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
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAdultAffectAmyloid beta-Protein PrecursorAnabolismAntioxidantsAreaAttentionBeta CellBiogenesisCell physiologyCellsDataDoxycyclineERBB3 geneEpidermal Growth Factor ReceptorFGF21 geneFamilyFatty acid glycerol estersFerritinFunctional disorderFundingGDF15 geneGenetic TranscriptionHomeostasisHousekeepingHyperinsulinismHyperplasiaImpairmentIronLinkMediatingMediator of activation proteinMetabolicMethodsMitochondriaMitochondrial MatrixModelingMusObesityOrganOxidative StressPancreasPhenotypePhysiologyPlayPreventionProcessProductionReactive Oxygen SpeciesRoleSiteStructure of beta Cell of isletSystemTimeTissue ExpansionTranslatingUp-RegulationYY1 Transcription Factoradipokinesadiponectinbasecatalaseexperimental studygain of functionimprovedin vivolipid biosynthesislipid metabolismloss of functionmitochondrial dysfunctionmouse modeloverexpressionpreventreceptorreconstitutionresponsesubcutaneoustooltranscription factor
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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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
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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