Cide Proteins and Regulation of Energy Expenditure

描述：这项建议的主要目标是确定与维持人类脂肪细胞的白色和白色表型相关的分子机制，并对肥胖和2型糖尿病患者脂肪酸(FA)诱导的胰岛素抵抗进行调节。第三种类型的脂肪细胞的鉴定和特性称为“白褐色” 或者“米色”或“棕色”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细胞。值得注意的是，白色脂肪细胞可以在各种刺激下具有黄褐色脂肪细胞的特征，但其机制(S)尚不完全清楚。事实上，UCP1和CIDEA是褐变或脆化的最显著的标志，然而CIDEA在棕色脂肪细胞中或在脆化过程中的作用机制仍然不清楚。我们和其他人以前发现了CIDE蛋白的成员，FSP27(也称为CIDEC)和CIDEA，是在脂肪代谢中发挥作用的脂滴相关蛋白。FSP27在白色脂肪细胞中高表达，而CIDEA在棕色脂肪细胞中高表达。我们的初步数据显示，a)FSP27负向调节脂肪分解，b)与ATGL/Desnutrin相互作用，ATGL/Desnutrin是催化甘油三酯第一步水解的限速酶，c)FSP27基因敲除促进脂肪组织中脂肪酸的氧化，d)CIDEA基因敲除抑制TZD诱导的人白色脂肪细胞的脆化。CIDEA与脂肪细胞中的FSP27相互作用，也定位于细胞核中，与肝X受体(LXR)相互作用，增加脂肪细胞中FA的氧化。因此，我们推测FSP27和CIDEA分别通过调节ATGL介导的脂解和/或核因子，在调节白色和白色表型中发挥关键作用，从而维持对脂肪的生理功能至关重要的能量平衡。 人体脂肪组织的储存和产热作用。这项工作将阐明FSP27和CIDEA通过调节人类脂肪细胞的白色和白色表型在能量储存和消耗中的作用机制，并可能为降低肥胖和相关代谢性疾病的风险的治疗方法的开发提供新的靶点。

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.