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：
PHILIPP E SCHERER
金额：
$ 49.73万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10395460
关键词：
Address Adipocytes Adipose tissue Adult Affect Amyloid beta-Protein Precursor Anabolism Antioxidants Area Attention Beta Cell Biogenesis Cell physiology Cells Data Doxycycline ERBB3 gene Epidermal Growth Factor Receptor FGF21 gene Family Fatty acid glycerol esters Ferritin Functional disorder Funding GDF15 gene Genetic Transcription Homeostasis Housekeeping Hyperinsulinism Hyperplasia Impairment Iron Link Mediating Mediator of activation protein Metabolic Methods Mitochondria Mitochondrial Matrix Modeling Mus Obesity Organ Oxidative Stress Pancreas Phenotype Physiology Play Prevention Process Production Reactive Oxygen Species Role Site Structure of beta Cell of islet System Time Tissue Expansion Translating Up-Regulation YY1 Transcription Factor adipokines adiponectin base catalase experimental study gain of function improved in vivo lipid biosynthesis lipid metabolism loss of function mitochondrial dysfunction mouse model overexpression prevent receptor reconstitution response subcutaneous tool transcription factor

Address Adipocytes Adipose tissue Adult Affect Amyloid beta-Protein Precursor Anabolism Antioxidants Area Attention Beta Cell Biogenesis Cell physiology Cells Data Doxycycline ERBB3 gene Epidermal Growth Factor Receptor FGF21 gene Family Fatty acid glycerol esters Ferritin Functional disorder Funding GDF15 gene Genetic Transcription Homeostasis Housekeeping Hyperinsulinism Hyperplasia Impairment Iron Link Mediating Mediator of activation protein Metabolic Methods Mitochondria Mitochondrial Matrix Modeling Mus Obesity Organ Oxidative Stress Pancreas Phenotype Physiology Play Prevention Process Production Reactive Oxygen Species Role Site Structure of beta Cell of islet System Time Tissue Expansion Translating Up-Regulation YY1 Transcription Factor adipokines adiponectin base catalase experimental study gain of function improved in vivo lipid biosynthesis lipid metabolism loss of function mitochondrial dysfunction mouse model overexpression prevent receptor reconstitution response subcutaneous tool transcription factor

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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.

白脂肪组织生理学，线粒体功能和脂联素近年来，人们一直致力于更好地了解棕色和米色脂肪细胞在经典上以高线粒体含量为特征。但是，白色脂肪细胞中的线粒体，基本生理和“家政”之外的线粒体仍然广泛未表征。我们已经开发了可以解决脂肪细胞特定操纵的系统线粒体功能，以诱导的方式。这允许诱导关键的线粒体组件成年小鼠，不包括不良的发育效果。在以前的资金期间，我们有检查了许多模型，其中脂肪细胞线粒体功能被选择性增强或妥协。我们的新模型之一使我们能够特别增强线粒体活性氧（ROS）脂肪细胞中的水平。这具有深远的本地和系统的影响，这使我们陷入了以下内容假设：脂肪细胞线粒体ROS水平的降低是脂肪组织对全身代谢改变的重塑和适应状况。通过仔细的定时和滴定线粒体活动和ROS水平，我们将检查一下以下领域的假设：a）在成熟脂肪细胞中的细胞水平； b）在微环境中在整个脂肪组织重塑的水平上； c）在有机水平上评估的系统效应脂肪细胞衍生的ROS，特别关注胰腺β细胞。具体来说，我们建议解决采用以下分层方法的基本机制：在AIM 1中，我们将研究脂肪细胞特异性线粒体功能障碍和线粒体生成的ROS在局部细胞上脂肪细胞的稳态。在AIM 2中，我们将定义脂肪细胞特异性线粒体的影响在局部脂肪组织微环境，功能和功能和线粒体生成的ROS和线粒体生成的ROS 重塑。在AIM 3中，我们将解决脂肪细胞特异性线粒体功能障碍和线粒体衍生的ROS在系统性代谢稳态上。这些研究结合在一起，使我们能够仔细剖析改变线粒体功能对脂联素产生的影响，白色脂肪细胞和脂肪组织的自适应重塑。而线粒体的既定作用棕色脂肪细胞中的功能得到广泛赞赏，我们的数据论证是线粒体功能的相关性在白色脂肪细胞中，被错误地被低估了。我们生成了一个独特的工具集，使我们能够系统地处理“线粒体功能障碍”的问题，实际上，此工具集有助于我们有条不紊地定义术语“功能障碍”。我们也想更好地理解管理的机制脂联素的产生和释放。根据我们的初步数据，我们坚信线粒体活动在此过程中起着至关重要的作用。此外，线粒体ROS对脂肪垫的自适应重塑以及与胰腺中β细胞的脂肪细胞的串扰。