A novel axis regulates adipocyte plasticity

描述（由申请人提供）：肥胖、胰岛素抵抗和2型糖尿病（T2DM）影响了十分之一的美国成年人，每年的直接医疗费用接近1200亿美元。很明显，能量储存和利用的慢性改变，如肥胖，导致非脂肪组织的脂质沉积，这与胰岛素抵抗和2型糖尿病密切相关。因此，脂肪细胞作为脂质储存能量的能力是T2DM的一个重要组成部分，它们产生的关键代谢脂肪因子调节全身胰岛素敏感性，强烈地增强了它们的重要性。脂肪细胞功能的特征，包括脂肪代谢和脂肪因子的表达，受到过氧化物酶体增殖物激活受体γ (PPAR?)的严格调控。治疗PPAR吗?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，并伴有严重的副作用，包括水肿、骨质流失、膀胱癌和心力衰竭。这些发现强调了当前T2DM药物的不足，需要创新治疗方法来促进PPAR的有益作用。，同时尽量减少不良影响。我发现小的泛素相关修饰物（SUMO） e2偶联酶Ubc9及其同源microRNA （miR-30a）是一种调节PPAR的新型信号环。脂肪细胞中的转激活和能量平衡基因。我的研究结果表明Ubc9/miR-30a轴受PPAR？并促进了反映米色脂肪细胞的基因表达谱。因此，我假设miR-30a下调Ubc9以促进脂肪组织的胰岛素敏感性和能量消耗。以下具体目的将使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。目的1将确定Ubc9/miR-30a轴在促进与能量消耗增加相关的代谢谱中的作用。Aim 2将明确抗糖尿病PPAR调控miR-30a的分子机制。配体。目的3将使用T2DM小鼠模型来确定脂肪细胞中外源性miR-30a表达对胰岛素敏感性的影响。我预计我的研究将为脂肪细胞中控制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，Ubc9/miR-30a轴可能被用于管理T2DM的新疗法。

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.