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（由适用提供）：肥胖是一种迅速升级的流行病，其占美国医疗保健支出的占比其他任何医疗状况，总计超过1000亿美元。高血压是一种严重的心血管后果，部分原因是肌肉和儿童的交感神经活动增加（SNA）。但是，尚未确定这些机制。与先前对瘦素的研究并行，我们的最新数据表明，肥胖症显着放大了脑胰岛素的交感神经效果，这表明胰岛素可能起着比以前所欣赏的更大的作用。我们的主要目标是确定目前未知的敏感性的细胞分子机制。我们提出，肥胖感会感觉到胰岛素在SNA（下丘脑弧形核（ARCN））控制中的作用部位。几条间接证据表明，这种敏感性是由ARCN血管紧张素II（ANGII）AT1R激活介导的。首先，肥胖的人和饮食引起的肥胖症（DIO）的血浆血管含量升高。其次，全身ANGII阻滞可防止SNA的急性增加和胰岛素的慢性高血压作用。第三，DIO大鼠的高血压通过肾素 - 血管紧张素系统（RAS）的全身性阻滞而逆转，而用RAS的阻滞剂对肥胖人类进行处理会降低SNA。最后，ARCN表达AT1AR，然后将Angii显微注射到ARCN增加地图和SNA。因此，我们假设肥胖引起的Angii增加会扩大ARCN胰岛素增加SNA的作用。我们选择了DIO的啮齿动物模型来检验这一假设，因为与人类状况有广泛的相似性。 We will use complete 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 electrophysiological recordings and immunocytochemistry of identified ArcN neurons to systematically dissect the interdependency of InsR and AT1R in Neuropeptide Y and ARCN中的蛋白质素皮质素神经元以升高基本SNA。该核心信息以及Dreadds技术以及在肥胖和瘦大鼠的ARCN中使用病毒矢量的使用，或者使用病毒载体在肥胖和瘦大鼠的ARCN中使用AT1R，这将使我们能够确立这些神经调节剂作为交感神经的贡献者的作用，并最终导致肥胖受试者的高压发育和最终器官损害。