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:
    9021881
  • 负责人:
  • 金额:
    $ 54.61万
  • 依托单位:
  • 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

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.
 肥胖症是一种迅速升级的流行病,在美国,它比任何其他医疗条件都要占更多的医疗保健支出,每年超过1000亿美元。一种严重的心血管后果是高血压,部分原因是肌肉和肾脏的交感神经活动(SNA)增加。然而,机制尚未确定。与以前的研究与瘦素平行,我们最近的数据表明,肥胖显着放大脑胰岛素的交感神经兴奋作用,这表明胰岛素可能发挥更大的作用比以前认识到的。我们的主要目标是确定这种致敏的细胞分子机制,这是目前未知的。我们认为肥胖使胰岛素在SNA控制中的作用部位,即下丘脑弓状核(ArcN)敏感。一些间接证据表明,这种致敏作用是由增加的ArcN血管紧张素II(AngII)AT 1 R激活介导的。首先,血浆AngII水平在肥胖的人和患有饮食诱导的肥胖症(DIO)的大鼠中增加。第二,全身性血管紧张素II阻断防止SNA的急性增加和胰岛素的慢性高血压作用。第三,DIO大鼠中的高血压通过全身性阻断肾素-血管紧张素系统(RAS)而逆转,并且用RAS阻断剂治疗肥胖人降低SNA。最后,ArcN表达AT 1aR,并且向ArcN中微量注射AngII增加MAP和SNA。因此,我们假设肥胖诱导的AngII增加放大了ArcN胰岛素增加SNA的作用。我们选择了DIO的啮齿动物模型来测试这一假设,因为它与人类的情况有广泛的相似性。我们将使用互补的方法,包括脑纳米注射选择性抑制剂和测量多个交感神经的活性变化,显微解剖下丘脑组织的Western/qPCR分析,以及确定的ArcN神经元的电生理记录和免疫细胞化学,以系统地剖析InsR和AT 1 R在ArcN中的神经肽Y和阿黑皮素原神经元中的相互依赖性,以提高基础SNA。这一核心信息加上DREADDs技术和使用病毒载体来长期敲低肥胖和瘦大鼠ArcN中的InsR或AT 1 R,将使我们能够确定这些神经调节剂作为交感神经兴奋的贡献者的作用,并最终导致肥胖受试者的高血压发展和终末器官损伤。

项目成果

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VIRGINIA L. BROOKS其他文献

VIRGINIA L. BROOKS的其他文献

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{{ truncateString('VIRGINIA L. BROOKS', 18)}}的其他基金

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
  • 财政年份:
    2016
  • 资助金额:
    $ 54.61万
  • 项目类别:
Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy
怀孕期间胰岛素抵抗和心血管调节受损
  • 批准号:
    7846860
  • 财政年份:
    2008
  • 资助金额:
    $ 54.61万
  • 项目类别:
Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy
怀孕期间胰岛素抵抗和心血管调节受损
  • 批准号:
    7373988
  • 财政年份:
    2008
  • 资助金额:
    $ 54.61万
  • 项目类别:
Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy
怀孕期间胰岛素抵抗和心血管调节受损
  • 批准号:
    7637350
  • 财政年份:
    2008
  • 资助金额:
    $ 54.61万
  • 项目类别:
Humoral Interactions in long-term blood pressure control
长期血压控制中的体液相互作用
  • 批准号:
    6612925
  • 财政年份:
    2002
  • 资助金额:
    $ 54.61万
  • 项目类别:
Humoral Interactions in long-term blood pressure control
长期血压控制中的体液相互作用
  • 批准号:
    6751660
  • 财政年份:
    2002
  • 资助金额:
    $ 54.61万
  • 项目类别:
Humoral Interactions in long-term blood pressure control
长期血压控制中的体液相互作用
  • 批准号:
    6895198
  • 财政年份:
    2002
  • 资助金额:
    $ 54.61万
  • 项目类别:
Humoral Interactions in long-term blood pressure control
长期血压控制中的体液相互作用
  • 批准号:
    6506517
  • 财政年份:
    2002
  • 资助金额:
    $ 54.61万
  • 项目类别:
BLOOD PRESSURE REGULATION DURING PREGNANCY
怀孕期间的血压调节
  • 批准号:
    2219441
  • 财政年份:
    1988
  • 资助金额:
    $ 54.61万
  • 项目类别:
BLOOD PRESSURE REGULATION DURING PREGNANCY
怀孕期间的血压调节
  • 批准号:
    2028363
  • 财政年份:
    1988
  • 资助金额:
    $ 54.61万
  • 项目类别:

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