Hypothalamic CRH Neurons in Diet-induced Obesity

项目摘要 由于不良副作用，治疗肥胖症的治疗药物的开发一直没有成功 疗效有限。对体重调节的关键脑神经通路的描绘对于充分 了解肥胖的病理生理学，并设计有效的对抗肥胖的策略。鉴于速度之快 肥胖流行与最近的经济发展和高脂肪高热量的容易获得不谋而合 饮食(HFD)，人们普遍认为HFD摄入量的增加对人类肥胖有显著影响 发展。令人信服的人体研究也表明，压力对体重调节有深远的影响。 然而，关于应激和高脂饮食诱导肥胖的神经基础还知之甚少。主要的脑神经元 对应激源做出反应的是促肾上腺皮质激素释放激素(CRH)神经元，它们位于几个主要的 大脑部位，包括下丘脑室旁(PVH)。PVH CRH神经元帮助维持身体 应激源反应的动态平衡主要通过激素下丘脑-垂体轴(HPA)和直接 向下游神经元的投射已知与行为适应有关。 我们先前的结果表明，无论是高水平还是低水平钳制PVH CRH神经元的活动 导致神经元反应性降低，加剧高脂饮食诱导的肥胖(DIO)，这是 与血液皮质类固醇昼夜节律改变有关。重要的是，PVH CRH神经元的反应性是 HFD喂养会显著降低HPA轴的节律性。此外，体重- 减少啮齿动物的可变应激状态可增强PVH-CRH的反应性。新兴的研究也 提示PVH-CRH神经元对奖赏的反应性改变并调节对HFD的选择 入口处。这些观察结果导致了我们的中心假设，即PVH CRH神经元的反应性是基础 高脂饮食引起的肥胖。目标1中的实验将确定PVH CRH减少的机制 用HFD测定神经元反应性。AIM 2的实验将确定调节PVH的神经递质 CRH神经元在DIO中的作用主要集中在CRH和谷氨酸的释放上。目标3中的实验将测试 PVH CRH神经元的反应性介导了已知的由时间诱导的对代谢的有益影响。 限制进食和昼夜节律加强诺比莱汀治疗。 这些结果将填补在理解应激和HFD的神经基础方面的知识空白。 肥胖。鉴于越来越多的证据表明慢性压力对人类肥胖的影响，这项提案旨在 确定PVH CRH神经元反应性是DIO的基本机制与人类高度相关 肥胖对肥胖症的治疗具有重要意义。

Project Summary The development of therapeutic drugs to cure obesity has not been successful due to unwanted side effects and limited efficacy. Delineation of key brain neural pathways on body weight regulation is essential to fully understand the pathophysiology of obesity and to design an effective strategy against obesity. Given the rapid obesity epidemic coinciding with recent economic development and readily availability of high fat high caloric diet (HFD), it is well accepted that the increased HFD consumption contribute significantly to human obesity development. Compelling human studies also indicate a profound effect of stress on body weight regulation. However, little is known about the neural basis of stress and HFD induced obesity. The major brain neurons that respond to stressors are corticotropin releasing hormone (CRH) neurons, which are located in a few major brain sites including the paraventricular hypothalamus (PVH). PVH CRH neurons help maintain bodily homeostasis in response to stressors mainly through hormonal hypothalamus-pituitary axis (HPA) and direct projections to down-stream neurons known to be involved in behavioral adaptation. Our previous results demonstrate that clamping PVH CRH neuron activity at either high or low levels both leads to reduced neuron responsiveness and exacerbates high fat diet-induced obesity (DIO), which is associated with altered blood corticosteroid diurnal rhythms. Importantly, PVH CRH neuron responsiveness is dramatically reduced by HFD feeding, which is known to blunt HPA axis rhythmicity. In addition, body weight- reducing variable stress regimes in rodents augment PVH CRH responsiveness. Emerging studies also suggest that PVH CRH neuron responsiveness changes in response to reward and regulates choices on HFD intake. These observations lead to our central hypothesis that PVH CRH neuron responsiveness underlies HFD-induced obesity. Experiments in Aim 1 will determine the mechanism underlying reduced PVH CRH neuron responsiveness by HFD. Experiments in Aim 2 will identify the neurotransmitters that mediate the PVH CRH neuron effect in DIO with a focus on CRH and glutamate release. Experiments in Aim 3 will test whether PVH CRH neuron responsiveness mediates the known beneficial effects on metabolism induced by time- restricted feeding and circadian rhythm enhancing Nobiletin treatment. Results will fill in the knowledge gap in understanding the neural basis for integrating stress and HFD on obesity. Given the growing evidence on the impact of chronic stress in human obesity, this proposal aiming to identify PVH CRH neuron responsiveness as a fundamental mechanism for DIO is highly relevant to human obesity and significant for obesity treatment.