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：
10621045
负责人：
Bingzhong Xue
金额：
$ 8.41万
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 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10621045
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

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.

肥胖已成为世界范围内的流行病问题，并且是一组代谢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。这通过其受体生长激素促素受体作用的胃源性甲状腺激素生长素蛋白 1A（GHSR）是能量稳态的关键介体。 GHSR在大脑中广泛表达胃肠道迷走运动神经元。在当前的建议中，我们发现除了井外特征的迷走神经GHSR，从脊柱背根神经节发出的胃肠道感觉神经元（DRG）坚固地表达GHSR。另外，含DRG GHSR神经元的神经元支配胃肠道，并且 DRG GHSR明显受到精力充沛的挑战，包括食物剥夺和冷暴露，提示DRG生长素/GHSR信号对于调节能量稳态很重要。有趣的是，感官 GHSR缺失可防止饮食引起的肥胖症，这主要是由于增加的能量消耗增加脂肪组织交感神经流出和热生成。因此，我们已经确定了一种新的途径通过抑制脂肪组织对能量稳态负调节能量稳态，非处境感觉GHSR神经元。交感神经流出，生热和全身能量消耗。该项目的总体目标是在调节全身代谢中，测试生长素林/GHSR信号传导对周围感觉神经元的重要性稳态，并研究感觉GHSR调节脂肪组织的神经元机制同情流出。在特定目标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重新激活GHSR进行测试。在特定目标2中，神经元连接肠道感官GHSR信号传导与脂肪组织交感神经流出的电路将通过病毒道示踪剂映射。另外，中央黑色皮质素信号通路可能参与为A 将测试将感觉GHSR信号连接到脂肪组织交感神经流出的下游目标。完成该项目将大大扩展我们对神经内分泌能量调节的当前知识体内平衡，并将在预防和治疗肥胖症方面提供新颖的治疗靶标。