Adiporedoxin and the Regulation of Adipocyte Function in Human Obesity

 描述(申请人提供)：脂肪细胞具有能量储存和内分泌细胞的双重作用，这两种功能对维持代谢平衡至关重要。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功能。在胰岛素抵抗的肥胖者中，脂联素的产量很低。我们对啮齿动物脂肪细胞的研究发现了一个过氧化还蛋白家族成员，我们将其命名为脂肪氧化还蛋白(Adrx)。Adrx在小鼠和人脂肪细胞中的表达高度丰富，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呈正相关，与脂肪组织内质网关键标志物和细胞氧化还原应激呈负相关。此外，在饮食诱导的肥胖小鼠中，Adrx的表达减少，并与循环中最活跃的高分子脂联素(HMW)水平降低有关。这个应用程序的目标是确定Adrx在肥胖人类中的翻译重要性。我们的中心假设是，Adrx作为氧化还原感受器，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，并维持全身代谢动态平衡。我们的第一个特定目标是确定肥胖和糖耐量不同的男性和女性脂肪组织中Adrx的低表达是否与脂联素的组装和分泌减少以及循环中HMW和总脂联素水平(及其比率)的降低有关。第二个目的是确定Adrx的表达是否受到脂肪细胞和/或全身性胰岛素抵抗和氧化还原状态的影响。Aim 3将使用新分化的人类脂肪细胞：a)测试Adrx基因敲除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，以及b)Adrx对于预防脂肪细胞功能障碍的重要性，以应对营养和氧化应激的挑战。拟议的基础和临床研究的结合将填补关于人类脂肪细胞分泌组及其在肥胖中如何失调的知识的重要空白。此外，这项工作将测试我们关于Adrx和脂联素在年轻个体中表达的初步发现在代谢性疾病高风险的老年人群中的普适性。这些研究代表了未来开发饮食和药物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人群研究中开发有用的脂肪细胞功能生物标志物。

 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.