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 治疗肥胖症的治疗药物的开发由于不希望的副作用而没有成功 和有限的功效。对体重调节的关键脑神经通路的描绘是充分 了解肥胖的病理生理学，并设计有效的策略来对抗肥胖。鉴于快速 肥胖流行与最近的经济发展和高脂肪高热量的容易获得相吻合 虽然人们普遍认为高脂饮食（HFD）的摄入量增加会显著导致人类肥胖 发展令人信服的人类研究也表明压力对体重调节的深刻影响。 然而，很少有人知道的神经基础的压力和HFD引起的肥胖。大脑的主要神经元 对压力刺激有反应的是促肾上腺皮质激素释放激素（CRH）神经元，它们位于少数几个主要的 包括室旁下丘脑（PVH）的脑部位。CRH神经元帮助维持身体 应激反应的稳态主要通过激素下丘脑-垂体轴（HPA）和直接 投射到下游神经元，已知这些神经元参与行为适应。 我们以前的研究结果表明，无论是高水平还是低水平的钳制PVH CRH神经元活动， 导致神经元反应性降低并加剧高脂饮食诱导的肥胖症（DIO）， 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喂养显著降低了HPA轴的节律性，已知HFD喂养会钝化HPA轴的节律性。此外，体重- 减少啮齿类动物中的可变应激方案增加PVH CRH反应性。新兴研究还 提示PVH CRH神经元反应性在对奖励的反应中发生变化，并调节HFD的选择 摄入这些观察结果导致我们的中心假设，即PVH CRH神经元反应性是PVH CRH神经元反应性的基础。 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 神经元反应性HFD。目标2中的实验将确定介导PVH的神经递质 CRH神经元在DIO中的作用，重点是CRH和谷氨酸释放。目标3的实验将测试 PVH CRH神经元反应性介导已知的对时间诱导的代谢的有益作用。 限制进食和昼夜节律增强Nobiletin治疗。 结果将填补知识空白，了解整合压力和HFD的神经基础， 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，这项建议旨在 鉴定PVHCRH神经元反应性作为DIO基本机制与人类高度相关 对肥胖症的治疗具有重要意义。