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: 9021881
• 负责人: VIRGINIA L. BROOKS
• 金额: $ 54.61万
• 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/9021881
• 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 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; public health relevance; 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.