MicroRNAs in brown fat development and metabolism

描述（由申请人提供）：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。与白色脂肪相反，棕色脂肪是一种专门用于能量消耗的组织。它存在于成年人中，其活性是 与人类肥胖呈负相关。因此，棕色脂肪是肥胖症和代谢性疾病的潜在治疗靶组织。我们感兴趣的是棕色脂肪的发育和功能是如何由miRNAs调节的，miRNAs是一类不编码蛋白质但控制许多发育和细胞过程的小RNA。我们已经确定了一组选择性表达于棕色脂肪的miRNAs。我们发现，其中之一，当在棕色脂肪中表达时，显着扩大了小鼠的棕色脂肪库，因此，动物具有较少的白色脂肪量，并抵抗饮食诱导的肥胖。我们的假设是这种miRNA通过激活cGMP依赖的信号通路促进棕色脂肪细胞分化。在第一个目标中，我们将详细分析扩大的棕色脂肪库是否是真正的棕色脂肪和功能。我们将确定是否扩大棕色脂肪改善代谢参数，提高胰岛素敏感性。我们将确定膨胀的棕色脂肪是否可以预防遗传性肥胖。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促进棕色细胞分化。我们将研究miRNA是否抑制cGMP依赖性信号通路中负调节因子的表达。在第三个目标中，我们将确定miRNA是否激活cGMP依赖的信号通路。我们的研究可能会提供有用的信息，这种miRNA的模拟物是否具有治疗肥胖和代谢疾病的潜力。

DESCRIPTION (provided by applicant): 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.