新型脂肪细胞特异性小RNA miR-7E及其靶基因NNAT功能及其机制探究

microRNA逐渐被认识是调控脂稳态的重要因素之一，目前多报道其影响脂肪细胞分化及炎症细胞侵袭等，直接参与脂肪储积的研究不多见，这也是影响microRNA应用于代谢性疾病防治的主要原因。本研究对肥胖以及代谢活跃小鼠的脂肪组织进行组学分析和验证后，发现新型miR-7E特异性表于脂肪细胞，敲除后小鼠（miR-7E KO）脂解增加，体脂率降低。进一步鉴定其靶基因为NNAT，其生理功能研究十分欠缺。我们构建了NNAT脂肪组织特异性敲除（NNAT AKO）小鼠，其基础代谢率降低，皮下脂肪褐色化受阻，基础产热和适应性产热下降。本研究基于miR-7E KO和NNAT AKO小鼠模型，拟从互作蛋白，脂肪因子组装与分泌，以及单细胞技术检测脂肪组织异质性等角度，探索miRNA-E7及其靶基因NNAT的功能及机制，试图为皮下脂肪产热提供新机制，以及为microRNA作为干预机体脂紊乱防治提供有效分子。

Adipose tissue-derived microRNA is gradually recognized to regulate lipid homeostasis in vivo. Most of the studies demonstrate microRNAs control adipocyte differentiation and macrophage recruitment in adipose tissue through affecting main transcription regulators, which blocks the microRNA application in metabolic disorders. It is in need to explore new adipocyte-specific microRNAs directly control lipid accumulation or lipolysis. Based on human database and different animal models from obese and actively-catabolic mouse, miRNA-7E is chosen as our interest due to its adipocyte-specific expression, enhanced expressed in obese mice, monkey and human, and promoting triacylglycerol accumulation, which were confirmed by miRNA-7E knockout mice. Our study further demonstrates miR-7E targets gene NNAT, which is known for coding an ER-transmembrane protein neuronatin (Nnat). The knowledge about Nnat function is very limited although it is possibly involved in iron channel. We’ve made Nnat adipocyte-specific knockout (AKO) mice with a decreased basal metabolic rate, inhibited lipolysis, and decreased browning in subcutaneous adipose tissue (SAT). Our data indicates Nnat plays important roles in basal and stimulated thermogenesis through different mechanism. Based on our preliminary data from miR-7E KO and NNAT AKO mouse models, we will study the interaction proteins of Nnat, iron channels and the signals, adipokine assembly and secretion, and cell heterogeneity mediated by Nnat. The study will give us insights in new adipocyte-specific microRNA and the application in therapy against metabolic disorders, Nnat fuctions and the molecular mechanisms in metabolic homeostasis.