Role of sensory neuron ghrelin signaling in regulating metabolic homeostasis

感觉神经元生长素释放肽信号在调节代谢稳态中的作用

• 批准号: 9468054
• 负责人: Michael Alex Thomas
• 金额: $ 4.01万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-06 至 2019-09-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9468054
• 关键词: AVIL gene; Ablation; Adipose tissue; Afferent Neurons; Animals; Appetite Stimulants; Behavior Therapy; Behavioral; Body Temperature; Brain; Brown Fat; Capsaicin; Cardiovascular Diseases; Comorbidity; Complex; Data; Diabetes Mellitus; Diet; Eating; Economic Burden; Endocrine; Energy Intake; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Epidemic; Fasting; Food Intake Regulation; Food deprivation (experimental); Foundations; Future; GHS-R1a; Genes; Glucose; Goals; Health; High Fat Diet; Homeostasis; Hormones; Human; Impairment; Incidence; Injectable; Intervention; Intestines; Investigation; Knock-out; Knockout Mice; Knowledge; Link; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolic Control; Metabolic Diseases; Metabolism; Mission; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Overweight; Pancreas; Peripheral; Persons; Pharmacology; Phenotype; Physiological; Population; Predisposition; Prevention; Regulation; Reporter; Research; Resistance; Risk; Role; Signal Pathway; Signal Transduction; Spinal; Spinal Ganglia; Stimulus; Stomach; Stretching; System; Testing; Thermogenesis; Thinness; Time; Tracer; United States; Work; afferent nerve; blood glucose regulation; cell motility; combat; design; experimental study; feeding; gastrointestinal; gastrointestinal system; ghrelin; ghrelin receptor; health economics; increased appetite; insulin tolerance; metabolic phenotype; metabolic profile; neuronal growth; novel; novel strategies; offspring; receptor; response; restoration; time use; virtual

Project Summary/Abstract Obesity is a major health and economic burden with approximately 35% of United States citizens classified as either overweight or obese, and medical spending for treating obesity and its comorbidities exceeds $200 billion annually. The stomach-derived orexigenic hormone ghrelin is a key mediator of energy homeostasis and adiposity in humans due to its regulation of food intake, gut motility, energy expenditure, nutrient partitioning, glycemia, and body temperature. The ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR), is widely expressed in the brain and on gastrointestinal vagal sensory neurons, and neuronal GHSR knockout results in a profoundly beneficial metabolic profile and high fat diet (HFD)-induced obesity resistance. Moreover, ghsr knockout mice have impaired metabolic regulation during energetic challenges, and ghsr restoration in the brain does not fully restore ghrelin’s effects suggesting peripheral ghrelin signaling is critical for metabolic control. We discovered that in addition to the well characterized vagal GHSRs, gastrointestinal sensory neurons emanating from spinal dorsal root ganglia (DRG) robustly express GHSRs. In addition, DRG GHSR expression is markedly upregulated by energetic challenges suggesting a novel mechanism mediating ghrelin’s effects on energy homeostasis. As this is the first time these receptors have been identified on DRGs, their function and phenotype (i.e. whether they also detect gastric stretch or nutrients) is completely unknown. Thus, the overall goal of this project is to identify the phenotype and organs innervated by GHSR-containing DRGs, and to elucidate the overall necessity of DRG and vagal sensory neuron ghrelin signaling. A ghsrGFP reporter mouse will be used in conjunction with neuronal retrograde tracers to identify the organs innervated by GHSR-containing DRGs. In addition, immunohistochemical analysis measuring neuronal activity in response to peripheral manipulations designed to activate GHSR-GFP sensory neurons will elucidate the phenotype of these neurons. To test the necessity of sensory neuron ghrelin signaling for regulating metabolic homeostasis, we will generate a novel, sensory neuron-specific GHSR knockout mouse by crossing our ghsrloxP/loxP mouse line (that allow for Cre-recombinase dependent deletion of the ghsr gene) with our sensory neuron-specific Cre driver mice Advillin- Cre. With the resulting offspring, we will test the overall phenotype, ability to maintain metabolic homeostasis when energetically challenged, and susceptibility to diet-induced obesity. These overarching goals are in line with the National Institute of Diabetes and Digestive and Kidney Diseases mission to investigate the fundamental causes of obesity and other metabolic diseases including diabetes. Moreover, the findings from this study will greatly expand our knowledge of the neuroendocrine regulation of energy homeostasis, and will provide another point of attack for behavioral and/or pharmacological interventions to combat obesity.

项目总结/摘要 肥胖是一个主要的健康和经济负担，大约35%的美国公民 分类为超重或肥胖，以及治疗肥胖的医疗支出及其 合并症每年超过2000亿美元。胃源性食欲素是一种 由于其调节食物摄入， 肠道运动、能量消耗、营养分配、消化和体温。的 生长激素促分泌素受体1a（GHSR）广泛表达于脑内 和胃肠道迷走神经感觉神经元，神经元GHSR敲除导致深刻的 有益的代谢特征和高脂饮食（HFD）诱导的肥胖抵抗。此外， 基因敲除小鼠在能量挑战和ghsr恢复期间的代谢调节受损 并不能完全恢复生长激素释放肽的作用，这表明外周生长激素释放肽信号是 对代谢控制至关重要我们发现，除了迷走神经的特征外， GHSRs是从脊髓背根神经节（DRG）发出的胃肠感觉神经元， 表达GHSR。此外，DRG GHSR表达被能量刺激显著上调， 提示一种新的机制介导胃饥饿素对能量稳态的影响。由于这是 这些受体首次在DRG上被鉴定，它们的功能和表型（即是否 它们还检测胃拉伸或营养）是完全未知的。因此， 本项目旨在鉴定含GHSR的DRG所支配的表型和器官， 阐明DRG和迷走神经感觉神经元ghrelin信号传导的整体必要性。一个ghsrGFP 报告小鼠将与神经元逆行示踪剂结合使用以鉴定器官 由含GHSR的DRG支配。此外，免疫组织化学分析测量神经元 响应于设计用于激活GHSR-GFP感觉神经元的外周操作的活性将 阐明这些神经元的表型。为了测试感觉神经元ghrelin信号传导的必要性， 为了调节代谢稳态，我们将产生一种新的感觉神经元特异性GHSR 通过杂交我们ghsrloxP/loxP小鼠系（其允许Cre-重组酶依赖性 ghsr基因的缺失）与我们的感觉神经元特异性Cre驱动小鼠Advillin-Cre。与 我们将测试其总体表型，维持代谢稳态的能力， 以及易患饮食诱导的肥胖症。这些总体目标 符合国家糖尿病、消化和肾脏疾病研究所的使命， 调查肥胖和其他代谢疾病包括糖尿病的根本原因。 此外，这项研究的发现将大大扩展我们对神经内分泌的认识。 调节能量稳态，并将提供另一个攻击点的行为和/或 药物干预来对抗肥胖。