Obesity-induced sympathoexcitation: role of brain insulin

肥胖引起的交感神经兴奋：脑胰岛素的作用

• 批准号: 9295162
• 负责人: VIRGINIA L. BROOKS
• 金额: $ 10万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-15 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9295162
• 关键词: ART protein; Accounting; Acute; Angiotensin II; Angiotensins; Attention; Binding; Brain; Cardiovascular system; Cells; Chronic; Coupled; Data; Development; Diet; Electrophysiology (science); Epidemic; Exhibits; Failure; Gatekeeping; Goals; Health; Health Expenditures; High Fat Diet; Human; Hypertension; Hypothalamic structure; In Vitro; Individual; Insulin; Insulin Receptor; Kidney; Label; Lentivirus Vector; Leptin; Measurement; Mediating; Medical; Melanocortin 4 Receptor; Microinjections; Modeling; Molecular; Mus; Muscle; Nerve; Neuromodulator; Neurons; Obesity; Organ; Pathway interactions; Plasma; Play; Pro-Opiomelanocortin; Rattus; Receptor Activation; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Resistance; Rodent; Rodent Model; Role; Site; Sprague-Dawley Rats; Structure of nucleus infundibularis hypothalami; Sympathetic Nervous System; Techniques; Technology; Testing; Tissues; Viral Vector; Work; alpha-Melanocyte stimulating hormone; basal insulin; base; cell type; central sensitization; clinically significant; designer receptors exclusively activated by designer drugs; excitatory neuron; extracellular; feeding; immunocytochemistry; in vivo; inhibitor/antagonist; innovation; knock-down; neuropeptide Y; neuropeptide Y-Y1 receptor; novel therapeutics; paraventricular nucleus; prevent; receptor

 DESCRIPTION (provided by applicant): Obesity is a rapidly escalating epidemic that accounts for more health care expenditures in the US than any other medical condition, amounting to over $100 billion per year. One severe cardiovascular consequence is hypertension, due in part to increased sympathetic nerve activity (SNA) to muscle and the kidneys. However, the mechanisms have not been identified. In parallel to previous studies with leptin, our recent data indicate that obesity markedly amplifies the sympathoexcitatory effects of brain insulin, suggesting that insulin may play a greater role than previously appreciated. Our major goal is to identify the cellular-molecular mechanisms of this sensitization, which are currently unknown. We propose that obesity sensitizes insulin's site of action in the control of SNA, the hypothalamic arcuate nucleus (ArcN). Several lines of indirect evidence suggest that this sensitization is mediated by increased ArcN angiotensin II (AngII) AT1R activation. First, plasma AngII levels are increased in obese humans and rats with diet-induced obesity (DIO). Second, systemic AngII blockade prevents the acute increases in SNA and the chronic hypertensive actions of insulin. Third, hypertension in DIO rats is reversed by systemic blockade of the renin-angiotensin system (RAS), and treatment of obese humans with blockers of the RAS decreases SNA. Finally, the ArcN expresses AT1aR, and microinjection of AngII into the ArcN increases MAP and SNA. Therefore, we hypothesize that obesity-induced increases in AngII amplify the actions of ArcN insulin to increase SNA. We have chosen rodent models of DIO to test this hypothesis, because of broad similarities to the human condition. We will use complementary approaches, including brain nanoinjection of selective inhibitors and the measurement of the changes in activity of multiple sympathetic nerves, Western/qPCR analysis of microdissected hypothalamic tissue, and electrophysiologic recordings and immunocytochemistry of identified ArcN neurons to systematically dissect the interdependency of InsR and AT1R in Neuropeptide Y and pro-opiomelanocortin neurons in the ArcN to elevate basal SNA. This core information coupled with DREADDs technology and the use of viral vectors to chronically knockdown InsR or AT1R in the ArcN of obese and lean rats will allow us to establish the role of these neuromodulators as contributors to sympathoexcitation and ultimately to hypertension development and end organ damage in obese subjects.

 描述（由申请人提供）：肥胖是一种迅速升级的流行病，在美国，肥胖症所造成的医疗保健支出比任何其他疾病都多，每年超过 1000 亿美元。高血压是一种严重的心血管后果，部分原因是肌肉和肾脏的交感神经活动 (SNA) 增加。然而，其机制尚未确定。与之前的瘦素研究并行，我们最近的数据表明，肥胖显着放大了脑胰岛素的交感神经兴奋作用，这表明胰岛素发挥的作用可能比之前认为的更大。我们的主要目标是确定这种致敏作用的细胞分子机制，目前尚不清楚。我们认为肥胖使胰岛素在 SNA（下丘脑弓状核（ArcN））控制中的作用部位变得敏感。一些间接证据表明，这种致敏作用是由 ArcN 血管紧张素 II (AngII) AT1R 激活增加介导的。首先，肥胖人和饮食诱导肥胖（DIO）大鼠的血浆 AngII 水平升高。其次，全身性 AngII 阻断可防止 SNA 的急性增加和胰岛素的慢性高血压作用。第三，DIO 大鼠的高血压可通过肾素-血管紧张素系统 (RAS) 的全身阻断而逆转，并且用 RAS 阻断剂治疗肥胖人群会降低 SNA。最后，ArcN 表达 AT1aR，将 AngII 显微注射到 ArcN 中会增加 MAP 和 SNA。因此，我们假设肥胖引起的 AngII 增加会增强 ArcN 胰岛素增加 SNA 的作用。由于 DIO 与人类状况广泛相似，我们选择了 DIO 啮齿动物模型来检验这一假设。我们将使用补充方法，包括选择性抑制剂的脑纳米注射和多交感神经活性变化的测量、显微解剖的下丘脑组织的Western/qPCR分析以及已识别的ArcN神经元的电生理记录和免疫细胞化学，以系统地剖析神经肽Y和ArcN神经元中InsR和AT1R的相互依赖性。 ArcN 中的阿黑皮质素原神经元可提高基础 SNA。这一核心信息与 DREADDs 技术相结合，并使用病毒载体长期敲低肥胖和瘦大鼠 ArcN 中的 InsR 或 AT1R，将使我们能够确定这些神经调节剂在肥胖受试者中促进交感神经兴奋并最终导致高血压发展和终末器官损伤的作用。