Expression data from female C57BL/6J and B6.Cg-Mir146atm1.1Bal/J mice after 10 weeks of normal or high fat diet

The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin sensitivityresistance . MiR-146a-/- mice were subjected to a high fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a-/- mice gained significantly more body weight on a high fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de-novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3. 5 samples/group; groups: C57BL/6J normal diet (ND), C57BL/6J high fat diet (HFD), B6.Cg-Mir146atm1.1Bal/J ND , B6.Cg-Mir146atm1.1Bal/J HFD

肥胖相关代谢疾病的发病机制已被证实与白色脂肪组织（white adipose tissue, WAT）的炎症反应密切相关，但其分子互作调控网络尚未完全阐明。微小RNA-146a（miR-146a）可通过抑制促炎信号通路调控炎症进程。本研究旨在明确miR-146a在肥胖及胰岛素抵抗中的功能角色。
对miR-146a基因敲除（miR-146a-/-）小鼠进行高脂饲料喂养，随后开展代谢功能检测及白色脂肪组织转录组学分析；同时利用人类辛普森-戈拉比-贝姆尔综合征（Simpson-Golabi-Behmel syndrome, SGBS）脂肪细胞，完成了功能获得与功能缺失实验。
与对照组相比，miR-146a-/-小鼠在高脂饲料喂养下体重显著升高，伴随脂肪质量增加及脂肪细胞肥大，同时出现更严重的肝脏脂肪变性、胰岛素抵抗与糖耐量异常。同理，转染miR-146a抑制剂的脂肪细胞，其胰岛素刺激下的葡萄糖摄取能力显著下降；而转染miR-146a模拟物则可产生相反的效应。
本研究还鉴定出利钠肽受体3（natriuretic peptide receptor 3, NPR3）是脂肪细胞中miR-146a的直接靶基因；经CRISPR/Cas9介导的NPR3基因敲除，可增强脂肪细胞胰岛素刺激的葡萄糖摄取能力，并促进从头脂肪生成。
综上，miR-146a通过下调NPR3的表达，调控机体整体及脂肪细胞层面的胰岛素敏感性。
本实验每组设置5个样本，分组如下：C57BL/6J小鼠正常饮食（normal diet, ND）组、C57BL/6J小鼠高脂饮食（high fat diet, HFD）组、B6.Cg-Mir146atm1.1Bal/J小鼠正常饮食组、B6.Cg-Mir146atm1.1Bal/J小鼠高脂饮食组。