Hypothalamic CRH Neurons in Diet-induced Obesity

下丘脑 CRH 神经元在饮食引起的肥胖中的作用

• 批准号: 10749756
• 负责人: Qingchun Tong
• 金额: $ 41.62万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749756
• 关键词: Ablation; Adrenal Cortex Hormones; Adrenal Glands; Adult; Anxiety; Behavioral; Black race; Blood; Body Weight; Body Weight Changes; Body Weight decreased; Brain; Chronic stress; Circadian Rhythms; Closure by clamp; Code; Color; Complex; Consumption; Corticotropin-Releasing Hormone; Development; Diet; Diurnal Rhythm; Economic Development; Energy Metabolism; Fatty acid glycerol esters; Feedback; Feeding behaviors; Fiber; Food; Foundations; Functional disorder; GABA Receptor; Glutamate Receptor; Glutamates; Goals; High Fat Diet; Homeostasis; Hormonal; Hormone Responsive; Hormones; Human; Hypothalamic structure; Intake; Knowledge; Lead; Mediating; Metabolic; Metabolism; Mus; Neural Pathways; Neurons; Neurotransmitters; Obesity; Obesity Epidemic; Outcome; Pattern; Periodicity; Pharmaceutical Preparations; Pharmacological Treatment; Photometry; Pituitary Gland; Positioning Attribute; Prevention; Reducing diet; Regimen; Regulation; Research; Rewards; Rodent; Role; Signal Transduction; Site; Stress; Synapses; Testing; Therapeutic; Time-restricted feeding; Weight maintenance regimen; biological adaptation to stress; design; diet-induced obesity; effective therapy; experimental study; feeding; fighting; genetic approach; improved; mouse genetics; neural; neuronal excitability; neurotransmitter release; nobiletin; obesity development; obesity prevention; obesity treatment; postsynaptic; response; side effect; stressor; therapeutic development

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.

项目摘要 由于不必要的副作用，治疗药物的开发尚未成功 和有限的功效。在体重调节上的关键大脑神经途径的描述对于完全至关重要 了解肥胖的病理生理学，并设计有效的抗肥胖策略。给定快速 肥胖流行与最近的经济发展相吻合，并且很容易获得高脂肪的高热量 饮食（HFD），众所周知，增加的HFD消耗对人类肥胖有显着贡献 发展。引人入胜的人类研究还表明，压力对体重调节的深远影响。 但是，对压力和HFD诱发肥胖的神经基础知之甚少。主要的大脑神经元 对压力源的反应是皮质激素释放激素（CRH）神经元，该神经元位于少数主要 大脑部位，包括旁丘脑下丘脑（PVH）。 PVH CRH神经元有助于维持身体 稳态以应对压力源，主要通过荷尔蒙下丘脑 - 垂体轴（HPA）和直接 已知与行为适应有关的向下流神经元的预测。 我们先前的结果表明，将PVH CRH神经元夹在高水平或低水平上 导致神经元的反应降低，并加剧高脂饮食诱导的肥胖症（DIO），即 与血液皮质类固醇的改变有关。重要的是，PVH CRH神经元反应是 HFD喂养大大降低了，这是钝HPA轴节律性的已知。另外，体重 - 降低啮齿动物中的可变应力状态增加了PVH CRH响应能力。新兴研究也是如此 建议PVH CRH神经元的响应能力在响应奖励和调节HFD上的选择时发生变化 进气。这些观察结果导致了我们的中心假设，即PVH CRH神经元反应性是基础的 HFD引起的肥胖症。 AIM 1中的实验将确定降低PVH CRH的机制 HFD的神经元反应能力。 AIM 2中的实验将识别介导PVH的神经递质 CRH神经元在DIO中的效应，重点是CRH和谷氨酸释放。 AIM 3中的实验将测试是否 PVH CRH神经元反应性介导了对时间 - 受限的喂养和昼夜节律增强了诺比我们的治疗。 结果将填补了解整合压力和HFD神经基础的知识差距 肥胖。鉴于越来越多的证据证明了慢性压力对人类肥胖的影响，该提议旨在 识别PVH CRH神经元反应性作为DIO的基本机制与人类高度相关 肥胖症和对肥胖症的重要性。