A novel axis regulates adipocyte plasticity

调节脂肪细胞可塑性的新轴

• 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
• 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

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）影响美国十分之一的成年人，直接年度医疗费用接近1,200亿美元。像肥胖症一样，清楚的储能和利用中的慢性变化会导致非脂肪组织中的脂质沉积，这与胰岛素抵抗和T2DM紧密相关。因此，脂肪细胞作为脂质存储能量的能力是T2DM的关键组成部分，并且其关键代谢脂肪因子的产生可以调节系统性胰岛素敏感性，从而强烈增强其重要性。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伽玛（PPAR？）的严格调节。治疗性PPAR？噻唑烷二酮的激活增加了T2DM的胰岛素敏感性和脂肪储存效率，具有严重的副作用，包括水肿，骨质流失，膀胱癌和心力衰竭。这些发现突出了当前T2DM药物的不足以及对促进PPAR的有益作用的创新治疗的需求，同时最大程度地减少了不良影响。我发现了与泛素相关的小修饰符（SUMO）E2偶联酶UBC9及其同源microRNA（miR-30a）是调节PPAR的新型信号循环？脂肪细胞中的反式激活和能量平衡基因。我的发现表明UBC9/miR-30a轴由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。以下特定目的将使用现代化的生化方法和体内实验来确定UBC9/miR-30a轴如何调节脂肪细胞中的能量平衡。 AIM 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。 AIM 2将通过抗糖尿病PPAR定义miR-30a调节的分子机制？配体。 AIM 3将使用T2DM的小鼠模型来定义脂肪细胞中外源性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的能量平衡的复杂调节网络提供新的线索。如果我的假设是正确的，则可以在新的疗法中利用UBC9/miR-30a轴来管理T2DM。