MicroRNAs in brown fat development and metabolism

项目总结/摘要 我们的长期目标是了解控制棕色脂肪发育和功能的分子途径。在 与白色脂肪相反，棕色脂肪是专门消耗能量的组织。它存在于成人 它的活性与人类肥胖呈负相关。因此，棕色脂肪是潜在的有吸引力的 用于治疗肥胖症和代谢疾病的靶组织。我们感兴趣的是棕色脂肪是如何发育的 而功能是由miRNAs调节的，miRNAs是一类不编码蛋白质但控制许多蛋白质的小RNA。 发育和细胞过程。我们已经鉴定了一组选择性表达于 棕色脂肪我们发现，其中一个，当在棕色脂肪中表达时， 因此，这些动物具有较少的白色脂肪量，并且对饮食诱导的 肥胖我们的假设是，这种miRNA通过激活cGMP促进棕色脂肪细胞的分化。 依赖信号通路。在第一个目标，我们将详细分析是否扩大棕色脂肪库， 是真正的棕色脂肪，是功能性的。我们将确定膨胀的棕色脂肪是否能改善代谢 参数和增强胰岛素敏感性。我们将确定膨胀的棕色脂肪是否能阻止 遗传性肥胖在第二个目标中，我们将进行细胞培养研究，以进一步验证， 这种miRNA促进褐色细胞分化。我们将检测miRNA是否抑制了 cGMP依赖性信号通路中的负调节因子。在第三个目标中，我们将确定 miRNA激活cGMP依赖性信号通路。我们的研究可能会提供有用的信息 这种miRNA的模拟物是否对肥胖和代谢疾病具有治疗潜力。

Project Summary/Abstract Our long-range goal is to understand molecular pathways that govern brown fat development and function. In contrast to white fat, brown fat is a tissue that is specialized in energy expenditure. It is present in adult humans and its activity is inversely associated with human obesity. Thus, brown fat is potentially an attractive therapeutic target tissue for obesity and metabolic diseases. We are interested in how brown fat development and function is regulated by miRNAs, a class of small RNAs that do not encode protein yet control many developmental and cellular processes. We have identified a set of miRNAs that are selectively expressed in the brown fat. We found that, one of them, when expressed in the brown fat, remarkably expands the brown fat depots of mice, and as a result, the animals have less white fat mass and are resistant to diet-induced obesity. Our hypothesis is that this miRNA promotes brown fat cell differentiation by activating a cGMP- dependent signaling pathway. In the first aim, we will analyze in detail whether the expanded brown fat depots are true brown fat and are functional. We will determine whether the expanded brown fat improves metabolic parameters and enhances insulin sensitivity. We will determine whether the expanded brown fat prevents genetically predisposed obesity. In the second aim, we will perform cell culture studies to further validate that this miRNA promotes brown cell differentiation. We will examine whether the miRNA represses the expression of a negative regulator in the cGMP-dependent signaling pathway. In the third aim, we will determine whether the miRNA activates the cGMP-dependent signaling pathway. Our studies will likely provide useful information on whether mimics of this miRNA have therapeutic potentials for obesity and metabolic diseases.