White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin

白色脂肪组织生理学、线粒体功能和脂联素

基本信息

  • 批准号:
    10395460
  • 负责人:
  • 金额:
    $ 49.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-07-05 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin Much attention has been dedicated over recent years towards a better understanding of brown and beige adipocytes, which are classically characterized by high mitochondrial content. However, the role of mitochondria in white adipocytes, beyond basic physiology and “housekeeping”, remains vastly uncharacterized. We have developed systems in which we can address adipocyte-specific manipulation of mitochondrial function, in an inducible fashion. This allows for induction of key mitochondrial components in the adult mouse, excluding undesirable developmental effects. Over the previous funding period, we have examined a number of models in which adipocyte mitochondrial function was selectively enhanced or compromised. One of our new models allows us to specifically enhance mitochondrial reactive oxygen species (ROS) levels within the adipocyte. This has profound local and systemic effects that led us to the following hypothesis: THE LOWERING OF ADIPOCYTE MITOCHONDRIAL ROS LEVELS IS A PREREQUISITE FOR THE REMODELING AND ADAPTATION OF ADIPOSE TISSUE TO ALTERED SYSTEMIC METABOLIC CONDITIONS. By carefully timing and titrating mitochondrial activity and ROS levels, we will examine this hypothesis in the following areas: A) at the cellular level in the mature adipocyte; B) in the microenvironment at the level of whole adipose tissue remodeling; C) at the organismal level assessing systemic effects of adipocyte-derived ROS, with a specific focus on pancreatic beta cells. Specifically, we propose to address the underlying mechanisms with the following hierarchical approaches: In Aim 1, we will examine the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the LOCAL cellular homeostasis of the adipocyte. In Aim 2, we will define the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the local ADIPOSE TISSUE microenvironment, function and remodeling. In Aim 3, we will address the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-derived ROS on SYSTEMIC metabolic homeostasis. Combined, these studies enable us to carefully dissect the effects of altered mitochondrial function on adiponectin production, cellular physiology of the white adipocyte and adaptive remodeling of adipose tissue. While the established role of mitochondrial function in brown adipocytes is widely appreciated, our data argues that the relevance of mitochondrial function in the white adipocyte has been mistakenly undervalued. We have generated a unique toolset that allows us to systematically approach the question of “mitochondrial dysfunction” and, in fact, this toolset helps us to methodically define the term “dysfunction”. We also want to better understand the mechanisms governing adiponectin production and release. Based upon our preliminary data, we strongly believe that mitochondrial activity plays an essential role in this process. Furthermore, mitochondrial ROS exerts profound effects on the adaptive remodeling of fat pads as well as on the crosstalk of adipocytes with the beta cells in the pancreas.
White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin Much attention has been dedicated over recent years towards a better understanding of brown and beige adipocytes, which are classically characterized by high mitochondrial content. However, the role of mitochondria in white adipocytes, beyond basic physiology and “housekeeping”, remains vastly uncharacterized. We have developed systems in which we can address adipocyte-specific manipulation of mitochondrial function, in an inducible fashion. This allows for induction of key mitochondrial components in the adult mouse, excluding undesirable developmental effects. Over the previous funding period, we have examined a number of models in which adipocyte mitochondrial function was selectively enhanced or compromised. One of our new models allows us to specifically enhance mitochondrial reactive oxygen species (ROS) levels within the adipocyte. This has profound local and systemic effects that led us to the following hypothesis: THE LOWERING OF ADIPOCYTE MITOCHONDRIAL ROS LEVELS IS A PREREQUISITE FOR THE REMODELING AND ADAPTATION OF ADIPOSE TISSUE TO ALTERED SYSTEMIC METABOLIC CONDITIONS. By carefully timing and titrating mitochondrial activity and ROS levels, we will examine this hypothesis in the following areas: A) at the cellular level in the mature adipocyte; B) in the microenvironment at the level of whole adipose tissue remodeling; C) at the organismal level assessing systemic effects of adipocyte-derived ROS, with a specific focus on pancreatic beta cells. Specifically, we propose to address the underlying mechanisms with the following hierarchical approaches: In Aim 1, we will examine the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the LOCAL cellular homeostasis of the adipocyte. In Aim 2, we will define the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-generated ROS on the local ADIPOSE TISSUE microenvironment, function and remodeling. In Aim 3, we will address the effects of adipocyte-specific mitochondrial dysfunction and mitochondria-derived ROS on SYSTEMIC metabolic homeostasis. Combined, these studies enable us to carefully dissect the effects of altered mitochondrial function on adiponectin production, cellular physiology of the white adipocyte and adaptive remodeling of adipose tissue. While the established role of mitochondrial function in brown adipocytes is widely appreciated, our data argues that the relevance of mitochondrial function in the white adipocyte has been mistakenly undervalued. We have generated a unique toolset that allows us to systematically approach the question of “mitochondrial dysfunction” and, in fact, this toolset helps us to methodically define the term “dysfunction”. We also want to better understand the mechanisms governing adiponectin production and release. Based upon our preliminary data, we strongly believe that mitochondrial activity plays an essential role in this process. Furthermore, mitochondrial ROS exerts profound effects on the adaptive remodeling of fat pads as well as on the crosstalk of adipocytes with the beta cells in the pancreas.

项目成果

期刊论文数量(0)
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PHILIPP E SCHERER其他文献

PHILIPP E SCHERER的其他文献

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{{ truncateString('PHILIPP E SCHERER', 18)}}的其他基金

CORE 1 - Animal Phenotyping Core
核心 1 - 动物表型核心
  • 批准号:
    10512733
  • 财政年份:
    2022
  • 资助金额:
    $ 49.73万
  • 项目类别:
CORE 1 - Animal Phenotyping Core
核心 1 - 动物表型核心
  • 批准号:
    10657781
  • 财政年份:
    2022
  • 资助金额:
    $ 49.73万
  • 项目类别:
Physiological Role of Dedifferentiating Dermal Adipose Tissue
真皮脂肪组织去分化的生理作用
  • 批准号:
    10348609
  • 财政年份:
    2021
  • 资助金额:
    $ 49.73万
  • 项目类别:
Physiological Role of Dedifferentiating Dermal Adipose Tissue
真皮脂肪组织去分化的生理作用
  • 批准号:
    10532175
  • 财政年份:
    2021
  • 资助金额:
    $ 49.73万
  • 项目类别:
White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin
白色脂肪组织生理学、线粒体功能和脂联素
  • 批准号:
    9920126
  • 财政年份:
    2013
  • 资助金额:
    $ 49.73万
  • 项目类别:
White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin
白色脂肪组织生理学、线粒体功能和脂联素
  • 批准号:
    8557828
  • 财政年份:
    2013
  • 资助金额:
    $ 49.73万
  • 项目类别:
White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin
白色脂肪组织生理学、线粒体功能和脂联素
  • 批准号:
    8847709
  • 财政年份:
    2013
  • 资助金额:
    $ 49.73万
  • 项目类别:
White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin
白色脂肪组织生理学、线粒体功能和脂联素
  • 批准号:
    8696859
  • 财政年份:
    2013
  • 资助金额:
    $ 49.73万
  • 项目类别:
Novel Mechanisms Regulating the Adipocyte-Brain Hepatocyte Axis
调节脂肪细胞-脑肝细胞轴的新机制
  • 批准号:
    8308565
  • 财政年份:
    2010
  • 资助金额:
    $ 49.73万
  • 项目类别:
Novel Mechanisms Regulating the Adipocyte-Brain-Hepatocyte Axis
调节脂肪细胞-脑-肝细胞轴的新机制
  • 批准号:
    9100718
  • 财政年份:
    2010
  • 资助金额:
    $ 49.73万
  • 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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  • 财政年份:
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Enhancing Energy Expending Adipocytes in White Adipose Tissue
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  • 批准号:
    8827438
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  • 批准号:
    26450168
  • 财政年份:
    2014
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    $ 49.73万
  • 项目类别:
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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。
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    257256526
  • 财政年份:
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  • 批准号:
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    $ 49.73万
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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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    8520690
  • 财政年份:
    2013
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    $ 49.73万
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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
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    8629741
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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
  • 批准号:
    23700778
  • 财政年份:
    2011
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Investigation for the mechanisms of the emergence of brown adipocytes in white adipose tissue
白色脂肪组织中棕色脂肪细胞出现机制的研究
  • 批准号:
    21780261
  • 财政年份:
    2009
  • 资助金额:
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  • 项目类别:
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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
  • 批准号:
    7610781
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    2007
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