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.

项目概要/摘要 肥胖是大约 35% 的美国公民的主要健康和经济负担 分类为超重或肥胖，以及治疗肥胖及其相关疾病的医疗支出 胃源性促食欲激素胃饥饿素 (ghrelin) 每年带来的并发症价值超过 2000 亿美元。 由于其对食物摄入的调节，是人类能量稳态和肥胖的关键介质， 肠道蠕动、能量消耗、营养分配、血糖和体温。 生长素释放肽受体，即生长激素促分泌素受体 1a (GHSR)，在大脑中广泛表达 以及胃肠道迷走神经感觉神经元，神经元 GHSR 敲除会导致严重的 有益的代谢特征和高脂肪饮食（HFD）诱导的肥胖抵抗。 基因敲除小鼠在能量挑战和 ghsr 恢复过程中代谢调节受损 大脑中的 ghrelin 信号并不能完全恢复 ghrelin 的作用，这表明外周 ghrelin 信号传导是 我们发现除了特征明确的迷走神经外，对于代谢控制也至关重要。 GHSR，从脊髓背根神经节（DRG）强烈发出的胃肠道感觉神经元 此外，DRG GHSR 表达因能量挑战而显着上调。 提出了一种介导胃饥饿素对能量稳态影响的新机制。 这些受体首次在 DRG 上被识别，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。 该项目旨在鉴定包含 GHSR 的 DRG 所支配的表型和器官，并 阐明 DRG 和迷走神经感觉神经元 ghrelin 信号传导的总体必要性。 报告小鼠将与神经元逆行示踪剂结合使用来识别器官 受含有 GHSR 的 DRG 支配。另外，免疫组织化学分析测量神经元。 响应于旨在激活 GHSR-GFP 感觉神经元的外周操作的活动将 阐明这些神经元的表型，以测试感觉神经元生长素释放肽信号传导的必要性。 为了调节代谢稳态，我们将产生一种新型的感觉神经元特异性 GHSR 通过杂交我们的 ghsrloxP/loxP 小鼠品系（允许 Cre 重组酶依赖）来敲除小鼠 删除 ghsr 基因）与我们的感觉神经元特异性 Cre 驱动小鼠 Advillin-Cre 一起。 产生的后代，我们将测试整体表型、维持代谢稳态的能力 当精力充沛时，容易患上饮食引起的肥胖。 符合国家糖尿病、消化和肾脏疾病研究所的使命 研究肥胖和其他代谢疾病（包括糖尿病）的根本原因。 此外，这项研究的结果将极大地扩展我们对神经内分泌的认识。 能量稳态的调节，并将为行为和/或行为提供另一个攻击点 对抗肥胖的药物干预。