ALDH2介导lncRNA3785调控脂肪细胞分化在胰岛素抵抗中的机理研究

Insulin resistance, especially IR companied by visceral obesity is considered to be an important cause of diabetes in Asians, but the specific underlying molecular mechanism is still unclear. Related studies showed that abnormal adipocyte differentiation is vital for the development of visceral obesity and IR. Meanwhile, we recently found a new LncRNA-lncRNA3785 in the subcutaneous fat by high-throughput sequencing. Its expression was significantly down-regulated and specially associated with abdominal obesity and IR. Overexpression of lncRNA3785 promoted the differentiation of primary adipocytes and unregulated the expression of ALDH2 which could promote the differentiation of primary adipocytes itself via alleviating oxidative stress and inflammation. So we speculate that lncRNA3785 regulates adipocyte differentiation through affecting ALDH2 expression in the development of insulin resistance. So, we plan to expand the sample size to explore the clinical relevance between lncRNA 3785/ALDH2 with adipocyte differentiation and insulin resistance, and investigate the role and underlying molecular mechanism of lncRNA 3785/ALDH2 axis in adipocyte differentiation, adipogenesis and insulin resistance. This study is expected to clarify the main molecular mechanism of lncRNA3785 regulating IR, and provide a novel perspective for the clinical prevention and treatment of diabetes.

胰岛素抵抗(IR)，特别是伴发脂肪内脏型分布的IR是亚洲人糖尿病发生发展的重要原因，但其发生机制一直未能阐明。有研究报道皮下脂肪细胞分化障碍是脂肪内脏型分布及IR形成的关键。申请人前期用高通量测序技术发现一种全新的lncRNA—lncRNA3785，富集于皮下脂肪且其表达下调与腹型肥胖及IR密切相关；过表达lncRNA3785可促进脂肪细胞的分化。提示lncRNA3785在IR形成中的重要作用。另外，lncRNA3785可上调脂肪细胞ALDH2表达，而后者可缓解氧化应激及炎症反应对脂肪分化的核心分子PPARγ的抑制从而促进脂肪细胞分化。故推测：lncRNA3785可通过调控ALDH2表达促进脂肪细胞分化，进而缓解腹型肥胖及IR。该研究将揭示lncRNA3785对腹型肥胖及IR形成的作用及机理，有望为临床治疗腹型肥胖及IR乃至有效防治糖尿病提供重要的理论依据。

胰岛素抵抗(IR)，特别是伴发脂肪内脏型分布的IR是亚洲人糖尿病发生发展的重要原因， 但其发生机制一直未能阐明。有研究报道皮下脂肪细胞分化障碍是脂肪内脏型分布及IR形成的关键。项目组前期通过高通量测序技术发现一种全新的lncRNA—lnc3785，富集于皮下脂肪且其表达下调与腹型肥胖及IR密切相关。本研究通过体内及体外实验，观察lnc3785改变及其靶基因ALDH2表达，脂肪前体细胞增殖、分化及成脂功能的变化，脂质分布及胰岛素敏感性的变化，同时对lnc3785调控ALDH2的具体分子机制进行了探索。研究结果如下：（1）大鼠皮下脂肪中lnc3785及ALDH2的表达下调伴随脂肪前体细胞分化潜能的下降，糖耐量受损及胰岛素敏感性下降；在临床数据层面，lnc3785的人类同源体SALRNA1及ALDH2的表达与患者内脏脂肪沉积及胰岛素抵抗的程度成显著负相关；（2）体外细胞模型中，我们发现调控lnc3785的表达对脂肪前体细胞的增殖能力并无影响，但过表达lnc3785可增强脂肪前体细胞的分化潜能，沉默lnc3785则抑制脂肪前体细胞的分化成脂，同时lnc3785对脂肪前体细胞的作用会因ALDH2基因的沉默而消减，从而证实ALHD2是介导 lnc3785 促脂肪前体细胞分化的重要因素；（3）lnc3785并不能与ALDH2直接结合，但可与miR-137-3p结合，而miR-137-3p则可靶向ALDH2基因，对其进行负调控。Lnc3785可通过结合miR-137-3p，解除miR-137-3p对ALDH2的负调控，从而激活ALDH2表达，促进脂肪前体细胞分化;（4）初步探索性研究显示上/下调lnc15441亦可影响脂肪前体细胞的分化潜能。该项目对脂肪前体细胞分化及胰岛素抵抗发生机制的研究有助于为糖尿病及相关代谢性疾病的治疗新策略提供理论依据。