Cide Proteins and Regulation of Energy Expenditure

产品说明：该提案的主要目标是确定维持人类脂肪细胞“白色”和“brite”表型的相关分子机制，以及肥胖和2型糖尿病中脂肪酸（FA）诱导的胰岛素抵抗的调节结果。第三种脂肪细胞的鉴定和表征，称为“brite”（白色中的棕色） 或“米色”或“棕色样”脂肪细胞已经引起了相当大的关注，因为这些细胞被认为是调节能量的。值得注意的是，白色脂肪细胞可以通过各种刺激来采用brite脂肪细胞的特征，但其机制尚未完全了解。事实上，UCP 1和CIDEA是布朗宁或变亮的最突出的标志物，然而CIDEA在褐色脂肪细胞中或在变亮过程中的作用机制仍然是难以捉摸的。我们和其他人先前鉴定了锡德蛋白的成员，FSP 27（也称为CIDEC）和CIDEA，是在脂肪代谢中起作用的脂滴相关蛋白。FSP 27在白色脂肪细胞中高度表达，而CIDEA在棕色脂肪细胞中占优势。我们的初步数据显示a）FSP 27负调节脂解，B）与ATGL/Desnutrin相互作用，ATGL/Desnutrin是催化甘油三酯水解第一步的限速酶，和c）FSP 27敲低增强脂肪组织中的脂肪酸氧化，和d）CIDEA敲低抑制人白色脂肪细胞中TZD诱导的增亮。CIDEA与脂肪细胞中的FSP 27相互作用，并且还定位于细胞核中，在那里它与肝脏X受体（LXR）相互作用以增加脂肪细胞中的FA氧化。因此，我们假设FSP 27和CIDEA通过调节ATGL介导的脂解和/或核因子，分别在“白色”和“brite”表型的调节中发挥关键作用，从而维持脂肪生理功能所必需的能量平衡 储存和产热。这项工作将通过调节人类脂肪细胞中的白色与brite表型来确定FSP 27和CIDEA在能量储存和消耗中的作用机制，并可能为开发降低肥胖和相关代谢疾病风险的疗法提供新的靶点。

DESCRIPTION: The key goal of this proposal is to identify the molecular mechanisms associated in maintaining 'white' and 'brite' phenotype of human adipocytes, with consequences for the regulation of fatty acid (FA)-induced insulin resistance in obesity and type 2-diabetes. Identification and characterization of a third type of adipocytes known as 'brite' (brown-in-white) or 'beige' or 'brown-like' adipocytes has drawn considerable attention, as these cells are thought to regulate energy. Remarkably, the white adipocytes can adopt the characteristics of brite adipocytes by various stimuli, but the mechanism(s) are not fully understood. In fact, UCP1 and CIDEA are most prominent markers for browning or britening, yet the mechanism of action of CIDEA in brown adipocytes or during the britening process remains elusive. We and others previously identified members of CIDE proteins, FSP27 (also called CIDEC) and CIDEA, to be lipid droplet associated proteins playing a role in fat metabolism. FSP27 is highly expressed in white adipocytes, whereas CIDEA is predominant in brown. Our preliminary data shows that a) FSP27 negatively regulates lipolysis, b) interacts with ATGL/Desnutrin, a rate-limiting enzyme for catalyzing the first step of hydrolysis of triglycerides, and c) FSP27 knockdown enhance fatty acid oxidation in adipose tissue, and d) CIDEA knockdown suppresses TZD- induced britening in human white adipocytes. CIDEA interacts with FSP27 in adipocytes, and also localizes in the nucleus where it interacts with liver-X-receptor (LXR) to increase FA oxidation in adipocytes. Therefore, we hypothesize that FSP27 and CIDEA play a critical role in the regulation of 'white' and 'brite' phenotype, respectively, by regulating ATGL-mediated lipolysis and/or nuclear factors, thus maintaining an energy balance that is essential for the physiological function of fat storage and thermogenesis in human adipose tissue. The proposed work will define the mechanism of action of FSP27 and CIDEA in energy storage and expenditure by regulating white vs brite phenotype in human adipocytes, and might provide new targets for the development of therapies to decrease the risk of obesity and related metabolic diseases.