Crosstalk between sensory ghrelin signaling and adipose tissue sympathetic outflow regulates metabolic homeostasis

感觉生长素释放肽信号传导与脂肪组织交感神经流出之间的串扰调节代谢稳态

• 批准号: 10341181
• 负责人: Bingzhong Xue
• 金额: $ 51.72万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-09 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341181
• 关键词: Ablation; Adipose tissue; Afferent Neurons; Animal Model; Appetite Stimulants; Body Temperature; Brain; Brown Fat; Caliber; Capsaicin; Cardiovascular Diseases; Dependovirus; Dyslipidemias; Eating; Endocrine; Energy Metabolism; Epidemic; Fiber; Food deprivation (experimental); GHS-R1a; Gastrointestinal tract structure; Goals; Grant; High Fat Diet; Homeostasis; Hormones; Human; Injections; Insulin Resistance; Internal Ribosome Entry Site; Knowledge; Large Intestine; Malignant Neoplasms; Maps; Measures; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Metabolic; Metabolic Control; Metabolic Diseases; Mus; Nerve; Neurons; Neurosecretory Systems; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nutrient; Obesity; Organ; Pathway interactions; Peripheral; Regulation; Reporter; Risk Factors; Role; Sensory; Sensory Ganglia; Signal Pathway; Signal Transduction; Small Intestines; Spinal; Spinal Ganglia; Stimulus; Stomach; Stretching; Testing; Thermogenesis; Tracer; Vagotomy; Viral; Work; afferent nerve; cell motility; designer receptors exclusively activated by designer drugs; diet-induced obesity; gastrointestinal; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; lipid metabolism; nerve supply; neuronal circuitry; new therapeutic target; novel; obesity treatment; prevent; response

Obesity has become a world-wide epidemic problem, and is an independent risk factor for a panel of metabolic diseases, including insulin resistance/type 2 diabetes, dyslipidemia, cardiovascular diseases, and cancer. The stomach-derived orexigenic hormone ghrelin acting through its receptor growth hormone secretagogue receptor 1a (GHSR) is a key mediator of energy homeostasis. GHSR is widely expressed in the brain and on gastrointestinal vagal sensory neurons. In the current proposal, 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-containing neurons innervates the gastrointestinal tract, and DRG GHSR is markedly induced by energetic challenges, including food deprivation and cold exposure, suggesting DRG ghrelin/GHSR signaling is important in regulating energy homeostasis. Interestingly, sensory GHSR deletion protects against diet-induced obesity primarily due to increased energy expenditure via increased adipose tissue sympathetic outflow and thermogenesis. Thus, we have identified a novel pathway in which gut non-vagal sensory GHSR neurons negatively regulate energy homeostasis via suppression of adipose tissue sympathetic outflow, thermogenesis and whole body energy expenditure. The overall goal of this project is to test the importance of ghrelin/GHSR signaling on peripheral sensory neurons in regulating whole body metabolic homeostasis, and to investigate the neuronal mechanisms by which sensory GHSR regulates adipose tissue sympathetic outflow. In Specific Aim 1, the importance of sensory GHSR in regulating energy homeostasis will be tested using DRG sensory neuron-specific deletion or re-activation of GHSR. In Specific Aim 2, the neuronal circuitry connecting gut sensory GHSR signaling to adipose tissue sympathetic outflow will be investigated via viral tract tracer mapping. In addition, the possible involvement of central melanocortin signaling pathways as a downstream target connecting sensory GHSR signaling to adipose tissue sympathetic outflow will be tested. Completing this project will greatly expand our current knowledge of the neuroendocrine regulation of energy homeostasis, and will provide novel therapeutic targets in the preventing and treatment of obesity.

肥胖已成为一个世界性的流行病问题，是一组代谢性疾病的独立危险因素， 这些疾病包括胰岛素抵抗/2型糖尿病、血脂异常、心血管疾病和癌症。的 胃源性促食欲激素ghrelin通过其受体生长激素促分泌素受体起作用 1a（GHSR）是能量稳态的关键介质。GHSR广泛表达于大脑和 胃肠迷走神经感觉神经元在目前的提案中，我们发现，除了井， 特征性迷走神经GHSR，源自脊髓背根神经节（DRG）的胃肠感觉神经元 强烈表达GHSR。此外，DRG GHSR神经元支配胃肠道， DRG GHSR明显由能量挑战引起，包括食物剥夺和寒冷暴露， 提示DRG ghrelin/GHSR信号传导在调节能量稳态中是重要的。有趣的是， GHSR缺失防止饮食诱导的肥胖，主要是由于通过增加的能量消耗增加。 脂肪组织交感神经流出和产热。因此，我们已经确定了一种新的途径，其中肠道 非迷走感觉GHSR神经元通过抑制脂肪组织负性调节能量稳态 交感神经流出、产热和全身能量消耗。该项目的总体目标是 测试外周感觉神经元上的ghrelin/GHSR信号传导在调节全身代谢中的重要性 稳态，并探讨感觉GHSR调节脂肪组织的神经机制 交感神经流出在具体目标1中，感觉GHSR在调节能量稳态中的重要性将 使用DRG感觉神经元特异性缺失或GHSR再激活进行测试。在具体目标2中，神经元 将通过以下途径研究连接肠道感觉GHSR信号传导至脂肪组织交感神经流出的回路： 病毒道示踪物作图。此外，中枢黑皮质素信号通路可能参与了 将测试连接感觉GHSR信号传导至脂肪组织交感神经流出的下游靶标。 完成这个项目将大大扩展我们目前对能量的神经内分泌调节的知识 本发明提供了一种治疗肥胖症的新方法，该方法可以改善体内平衡，并将在预防和治疗肥胖症中提供新的治疗靶点。