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

基本信息

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
项目类别：
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

项目摘要

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（通过应用程序证明）：肥胖是一种迅速升级的触觉，医疗保健护理护理护理护理护理护理在任何人的医疗状况中都超过1000亿美元。一部分是对肌肉和肾脏的神经活动的一部分。对于货币的细胞分子摩变，我们提出了肥胖症胰岛素在SNA控制中的作用部位，下丘脑弧核（ARCN）是由ARCN血管素II（Angii）介导的。 AT1R活化。，肥胖的人的肥胖者最终降低了ARCN，而Angii的微注射会增加地图和SNA DIO的啮齿动物模式测试了这一假设，由于对人类状况的广泛可能系统地剖析了Inn神经肽Y和ARCN中的促蛋白酶质素神经元的跨性别的互动，并在基础上进行了sna。神经调节剂具有交感神经，并最终导致肥胖受试者的高血压发育最终器官损害。