棕色脂肪相关lncRNA-Blnc1改善肥胖相关代谢性疾病胰岛素抵抗的作用与机制研究

The major components of adipose tissue include white adipose tissue (WAT), brown adipose tissue (BAT) along with beige adipose tissue. WAT is regarded as a depot of energy and the source of obesity. Whereas BAT is the major sites of thermogenesis due to exhibiting abundant mitochondrion and therefore, inhibit lipogenesis as well as ameliorate hyperlipidemia through modulating uncoupling protein UCP1. Emerging body of evidence has indicated that either stimulating the function of BAT and beige adipose tissue or increasing the number of them is considered as an effective approach of improving obesity and disorder of lipometabolism. Series of lncRNAs have been confirmed to participate in regulating lipogenesis, which is modulated through multiple perspectives including chromosome remodeling, transcription and post transcription. The brown fat lncRNA1 (lncRNA-Blnc1) is associated with the differentiation of BAT. Our preliminary results have demonstrated that overexpression of Blnc1 in obese insulin resistant mice induced by high fat diet can effectively ameliorate insulin resistance, promote the differentiation from WAT to beige adipose tissue as well as stimulate mitochondrial energy metabolism, which might be regulated by binding with hnRNP K regulating PPARγ、Adiponectin genes. And we making an attempt at finding out the possibility that brown-related drugs such as beta 3-AR and PPAR gamma agonists are targeted at Blnc1 or regulated by Blnc1.

白色脂肪、棕色脂肪和米色脂肪是人体主要的脂肪组织。白色脂肪主要储存能量，是肥胖的根源；棕色脂肪富含线粒体，通过非偶联蛋白UCP1消耗能量并产热，是治疗肥胖以及脂肪代谢紊乱有效的疗法。一系列lncRNAs被证实参与调控脂肪的形成，分别从染色体重构、转录以及转录后多个层面参与调控，其中lncRNA-Blnc1(the Brown Fat lncRNA1)与棕色脂肪分化相关。本项目拟通过验证在高脂饮食诱导肥胖小鼠附睾组织中特异性Blnc1过表达及AP2启动子介导的脂肪组织特异性转基因小鼠可以有效改善其胰岛素抵抗状态，并促进白色脂肪棕色化及线粒体能量代谢，且该作用可能是通过结合hnRNP K调控PPARγ、Adiponectin等糖脂代谢相关基因进行的，试图依此寻找临床上棕色化相关药物如β3-AR、PPARγ激动剂靶向Blnc1或者受Blnc1调控的可能性。

棕色脂肪可以增加能量消耗、改善胰岛素抵抗，且近年来发现成人体内存在棕色脂肪，因此成为治疗肥胖及其相关代谢疾病的研究热点。研究者倾向于找到药物来促“棕色化”以期治疗肥胖，即诱导脂肪棕色化在治疗肥胖方面具有潜在的巨大的临床应用价值。但机制远未阐明。我们首次对棕色脂肪相关长链非编码 RNA（BAT-lncRNA）-Blnc1 在肥胖、2 型糖尿病以及代谢综合征等代谢相关性疾病中的功能进行验证，阐述过表达 Blnc1 可以通过促进白色脂肪棕色化改善肥胖等病理状态下的胰岛素抵抗和能量代谢状况。同时，我们还首次报道了与 Blnc1 直接结合的核内不均一核糖核蛋白 K-hnRNP K，并探索 hnRNP K调控 Blnc1 发挥功能的具体机制。我们还初步探讨了棕色化相关药物如β3-AR、PPARγ激动剂的靶向作用与 Blnc1 的调控关系，同时寻找 Blnc1 的下游靶基因和作用分子机制。除此以外，本项目还扩展探索了另外一个棕色脂肪相关的长链非编码RNA-H19在减少肥胖小鼠骨骼肌组织脂质过度堆积从而改善机体的胰岛素抵抗和糖耐量异常中的作用。该作用可能是H19通过招募hnRNPA1蛋白促进下游基因PGC1α、CPT1b等表达水平，从而增加骨骼肌细胞中线粒体能量代谢而实现。另外发现其环状转录本circH19 在代谢综合征患者血清中表达增高，是代谢综合征的独立危险因素，其表达水平与腰围、内脏脂肪面积等脂质代谢相关因素呈正相关。敲低circH19 促进人源脂肪干细胞（hADSCs）成脂分化以及脂质沉积，潜在的作用机制可能与circH19 的下调解除了对 PTBP1 的结合抑制作用，激活固醇调节元件结合蛋白 1（SREBP1）的核内转位，从而促进了下游脂质分化相关基因的表达有关。