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

基本信息

批准号：
10555316
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-09 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10555316
关键词：
Ablation Adipose tissue Afferent Neurons Animal Model Appetite Stimulants Body Temperature Brain Brown Fat Capsaicin Cardiovascular Diseases Dependovirus Diameter 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 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 Vertebral column Viral Visualization Work afferent nerve cell motility designer receptors exclusively activated by designer drugs diet-induced obesity gastrointestinal genetic approach ghrelin ghrelin receptor growth hormone secretagogue receptor lipid metabolism nerve supply neuronal circuitry new therapeutic target novel obesity treatment prevent receptor response

项目摘要

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，并且是一组代谢性疾病的独立危险因素。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。这胃源性食欲激素胃饥饿素通过其受体生长激素促分泌素受体发挥作用 1a (GHSR) 是能量稳态的关键调节因子。 GHSR 广泛表达于大脑和胃肠道迷走神经感觉神经元。在当前的提案中，我们发现除了井迷走神经 GHSR，源自脊髓背根神经节 (DRG) 的胃肠道感觉神经元强烈表达 GHSR。此外，含有 GHSR 的 DRG 神经元支配胃肠道，并且 DRG GHSR 明显是由能量挑战引起的，包括食物匮乏和寒冷暴露，表明 DRG ghrelin/GHSR 信号传导对于调节能量稳态很重要。有趣的是，感官 GHSR缺失可防止饮食诱发的肥胖，主要是由于通过增加能量消耗而增加脂肪组织交感神经流出和产热。因此，我们发现了一条新的途径，其中肠道非迷走神经感觉 GHSR 神经元通过抑制脂肪组织负向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 信号在调节全身代谢中的重要性体内平衡，并研究感觉 GHSR 调节脂肪组织的神经机制同情心流出。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 感觉神经元特异性删除或重新激活 GHSR 进行测试。在具体目标 2 中，神经元连接肠道感觉 GHSR 信号与脂肪组织交感神经流出的电路将通过以下方式进行研究病毒道示踪剂图谱。此外，中枢黑皮质素信号通路可能参与其中将测试连接感觉 GHSR 信号传导与脂肪组织交感神经流出的下游目标。完成这个项目将大大扩展我们目前对能量神经内分泌调节的认识稳态，并将为预防和治疗肥胖提供新的治疗靶点。