Adiporedoxin and the Regulation of Adipocyte Function in Human Obesity

脂孔还蛋白和人类肥胖中脂肪细胞功能的调节

• 批准号: 9333682
• 负责人: Susan K Fried
• 金额: $ 9.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-25 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333682
• 关键词: Adiporedoxin; Regulation; Adipocyte; Function; Human

 DESCRIPTION (provided by applicant): Adipocytes have dual roles as energy-storing and as endocrine cells, and both functions are critical to maintaining metabolic homeostasis. Adipocyte hormones (so-called adipokines) include leptin, adiponectin, and numerous other metabolically important proteins. Adiponectin is an especially important adipokine because it functions to enhance insulin action and prevent inflammation. In insulin resistant obese individuals, adiponectin production is low. Our studies in rodent adipocytes led to the discovery of a peroxiredoxin family member that we named adiporedoxin (Adrx). Adrx expression is highly enriched in both mouse and human adipocytes and Adrx protein is localized to the endoplasmic reticulum. Preliminary studies show that the expression of both Adrx mRNA and protein was directly correlated with levels of adiponectin within the tissue and inversely related to key markers of endoplasmic reticulum and cellular redox stress in human adipose tissue from young, lean and obese subjects. In addition, in diet- induced obese mice, Adrx expression was decreased and correlated with low levels of circulating high molecular weight (HMW) adiponectin, the most active form. The goal of this application is to determine the translational importance of Adrx in obese humans. Our central hypothesis is that Adrx acts as a redox sensor that links oxidative stress and inflammation in the adipocyte to the systemic redox state in order to regulate adipokine production and maintain systemic metabolic homeostasis. Our first specific aim is to determine if low expression of Adrx in adipose tissue of men and women with a range of obesity and glucose tolerance is associated with decreased assembly and secretion of adiponectin and with lower circulating levels of HMW and total adiponectin (and their ratio). The second aim is to determine if the expression of Adrx is affected by adipocyte and/or systemic insulin resistance and redox status. Aim 3 will use newly-differentiated human adipocytes to: a) test consequences of Adrx knockdown and overexpression on the secretome, insulin signaling, adipocyte metabolism, and redox status and b) the importance of Adrx for preventing adipocyte dysfunction in response to challenge of nutrient and oxidant stresses. The combination of proposed basic and clinical studies will fill important gaps in knowledge of the human adipocyte secretome and how it is dysregulated in obesity. In addition, this work will test the generalizability of our preliminary findings on Adrx and adiponectin expression in younger individuals, in an older population at high risk for metabolic disease. The proposed studies represent an important step toward future efforts to develop dietary and pharmacological approaches to improve the secretory and metabolic functions of human adipocytes, and will contribute to the development of useful biomarkers of adipocyte function in clinical and population studies.

 描述（由申请人提供）：脂肪细胞具有能量储存细胞和内分泌细胞的双重作用，这两种功能对于维持代谢稳态都至关重要。脂肪细胞激素（所谓的脂肪因子）包括瘦素、脂联素和许多其他代谢重要的蛋白质。脂联素是一种特别重要的脂肪因子，因为它具有增强胰岛素作用和预防炎症的作用。在胰岛素抵抗的肥胖个体中，脂联素的产生量较低。我们对啮齿动物脂肪细胞的研究发现了一种过氧化还蛋白家族成员，我们将其命名为脂孔还蛋白 (Adrx)。 Adrx 表达在小鼠和人类脂肪细胞中高度富集，并且 Adrx 蛋白定位于内质网。初步研究表明，Adrx mRNA 和蛋白的表达与组织内脂联素水平直接相关，与年轻、瘦身和肥胖受试者的人体脂肪组织中内质网和细胞氧化还原应激的关键标志物呈负相关。此外，在饮食诱导的肥胖小鼠中，Adrx 表达降低，并与循环高分子量 (HMW) 脂联素（最活跃的形式）水平低相关。该应用的目标是确定 Adrx 在肥胖人群中的转化重要性。我们的中心假设是 Adrx 作为氧化还原传感器，将脂肪细胞中的氧化应激和炎症与全身氧化还原状态联系起来，以调节脂肪因子的产生并维持全身代谢稳态。我们的第一个具体目标是确定患有一系列肥胖和糖耐量的男性和女性脂肪组织中 Adrx 的低表达是否与脂联素组装和分泌减少以及 HMW 和总脂联素（及其比率）循环水平较低有关。第二个目的是确定 Adrx 的表达是否受到脂肪细胞和/或全身胰岛素抵抗和氧化还原状态的影响。目标 3 将使用新分化的人类脂肪细胞来：a）测试 Adrx 敲低和过度表达对分泌组、胰岛素信号、脂肪细胞代谢和氧化还原状态的影响；b）Adrx 对于预防脂肪细胞功能障碍以应对营养和氧化应激的挑战的重要性。所提出的基础研究和临床研究的结合将填补人类脂肪细胞分泌组及其在肥胖中如何失调的知识空白。此外，这项工作将测试我们关于 Adrx 和脂联素表达的初步发现在年轻个体和代谢疾病高风险老年人群中的普遍性。拟议的研究代表了未来努力开发饮食和药理学方法以改善人类脂肪细胞的分泌和代谢功能的重要一步，并将有助于在临床和群体研究中开发有用的脂肪细胞功能生物标志物。