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.


项目成果

期刊论文数量(0)
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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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