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

肥胖已经成为一个世界性的流行病问题，并且是一组新陈代谢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。这个 胃源性促食欲激素Ghrelin通过其受体生长激素促分泌受体发挥作用 1a(GHSR)是能量动态平衡的关键调节因子。GHSR在大脑和其他组织中广泛表达 胃肠迷走感觉神经元。在目前的提案中，我们发现除了油井之外， 迷走神经--背根节(DRG)的胃肠感觉神经元 强势表达GHSR。此外，含有DRG GHSR的神经元支配胃肠道，以及 DRG GHSR明显是由能量挑战引起的，包括食物匮乏和寒冷暴露， 提示DRG ghrelin/GHSR信号在调节能量动态平衡中起重要作用。有趣的是，感官 GHSR缺失可预防饮食引起的肥胖，主要原因是通过增加 脂肪组织交感神经流出和生热。因此，我们已经确定了一条新的途径，在其中肠道 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、生热和全身能量消耗。这个项目的总体目标是 检测外周感觉神经元Ghrelin/GHSR信号在调节全身代谢中的重要性 动态平衡，并探讨感觉性GHSR调节脂肪组织的神经机制 感同身受的流出。在具体目标1中，感觉GHSR在调节能量平衡方面的重要性将 通过DRG感觉神经元特异性删除或重新激活GHSR进行测试。在特定目标2中，神经元 连接肠道感觉GHSR信号到脂肪组织交感神经流出的回路将通过 病毒道示踪剂测绘。此外，中枢黑素皮质素信号通路可能参与作为一种 将测试连接感觉GHSR信号与脂肪组织交感神经流出的下游靶点。 完成这个项目将极大地扩展我们目前对能量的神经内分泌调节的知识 动态平衡，将在预防和治疗肥胖症方面提供新的治疗靶点。

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.