A novel axis regulates adipocyte plasticity

描述(申请人提供)：肥胖、胰岛素抵抗和2型糖尿病(T2 DM)影响着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变化，就像肥胖一样，会导致非脂肪组织中的脂肪沉积，这与胰岛素抵抗和T2 DM密切相关。因此，脂肪细胞以脂类的形式储存能量的能力是T2 DM的关键组成部分，它们产生的关键代谢性脂肪因子调节全身胰岛素敏感性，有力地加强了它们的重要性。脂肪细胞的功能特征，包括脂肪代谢和脂肪因子的表达，都受到过氧化物酶体增殖物激活受体γ(PPAR？)的严格调控。治疗性PPAR？噻唑烷二酮类药物的激活增加了T2 DM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，包括浮肿、骨质丢失、膀胱癌和心力衰竭。这些发现突显了目前T2 DM药物的不足，以及需要创新的治疗方法来促进PPAR？的有益影响，同时将不良影响降至最低。我发现了小泛素相关修饰物(SUMO)E2结合酶Ubc9及其同源microRNA(miR-30a)作为一种新的信号环，调节PPAR？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轴受PPAR？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的表达，以促进脂肪组织中的胰岛素敏感性和能量消耗。以下具体目标将使用现代生化方法和活体实验来确定Ubc9/miR-30a轴如何调节脂肪细胞的能量平衡。目标1将确定Ubc9/miR-30a轴在促进与能量消耗增加相关的代谢谱方面的作用。目的2将明确抗糖尿病PPAR调节miR-30a的分子机制？配基。AIM 3将使用T2 DM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，我的研究将为了解控制脂肪细胞能量平衡的复杂调控网络提供新的线索。如果我的假设是真的，Ubc9/miR-30a轴可能被用于治疗T2 DM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.