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.

项目概要 由于副作用，治疗肥胖症的治疗药物的开发尚未成功 并且功效有限。描述体重调节的关键大脑神经通路对于充分发挥体重调节作用至关重要 了解肥胖的病理生理学并设计有效的肥胖策略。鉴于快速 肥胖症的流行与最近的经济发展和高脂肪高热量的容易获得相一致 饮食（HFD），人们普遍认为，HFD 消费的增加会导致人类肥胖 发展。令人信服的人类研究还表明压力对体重调节有深远的影响。 然而，人们对压力和 HFD 引起的肥胖的神经基础知之甚少。主要大脑神经元 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神经元中。 大脑部位包括室旁下丘脑 (PVH)。 PVH CRH 神经元帮助维持身体 主要通过激素下丘脑-垂体轴 (HPA) 和直接应激反应来实现体内平衡 对已知参与行为适应的下游神经元的预测。 我们之前的结果表明，将 PVH CRH 神经元活动钳制在高或低水平都可以 导致神经元反应性降低并加剧高脂肪饮食诱发的肥胖（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 神经元反应性是 HFD 喂养会显着降低 HPA 轴的节律性。另外，体重—— 减少啮齿类动物的可变应激状态可增强 PVH CRH 反应能力。新兴研究还 表明 PVH CRH 神经元响应性因奖励而变化并调节 HFD 的选择 摄入量。这些观察结果引出了我们的中心假设：PVH CRH 神经元反应性是其基础 HFD 引起的肥胖。目标 1 中的实验将确定减少 PVH CRH 的潜在机制 HFD 的神经元反应。目标 2 中的实验将确定介导 PVH 的神经递质 DIO 中的 CRH 神经元效应，重点是 CRH 和谷氨酸释放。目标 3 中的实验将测试是否 PVH CRH 神经元反应性介导时间诱导的对代谢的已知有益影响 限制喂养和昼夜节律增强川陈皮素治疗。 结果将填补理解整合压力和 HFD 的神经基础的知识空白 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，该提案旨在 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，对肥胖治疗具有重要意义。