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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：
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

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.