Regulation of energy and glucose homeostasis by endogenous hypothalamic FGF1

内源性下丘脑 FGF1 对能量和葡萄糖稳态的调节

基本信息

批准号：
10191788
负责人：
Jarrad M Scarlett
金额：
$ 13.24万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10191788
关键词：
Acute Adult Affect Animals Antibodies Antidiabetic Drugs Area Award Bilateral Biochemical Body Weight Body Weight decreased Brain Calories Cell Line Cell Nucleus Cells Cerebrospinal Fluid Chronic Chronic Disease Consumption Data Dependovirus Desire for food Diabetes Mellitus Diet Disease remission Enterobacteria phage P1 Cre recombinase Expenditure FGF1 gene FGF19 gene FGF21 gene Family Fasting Fibroblast Growth Factor Food Funding Gliosis Glucose Glucose Intolerance Homeostasis Hypothalamic structure Immunohistochemistry In Situ Hybridization Infusion procedures Injections Investigation Knock-out Lipids LoxP-flanked allele Medical Messenger RNA Metabolic Microinjections Modeling Modernization Morbidity - disease rate Mus Neuroglia Neuronal Injury Neurons Non-Insulin-Dependent Diabetes Mellitus Nutritional status Obesity Patient-Focused Outcomes Peripheral Physiological Play Population Primates Proteins Public Health Regulation Reporting Research Resources Rodent Rodent Model Role Signal Transduction Societies Surveys Synapses Testing Treatment outcome Weight Gain Work base blood glucose regulation cell type cost diabetic effective therapy energy balance glucose tolerance human model improved interest laser capture microdissection member metabolic phenotype mind control mortality novel obesity development obesity treatment pre-clinical response sedentary lifestyle stem targeted treatment western diet

项目摘要

Project Summary Over the past 3 decades, obesity and type 2 diabetes (T2D) have emerged as among the most common and costly chronic diseases confronting modern society. Treatment outcomes for patients affected with obesity or T2D have shown minimal improvement due to the absence of non-surgical medical treatments that have sustained efficacy. Therefore, an urgent need for new, more effective treatment options therefore exists, and strategies targeting the brain have important potential to meet this need. As one example of relevant preclinical work, our group has recently shown that signaling in the brain by exogenous administration of members of the fibroblast growth factor (FGF) family produces potent weight-loss and anti-diabetic effects. Our K08 proposal focused on the integrated central and peripheral mechanisms underlying the sustained anti-diabetic action of exogenous FGF1 in rodent models of obesity and T2D. In this application, we propose a parallel line of studies that will investigate the role of endogenous hypothalamic FGF1 signaling in the regulation of energy and glucose homeostasis. We have recently found that FGF1 is endogenously expressed by tanycytes and cells distributed in a number of key hypothalamic areas implicated in the control of body weight and glucose. Further, we have observed that endogenous hypothalamic FGF1 expression is regulated fasting and refeeding and in preliminary studies that deleting FGF1 from either hypothalamic neurons or tanycytes induces weight gain and glucose intolerance on chow diet. These data support the premise that endogenous hypothalamic FGF1 signaling plays a physiologic role in the regulation of energy and glucose homeostasis. We will investigate this hypothesis by determining the specific hypothalamic nuclei and cell types that express FGF1, identify which of these populations respond to acute and chronic changes in metabolic status and diet, and the extent to which disrupting endogenous hypothalamic FGF1 signaling is sufficient to promote the development of obesity and glucose intolerance. The data obtained from these investigations will form the basis of a new line of research centered on endogenous hypothalamic FGF1 signaling as a novel target to treat obesity and T2D.

项目概要在过去 30 年中，肥胖和 2 型糖尿病 (T2D) 已成为最常见和最常见的疾病之一。现代社会面临着昂贵的慢性疾病。肥胖症患者的治疗结果或由于缺乏非手术治疗，T2D 的改善甚微。持续疗效。因此，迫切需要新的、更有效的治疗方案，并且针对大脑的策略具有满足这一需求的重要潜力。作为相关临床前的一个例子工作中，我们的小组最近表明，通过外源性施用神经元成员在大脑中发出信号成纤维细胞生长因子 (FGF) 家族具有有效的减肥和抗糖尿病作用。我们的K08提案重点关注持续抗糖尿病作用背后的综合中枢和外周机制肥胖和 T2D 啮齿动物模型中的外源 FGF1。在此应用中，我们提出了并行研究将研究内源性下丘脑 FGF1 信号在能量和葡萄糖调节中的作用体内平衡。我们最近发现FGF1是由单胞和分布的细胞内源性表达的下丘脑的一些与体重和血糖控制有关的关键区域。进一步，我们有观察到内源性下丘脑 FGF1 表达受到禁食和再进食的调节，并且在初步研究中研究表明，从下丘脑神经元或单细胞中删除 FGF1 会导致体重增加和血糖升高对食物饮食不耐受。这些数据支持内源性下丘脑 FGF1 信号传导发挥作用的前提在能量和葡萄糖稳态调节中的生理作用。我们将通过以下方式研究这个假设确定表达 FGF1 的特定下丘脑核和细胞类型，确定其中哪些人群对代谢状态和饮食的急性和慢性变化的反应，以及破坏的程度内源性下丘脑 FGF1 信号传导足以促进肥胖和血糖的发展不宽容。从这些调查中获得的数据将构成以内源性下丘脑 FGF1 信号传导作为治疗肥胖和 T2D 的新靶点。