脂联素特异性调节的miR1934在脂肪组织炎症中的作用及机制研究

The low-grade pro-inflammatory state in obesity is considered to build the common soil for the development of obesity-linked disorders. Resetting the immunological balance in white adipose tissue (WAT) may be a crucial approach for the future management of the metabolic syndrome. Adiponectin (ApN) has emerged as a master regulator of inflammatory homeostasis. Several studies have highlighted its anti-inflammatory action on adipose tissue. More recently, microRNAs have been highlighted as new potential biomarkers and therapeutic targets for obesity and related metabolic syndrome. microRNA are endogenous 22 nucleotide RNAs that can bind to the sequence localized in the 3'-untranslated region of their target mRNAs and destabilize mRNA or inhibit mRNA translation. miRNAs play an important role in the regulation of many biological pathways. Thus we hypothesize that microRNA targets of ApN could probably mediate the anti-inflammatory effect of ApN and participate in regulation of WAT inflammatory process. We took advantage of our ApN overexpression mice (ApN-Overex) and ApN knockout mice (ApN-KO) to carry on microRNA array. Finally we found miR1934 is a specific microRNA target of ApN in WAT. We aim to further investigate the roles of miR1934 involved in WAT inflammation in both in vitro and in vivo differentiated adipocytes. We will also study the therapeutic effect of miR1934 in ApN-KO mice.

肥胖时脂肪组织(WAT)慢性炎症是肥胖相关的代谢性疾病发展的共同土壤。改善肥胖时WAT的炎症状态是治疗代谢综合征的关键措施。脂联素是重要的抗炎症因子，能改善WAT炎症状态。近来，microRNA被认为是新的肥胖和代谢综合征的治疗策略。microRNA是内源性的非编码RNA,常通过抑制基因表达而参与调节多个生物过程。因此我们推测脂联素的靶microRNA可能介导了脂联素的抗炎症作用，并具有调节WAT炎症/免疫的功能。我们已利用脂联素转基因小鼠(ApN-Overex)和脂联素基因敲除小鼠(ApN-KO) 的WAT 进行了microRNA 芯片筛选。我们发现miR1934是脂联素特异性调节的靶microRNA。 我们拟采用过表达和敲除miR1934的方式，在体外和体内脂肪细胞中研究miR1934参与炎症调节的功能及分子机制，并观察miR1934在ApN-KO 小鼠体内的抗炎症作用及代谢变化。

脂联素（Adiponectin, ApN）是脂肪细胞分泌的最主要抗炎细胞因子。我们以前的研究发现miR1934是小鼠体内脂肪组织中受脂联素调节的microRNA。该课题进一步研究了miR1934是否参与调节脂肪细胞的炎症反应。miR1934在高脂饮食诱发的肥胖小鼠的内脏脂肪组织中的表达明显低于普通饮食喂养的小鼠。并且与正常体重者相比，miR1934在肥胖患者的脂肪组织和血循环中的表达也是降低的。血液循环中miR1934的表达与体质指数（BMI）、腰围（WC）、空腹胰岛素、胰岛素抵抗指数（HOMA-IR）、低密度胆固醇（LDL-c） 和 C-反应蛋白（hs-CRP）负相关，而与胰岛素敏感指数（HOMA-IS）正相关。此外，miR1934的表达在TNF-α处理的3T3-L1脂肪细胞中降低，而在3T3-L1脂肪细胞中过表达miR1934可抑制TNF-α诱导的炎症因子（IL-6, MCP-1）的表达。将过表达miR1934的前脂肪细胞注射入裸鼠背部皮下，使其在体内分化为成熟脂肪组织。miR1934在体内分化成熟的脂肪组织中过表达也可以抑制脂肪组织炎症因子IL-6、TNF-α、IL-1β的mRNA表达，并可以升高IL-10的mRNA表达。我们的研究发现miR1934具有抗脂肪细胞炎症的作用，是调控脂肪细胞炎症的新的机制。