巨噬细胞FTO基因缺失减轻高脂饮食导致的肥胖和胰岛素抵抗机制研究

Obesity is an important cause of type 2 diabetes, high blood pressure, and cardiovascular diseases, it has already become one of the major diseases that harm human health. However, the molecular mechanism of obesity formation is still unclear. The fat mass and obesity-associated (FTO) gene is the first GWAS-identified obesity susceptibility gene. For the first time, we constructed the macrophage-specific FTO knockout mice, and found that macrophage FTO deficiency alleviated high fat-diet induced obesity and insulin resistance without affecting mice weight development. FTO deficiency reduced the expression of macrophage inflammatory factor induced by LPS in macrophage. Therefore, we speculate that FTO cause obesity and insulin resistance by promoting macrophage inflammatory factor expression and increasing inflammatory response in high-fat diet mice. In order to study the mechanism of FTO regulating obesity and insulin resistance, the following researches will be carried out: A, Explore the target genes through which FTO regulate the macrophage inflammatory factor expression by whole transcriptome sequencing; B, By mRNA m6A methylation sequencing and considering the results of A to confirm the key target genes through which FTO regulate the macrophage inflammatory factor expression, for FTO is a mRNA m6A demethylase; C, Purify the key target genes' mRNA for mRNA m6A sequencing to ensure the key m6A methylation sites. This project will clarify the mechanisms of macrophages FTO regulating obesity and insulin resistance, and provide potential drug targets for obesity and related diseases prevention and treatment.

肥胖是2型糖尿病、高血压和心血管疾病发生的重要诱因，已成为危害人类健康的重要疾病之一，而肥胖发生的分子机制仍不明晰。FTO基因是第一个利用GWAS被证实与肥胖相关的易感基因。我们首次构建了巨噬细胞FTO缺失工程小鼠，发现巨噬细胞FTO缺失在不影响小鼠体重发育的情况下减轻高脂饮食导致的肥胖和胰岛素抵抗，FTO缺失减轻LPS诱导的巨噬细胞炎症因子表达。我们认为在高脂饮食情况下，FTO促进巨噬细胞炎症因子表达，加重小鼠机体炎症反应，导致肥胖和胰岛素抵抗的发生。本项目拟开展：①通过全转录组测序，初步寻找FTO调控巨噬细胞炎症因子表达的靶基因；②FTO是m6A去甲基化酶，通过m6A测序，结合①的结果确定FTO调控的关键靶基因；③纯化关键靶基因mRNA，并通过m6A测序确定FTO影响的关键甲基化位点。本项目的实施将阐明巨噬细胞FTO调控肥胖和胰岛素抵抗发生的机制，为肥胖的预防和治疗提供潜在的药物靶点。

肥胖是2型糖尿病、高血压和心血管疾病发生的重要诱因，已成为危害人类健康的重要疾病之一。FTO基因是第一个利用GWAS被证实与肥胖相关的易感基因，但是FTO基因影响肥胖的机制仍不清楚。本项目研究了巨噬细胞FTO基因在肥胖和胰岛素抵抗中的作用和相关机制。我们首次构建了巨噬细胞FTO缺失工程小鼠，发现巨噬细胞FTO缺失在不影响小鼠体重发育的情况下减轻高脂饮食导致的肥胖和胰岛素抵抗，机制上我们发现FTO通过激活NF-κB 和 JNK炎症信号通路，上调巨噬细胞炎症因子表达，进而调控小鼠肥胖和胰岛素抵抗。本项目的实施将阐明巨噬细胞FTO调控肥胖和胰岛素抵抗发生的机制，为肥胖的预防和治疗提供潜在的药物靶点。