Cide Proteins and Regulation of Energy Expenditure

Cide 蛋白质和能量消耗的调节

• 批准号: 9115787
• 负责人: Vishwajeet Puri
• 金额: $ 33.41万
• 依托单位: OHIO UNIVERSITY ATHENS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115787
• 关键词: Adipocytes; Adipose tissue; Adopted; Attention; Biology; Cell Nucleus; Cells; Characteristics; Data; Energy Metabolism; Enzymes; Expenditure; Family member; Fatty Acids; Fatty acid glycerol esters; Genes; Glycerol; Goals; Health; Heating; Human; Hydrolysis; Insulin Resistance; Lipase; Lipids; Lipolysis; Liver; Maps; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Molecular; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Receptors; Obesity; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Physiologic Thermoregulation; Physiological; Play; Process; Protein Family; Proteins; Regulation; Role; Stimulus; Testing; Thermogenesis; Transcriptional Regulation; Triglycerides; Visceral; Work; density; energy balance; farmer; fatty acid oxidation; insulin signaling; interdisciplinary collaboration; lipid metabolism; member; obesity risk; receptor; subcutaneous; therapy development; transcription factor

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.

描述：该提案的主要目标是确定与维持人类脂肪细胞“白色”和“明亮”表型相关的分子机制，以及对肥胖和 2 型糖尿病中脂肪酸 (FA) 诱导的胰岛素抵抗的调节的影响。被称为“brite”（棕白色）的第三种脂肪细胞的鉴定和表征 或“米色”或“棕色样”脂肪细胞引起了相当大的关注，因为这些细胞被认为可以调节能量。值得注意的是，白色脂肪细胞可以通过各种刺激而采用白色脂肪细胞的特征，但其机制尚不完全清楚。事实上，UCP1 和 CIDEA 是褐变或褐变最显着的标记，但 CIDEA 在棕色脂肪细胞中或褐变过程中的作用机制仍然难以捉摸。我们和其他人之前确定了 CIDE 蛋白的成员 FSP27（也称为 CIDEC）和 CIDEA，它们是脂滴相关蛋白，在脂肪代谢中发挥作用。 FSP27 在白色脂肪细胞中高度表达，而 CIDEA 主要在棕色脂肪细胞中表达。我们的初步数据表明，a) FSP27 负向调节脂肪分解，b) 与 ATGL/Desnutrin（一种催化甘油三酯水解第一步的限速酶）相互作用，c) FSP27 敲低增强脂肪组织中的脂肪酸氧化，d) CIDEA 敲低抑制 TZD 诱导的人白蛋白变黄 脂肪细胞。 CIDEA 与脂肪细胞中的 FSP27 相互作用，并且还定位于细胞核，与肝脏 X 受体 (LXR) 相互作用，增加脂肪细胞中的 FA 氧化。因此，我们假设 FSP27 和 CIDEA 分别通过调节 ATGL 介导的脂肪分解和/或核因子，在“白色”和“brite”表型的调节中发挥关键作用，从而维持对脂肪生理功能至关重要的能量平衡 人体脂肪组织中的储存和产热。拟议的工作将通过调节人类脂肪细胞中的white vs brite表型来定义FSP27和CIDEA在能量储存和消耗方面的作用机制，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标。