Adipocyte dysfunction: modulation of weight loss associated miR

脂肪细胞功能障碍：减肥相关 miR 的调节

• 批准号: 391022982
• 负责人: Dr. Ronald Biemann
• 金额: --
• 依托单位: Institut für Klinische Chemie und Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391022982?language=en
• 关键词: Adipocyte; dysfunction; modulation; weight; loss

Increasing prevalence of the metabolic syndrome (MetS) represents a major public health burden. The underlying mechanism involves obesity associated metabolically stressed adipocytes and accumulation of proinflammatory macrophages in adipose tissue. Interaction between proinflammatory macrophages and lipid laden adipocytes is suggested to contribute to adipose tissue dysfunction and to promote local insulin resistance, lipid spillover and systemic low-grade inflammation.So far, lifestyle-induced weight loss is regarded as efficient therapy to ameliorate MetS and to prevent type 2 diabetes and CVD in individuals with MetS. However, information about the molecular pathways that promote reversibility of adipocyte dysfunction in patients with MetS is scarce at best. Adipocytes and adipose tissue macrophages react to weight loss by alterations of cell specific gene expression, which is regulated by microRNA´s (miR). Hence, modulation of adipose and macrophage specific miR expression may represent a molecular target to improve adipose tissue dysfunction in individuals with MetS. To identify weight loss associated miR, we analyzed mRNA and miR expression in subcutaneous adipose tissue of individuals with MetS. 74 non-smoking, non-diabetic men aged between 45 and 55 years with MetS as defined by the International Diabetes Federation guidelines were randomized to a 6 months tele-monitored lifestyle-induced weight loss intervention group or to a control arm. First results of this study were already published by us in 2016 (Scientific Reports, Nature Publishing Group). By paired analysis we identified 7 miR that were differently regulated following lifestyle-induced weight loss. Target prediction analysis revealed that two specific miR have potential binding sites in differently regulated genes that can be predominantly clustered by function for lipid metabolism and for macrophage activity. We now aim to exploit these data to ascertain whether modulation of the identified weight loss associated miR regulate adipocyte function in regard to adipogenesis, ROS production, insulin sensitivity, macrophage differentiation, macrophage activation and adipocyte-macrophage interaction. As mouse orthologues exist only for a subset of identified miR and as species differences in regard to the pathophysiological mechanisms underlying MetS and lifestyle induced gene expression are highly likely, we will analyze the function of identified miR on adipocytes and macrophages using human in vitro models. With this approach we hope to identify new pathways ameliorating obesity related adipocyte dysfunction.The following goals will be investigated:Goal 1a: Impact of HSA-miR-548y on adipocyte VLDL uptakeGoal 1b: Impact of HSA-miR-548y on macrophage differentiation and activation Goal 2: Impact of identified miR on adipocyte differentiation, ROS production and insulin sensitivityGoal 3: Impact of identified miR on adipocyte-macrophage interaction

代谢综合征（MetS）患病率的增加是一个主要的公共卫生负担。潜在的机制涉及肥胖相关的代谢应激脂肪细胞和脂肪组织中促炎巨噬细胞的积累。促炎巨噬细胞与脂质脂肪细胞之间的相互作用可能导致脂肪组织功能障碍，并促进局部胰岛素抵抗、脂质外溢和全身性低度炎症。到目前为止，生活方式引起的减肥被认为是改善MetS和预防2型糖尿病和心血管疾病的有效治疗方法。然而，关于促进MetS患者脂肪细胞功能障碍可逆性的分子途径的信息充其量是很少的。脂肪细胞和脂肪组织巨噬细胞对体重减轻的反应是通过改变细胞特异性基因表达，这是由microRNA ' s （miR）调节的。因此，调节脂肪和巨噬细胞特异性miR表达可能是改善MetS患者脂肪组织功能障碍的分子靶点。为了确定与体重减轻相关的miR，我们分析了met患者皮下脂肪组织中mRNA和miR的表达。74名年龄在45岁至55岁之间的非吸烟、非糖尿病男性，根据国际糖尿病联合会指南的定义患有MetS，被随机分为6个月的远程监测生活方式诱导的减肥干预组或对照组。我们已经在2016年发表了第一批研究结果（science Reports, Nature Publishing Group）。通过配对分析，我们确定了7种miR在生活方式引起的体重减轻后受到不同的调节。靶标预测分析显示，两个特异性miR在不同的调控基因中具有潜在的结合位点，这些基因主要通过脂质代谢和巨噬细胞活性的功能聚集。我们现在的目标是利用这些数据来确定体重减轻相关miR的调节是否调节脂肪细胞在脂肪形成、ROS产生、胰岛素敏感性、巨噬细胞分化、巨噬细胞活化和脂肪细胞-巨噬细胞相互作用方面的功能。由于小鼠同源物只存在于已鉴定的miR的一个子集，并且在MetS和生活方式诱导的基因表达的病理生理机制方面的物种差异非常可能，我们将使用人类体外模型分析已鉴定的miR对脂肪细胞和巨噬细胞的功能。通过这种方法，我们希望找到改善肥胖相关脂肪细胞功能障碍的新途径。以下目标将被研究：目标1a: HSA-miR-548y对脂肪细胞VLDL摄取的影响目标1b: HSA-miR-548y对巨噬细胞分化和激活的影响目标2：已鉴定miR对脂肪细胞分化、ROS产生和胰岛素敏感性的影响目标3：已鉴定miR对脂肪细胞-巨噬细胞相互作用的影响