A novel axis regulates adipocyte plasticity

调节脂肪细胞可塑性的新轴

基本信息

批准号：
8631084
负责人：
Sean Hartig
金额：
$ 14.8万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2013-04-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631084
关键词：
2,4-thiazolidinedione Adipocytes Adipose tissue Adult Adverse effects Affect Agonist Biochemical Biological Assay Body Composition Body Weight Cell Respiration Characteristics Chronic Chronic stress Complex Data Deposition Development Diabetic mouse Diet Edema Energy Intake Energy Metabolism Enzymes Equation Exhibits Expenditure Fatty Acids Fatty acid glycerol esters Feedback Funding Gene Expression Gene Expression Profile Gene Expression Regulation Genes Goals Health Heart failure Human In Vitro Insulin Resistance Ligands Lipids Luciferases Malignant neoplasm of urinary bladder Medical Messenger RNA Metabolic Metabolism MicroRNAs Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Receptors Obesity PPAR gamma Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Prevention Production Public Health Regulation Reporter Research Research Personnel Risk Role Serum Signal Transduction Testing Therapeutic Thiazolidinediones Tissues Training Transactivation Ubiquitin United States adipokines bone loss chromatin immunoprecipitation cost diabetic energy balance fatty acid oxidation feeding glucose tolerance improved in vivo in vivo Model inhibitor/antagonist innovation insight insulin sensitivity insulin signaling lipid metabolism mouse model novel programs public health relevance research study response subcutaneous therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) affects one in 10 U.S. adults with direct annual medical costs near $120 billion. It is clear chronic alterations in energy storage and utilization, as in obesity, causes lipid deposition in non-adipose tissues, which is tightly associated with insulin resistance and T2DM. Thus, the ability of adipocytes to store energy as lipids is a crucial component of T2DM, and their production of key metabolic adipokines to regulate systemic insulin sensitivity, strongly reinforces their importance. Characteristics of adipocyte function, including fat metabolism and adipokine expression, are tightly regulated by peroxisome proliferator activated receptor gamma (PPAR?). Therapeutic PPAR? activation by thiazolidinediones increases insulin sensitivity and fat storage efficiency in T2DM with serious, negative side effects including edema, bone loss, bladder cancer, and heart failure. These findings highlight the inadequacy of current T2DM drugs and the need for innovative treatments to promote the beneficial effects of PPAR?, while minimizing undesirable effects. I discovered the small ubiquitin-related modifier (SUMO) E2-conjugation enzyme Ubc9 and its cognate microRNA (miR-30a) as a novel signaling loop which regulates PPAR? transactivation and energy balance genes in adipocytes. My findings suggest the Ubc9/miR-30a axis is regulated by PPAR? and promotes a gene expression profile which reflects beige adipocytes. Therefore, I hypothesize miR-30a down-regulates Ubc9 to promote insulin sensitivity and energy expenditure in adipose tissue. The following specific aims will use modern biochemical approaches and in vivo experiments to identify how the Ubc9/miR-30a axis regulates energy balance in adipocytes. Aim 1 will define the role of the Ubc9/miR-30a axis in promoting a metabolic profile associated with increased energy expenditure. Aim 2 will define the molecular mechanism of miR-30a regulation by anti-diabetic PPAR? ligands. Aim 3 will use mouse models of T2DM to define the impact of exogenous miR-30a expression in adipocytes on insulin sensitivity. I anticipate that my studies will provide new clues into the complex regulatory networks controlling energy balance in fat cells. If my hypothesis is true, the Ubc9/miR-30a axis might be exploited in novel therapies to manage T2DM.

描述（由申请人提供）：肥胖、胰岛素抵抗和 2 型糖尿病 (T2DM) 影响十分之一的美国成年人，每年直接医疗费用接近 1,200 亿美元。很明显，能量储存和利用的慢性改变（如肥胖）会导致非脂肪组织中的脂质沉积，这与胰岛素抵抗和 T2DM 密切相关。因此，脂肪细胞以脂质形式储存能量的能力是 T2DM 的重要组成部分，并且它们产生调节全身胰岛素敏感性的关键代谢脂肪因子，强烈增强了其重要性。脂肪细胞功能的特征，包括脂肪代谢和脂肪因子表达，受到过氧化物酶体增殖物激活受体γ（PPAR？）的严格调节。治疗性PPAR？噻唑烷二酮类药物的激活可增加 T2DM 患者的胰岛素敏感性和脂肪储存效率，并带来严重的副作用，包括水肿、骨质流失、膀胱癌和心力衰竭。这些发现凸显了当前 T2DM 药物的不足，以及需要创新疗法来促进 PPAR 的有益作用，同时最大限度地减少不良影响。我发现了小泛素相关修饰剂 (SUMO) E2 结合酶 Ubc9 及其同源 microRNA (miR-30a) 作为调节 PPAR? 的新型信号环路？脂肪细胞中的反式激活和能量平衡基因。我的研究结果表明 Ubc9/miR-30a 轴受 PPAR 调节？并促进反映米色脂肪细胞的基因表达谱。因此，我假设 miR-30a 下调 Ubc9 以促进脂肪组织中的胰岛素敏感性和能量消耗。以下具体目标将利用现代生化方法和体内实验来确定 Ubc9/miR-30a 轴如何调节脂肪细胞的能量平衡。目标 1 将定义 Ubc9/miR-30a 轴在促进与能量消耗增加相关的代谢特征中的作用。目标 2 将定义抗糖尿病 PPAR 调节 miR-30a 的分子机制？配体。目标 3 将使用 T2DM 小鼠模型来确定脂肪细胞中外源 miR-30a 表达对胰岛素敏感性的影响。我预计我的研究将为控制脂肪细胞能量平衡的复杂调节网络提供新线索。如果我的假设成立，那么 Ubc9/miR-30a 轴可能会被用于治疗 T2DM 的新疗法。