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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：
9920126
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/9920126
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 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

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.

白色脂肪组织生理学、线粒体功能和脂联素近年来，人们越来越关注棕色和米色的更好理解脂肪细胞的典型特征是线粒体含量高。然而，角色白色脂肪细胞中的线粒体，除了基本生理学和“内务管理”之外，仍然大量存在没有特征的。我们开发了可以解决脂肪细胞特异性操作的系统线粒体功能，以诱导方式。这允许诱导关键线粒体成分成年小鼠，排除不良的发育影响。在上一个资助期间，我们有研究了许多模型，其中脂肪细胞线粒体功能被选择性增强或妥协了。我们的新模型之一使我们能够特异性增强线粒体活性氧脂肪细胞内的（ROS）水平。这具有深远的局部和系统性影响，使我们得出以下结论假设：脂肪细胞线粒体 ROS 水平降低是脂肪组织对改变的全身代谢的重塑和适应状况。通过仔细计时和滴定线粒体活性和 ROS 水平，我们将检查这一点在以下领域的假设：A）在成熟脂肪细胞的细胞水平； B) 微环境在整个脂肪组织重塑的水平上； C）在有机体水平上评估系统性影响脂肪细胞衍生的 ROS，特别关注胰腺 β 细胞。具体来说，我们建议解决具有以下分层方法的基本机制：在目标 1 中，我们将检查以下因素的影响：脂肪细胞特异性线粒体功能障碍和线粒体产生的 ROS 对局部细胞的影响脂肪细胞的稳态。在目标 2 中，我们将定义脂肪细胞特异性线粒体的影响功能障碍和线粒体产生的 ROS 对局部脂肪组织微环境、功能和重塑。在目标 3 中，我们将解决脂肪细胞特异性线粒体功能障碍的影响和线粒体衍生的 ROS 对系统代谢稳态的影响。综合起来，这些研究使我们能够仔细剖析线粒体功能改变对脂联素产生、细胞生理学的影响白色脂肪细胞和脂肪组织的适应性重塑。虽然线粒体的作用已经确定棕色脂肪细胞的功能受到广泛认可，我们的数据表明线粒体功能的相关性在白色脂肪细胞中，它被错误地低估了。我们生成了一个独特的工具集，使我们能够系统地解决“线粒体功能障碍”的问题，事实上，这个工具集可以帮助我们有条理地定义术语“功能障碍”。我们还希望更好地了解控制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这个过程中起着至关重要的作用。此外，线粒体 ROS 对脂肪垫的适应性重塑以及脂肪细胞与胰腺中β细胞的串扰。