Human adipose tissue in control of sympathetic tone and metabolic rate

人类脂肪组织控制交感神经张力和代谢率

基本信息

  • 批准号:
    10749552
  • 负责人:
  • 金额:
    $ 72.54万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-01 至 2027-08-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Sympathetic outflow to adipose tissue regulates whole body energy homeostasis by stimulating lipolysis in white adipocytes and thermogenesis in brown or beige adipocytes. Using a novel approach to study human adipose tissue in mice [1, 2], we have found that, during development, human adipocytes express a high level of monoamine oxidase A (MAOA), a major mechanism for degradation of norepinephrine, and a known target of antidepressant drugs [3]. Notably, expression of Maoa is virtually undetectable in mouse adipocytes, indicating that this control mechanism may have evolved to meet the metabolic features of larger species. We find that human adipocyte MAOA is decreased during beige adipose tissue development, potentially increasing norepinephrine bioavailability, adrenergic tone and thermogenic capacity. Thus, MAOA expression in human adipocytes is a previously underappreciated, key mechanism controlling adipose tissue functions, potentially underlying susceptibility to obesity and metabolic disease. In this proposal, we will further test the hypothesis that adipocyte MAOA controls systemic energy homeostasis through its effects on adipose tissue sympathetic responsiveness. We have developed methodologies to obtain large numbers of human multipotent mesenchymal progenitor cells that can differentiate into multiple adipocyte subtypes, and can generate functional adipose tissue upon implantation in vivo. We have also successfully deleted MAOA from these cells using a novel nanoparticle-based, CRISPR-Cas9 protein delivery technique, resulting in a >90% depletion of MAOA protein while avoiding non-specific effects of expressed Cas9. Leveraging these technologies, we shall: Aim 1. Test the hypothesis that human adipocyte MAOA limits lipolytic and thermogenic responses to norepinephrine. We will measure lipolysis and induction of thermogenesis in control and MAOA-deleted human adipocytes exposed to norepinephrine, as well as steady-state norepinephrine levels and dependency on the monoamine transporter Oct3. Aim 2. We will test the hypothesis that MAOA in human adipocytes regulates the development and responsiveness of thermogenic adipose tissue in vivo. We will measure the rate and extent of vascularization and innervation, and thermogenic responsiveness to environmental stimuli of tissue developed in NSG mice from control or MAOA deleted human adipocytes. Aim 3. We will test the hypothesis that expression of MAOA in adipocytes will determine susceptibility to obesity, systemic insulin sensitivity and systemic glucose homeostasis. We will analyze weight gain, adipocyte size, insulin sensitivity, glucose disposal under hyper insulinemic, hyperglycemic clamps, and basal metabolic rate in mice harboring adipose depots formed from control or MAOA deleted human adipocytes, and in mice overexpressing MaoA in subcutaneous adipose tissue. These aims will provide the basis for further development of tissue specific MAOA-targeting strategies as novel therapeutics for metabolic disease.
摘要 交感神经流出到脂肪组织通过刺激脂肪分解调节全身能量稳态, 白色脂肪细胞和棕色或米色脂肪细胞产热。用一种新的方法来研究人类 在小鼠的脂肪组织中[1,2],我们发现,在发育过程中,人脂肪细胞表达高水平的 单胺氧化酶A(MAOA)是降解去甲肾上腺素的主要机制, 抗抑郁药的靶点[3]。值得注意的是,Maoa的表达在小鼠脂肪细胞中几乎检测不到, 这表明这种控制机制可能已经进化以满足较大物种的代谢特征。我们 发现人类脂肪细胞MAOA在米色脂肪组织发育过程中减少, 去甲肾上腺素生物利用度、肾上腺素张力和产热能力。因此,MAOA在人类中的表达 脂肪细胞是以前未被充分认识的控制脂肪组织功能的关键机制, 潜在的肥胖和代谢疾病的潜在易感性。在本提案中,我们将进一步测试 假设脂肪细胞MAOA通过其对脂肪组织的作用控制全身能量稳态 交感反应我们已经开发出方法来获得大量的人类多能 间充质祖细胞可以分化成多种脂肪细胞亚型,并可以产生 功能性脂肪组织。我们还成功地从这些细胞中删除了MAOA 使用一种新的基于纳米颗粒的CRISPR-Cas9蛋白质递送技术, MAOA蛋白,同时避免表达的Cas9的非特异性作用。利用这些技术,我们 应:目标1。检验人类脂肪细胞MAOA限制脂解和产热反应的假设, 去甲肾上腺素我们将测量对照组和MAOA缺失组的脂解和产热诱导, 暴露于去甲肾上腺素的人脂肪细胞,以及稳态去甲肾上腺素水平和对 单胺转运蛋白Oct 3。目标2.我们将检验人类脂肪细胞中MAOA的假设 调节体内产热脂肪组织的发育和反应性。我们将测量 血管化和神经支配的速率和程度,以及对环境刺激的产热反应, 在NSG小鼠中从对照或MAOA缺失的人脂肪细胞发育的组织。目标3.我们将测试 假设脂肪细胞中MAOA表达将决定对肥胖、全身胰岛素 敏感性和全身葡萄糖稳态。我们将分析体重增加,脂肪细胞大小,胰岛素敏感性, 高胰岛素血症、高血糖钳夹下的葡萄糖处置和基础代谢率 从对照或MAOA缺失的人脂肪细胞形成的脂肪贮库,以及在小鼠中过表达MaoA, 皮下脂肪组织这些目标将为进一步开发组织特异性 MAOA靶向策略作为代谢性疾病的新疗法。

项目成果

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Silvia Corvera其他文献

Silvia Corvera的其他文献

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{{ truncateString('Silvia Corvera', 18)}}的其他基金

Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
  • 批准号:
    10019532
  • 财政年份:
    2019
  • 资助金额:
    $ 72.54万
  • 项目类别:
Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
  • 批准号:
    10166839
  • 财政年份:
    2019
  • 资助金额:
    $ 72.54万
  • 项目类别:
Mechanisms of human adipose depot development and impact of Diabetes
人体脂肪库发育机制及糖尿病的影响
  • 批准号:
    10418655
  • 财政年份:
    2019
  • 资助金额:
    $ 72.54万
  • 项目类别:
University of Massachusetts Center for Clinical and Translational Science
马萨诸塞大学临床与转化科学中心
  • 批准号:
    9127400
  • 财政年份:
    2015
  • 资助金额:
    $ 72.54万
  • 项目类别:
FASEB SRC on Glucose transport: Gateway for metabolic systems Biology
FASEB SRC 关于葡萄糖转运:代谢系统生物学的门户
  • 批准号:
    8595738
  • 财政年份:
    2013
  • 资助金额:
    $ 72.54万
  • 项目类别:
Medical Scientist Training at UMMS Administrative Supplement
UMMS 医学科学家培训行政补充
  • 批准号:
    9900318
  • 财政年份:
    2013
  • 资助金额:
    $ 72.54万
  • 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
  • 批准号:
    8187450
  • 财政年份:
    2011
  • 资助金额:
    $ 72.54万
  • 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
  • 批准号:
    8470640
  • 财政年份:
    2011
  • 资助金额:
    $ 72.54万
  • 项目类别:
Adipose Tissue Angiogenesis and Metabolic Disease
脂肪组织血管生成和代谢疾病
  • 批准号:
    8668046
  • 财政年份:
    2011
  • 资助金额:
    $ 72.54万
  • 项目类别:
FASEB SRC on Glucose Transporters, Signaling and Diabetes
关于葡萄糖转运蛋白、信号传导和糖尿病的 FASEB SRC
  • 批准号:
    8200163
  • 财政年份:
    2011
  • 资助金额:
    $ 72.54万
  • 项目类别:

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Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b
成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
  • 批准号:
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食物源性因子在白色脂肪组织中诱导棕色样脂肪细胞
  • 批准号:
    26450168
  • 财政年份:
    2014
  • 资助金额:
    $ 72.54万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
WAT-on-a-chip - Development of a micofluidic, microphysiologic in vitro adipose tissue model for high-throughput drug screening based on hiPSC-derived adipocytes.
WAT-on-a-chip - 开发微流体、微生理体外脂肪组织模型,用于基于 hiPSC 衍生脂肪细胞的高通量药物筛选。
  • 批准号:
    257256526
  • 财政年份:
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  • 资助金额:
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Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
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  • 资助金额:
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增强白色脂肪组织中的能量消耗脂肪细胞
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  • 财政年份:
    2013
  • 资助金额:
    $ 72.54万
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Enhancing Energy Expending Adipocytes in White Adipose Tissue
增强白色脂肪组织中的能量消耗脂肪细胞
  • 批准号:
    8629741
  • 财政年份:
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运动训练对白色脂肪组织内脂肪细胞形成的影响
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  • 财政年份:
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白色脂肪组织中棕色脂肪细胞出现机制的研究
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    21780261
  • 财政年份:
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LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
路易斯安那 COBRE:P1:在白色脂肪组织中诱导产热棕色脂肪细胞
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    7610781
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