD-水中添加丙酸盐 喂食的小鼠降低了空腹血糖并改善了葡萄糖耐量。丙酸是已知最有效的内源配体 对于 FFAR3，FFAR3 KO 小鼠表现出葡萄糖耐量破坏，因此我们假设 FFAR3 在 迷走神经连接微生物组产生的丙酸盐和控制葡萄糖稳态的中枢神经系统。的确， 我们发现 Ffar3 在迷走神经感觉神经元中积极翻译。用 FFAR3 配体处理迷走神经培养物， 丙酸，激活神经元并增加 Glp1r 的神经元翻译。迷走神经GLP1R的功能和表达是 肥胖啮齿动物模型中失调，但其分子机制尚不清楚。我们假设 丙酸信号通过迷走神经中的 FFAR3 增加 Glp1r 表达并改善葡萄糖稳态。我们 将通过以下目标来检验这一假设。目标 1 将评估丙酸盐是否激活迷走神经元并增加 Glp1r 在迷走神经器官培养中通过 FFAR3 进行翻译。我们将通过利用核糖核酸标签基因小鼠来实现这一目标 允许对翻译中的基因进行细胞特异性评估的模型。我们将评估葡萄糖调节基因的翻译 在表达 FFAR3 的迷走神经节和 FFAR3KO 小鼠的迷走神经节中进行丙酸刺激后。目标 2 将评估 丙酸是否需要迷走神经 FFAR3 来改善 WD 喂养的雄性和雌性小鼠体内的葡萄糖耐受不良。 为了实现这一目标，我们将利用一种新型 FFAR3 floxed 小鼠模型，并仅从迷走神经中基因消除 FFAR3 神经元。我们将用西式饮食挑战对照和迷走神经 FFAR3KO 小鼠，辅以生理盐水或 丙酸盐，以确定丙酸盐是否通过 FFAR3 改善 WD 诱导的葡萄糖不耐受。总的来说，我们期望这项研究 提高对丙酸和 FFAR3 如何促进葡萄糖稳态自主控制的理解 能量平衡。拟议的研究将阐明治疗 2 型糖尿病的新信号通路。