Nuclear receptor, RORa plays a critical role in obesity-associated inflammation, hepatic steatosis, and insulin resistance

We demonstrated that RORa-deficient staggerer mice (RORasg/sg) fed with a high fat diet (HFD) showed reduced adiposity and hepatic triglyceride levels compared to wild type (WT) littermates and were resistant to the development of hepatic steatosis, adipose-associated inflammation, and insulin resistance. Gene expression profiling showed that many genes involved in triglyceride synthesis and storage, including Cidec, Cidea, and Mogat1, were expressed at much lower levels in liver of RORasg/sg mice. In addition to reduced lipid accumulation, inflammation was greatly diminished in white adipose tissue (WAT) of RORasg/sg mice fed with a HFD. The infiltration of macrophages and the expression of many immune-response and pro-inflammatory genes, including those encoding various chemo/cytokines, toll-like receptors, and TNF signaling proteins, were significantly reduced in RORasg/sg WAT. Moreover, RORasg/sg mice fed with a HFD were protected from the development of insulin resistance. Together, these results indicate that RORa plays a critical role in the regulation of several aspects of metabolic syndrome. Therefore, RORa may provide a novel therapeutic target in the management of obesity and associated metabolic diseases. Liver and white adipose tissue (WAT) total RNAs were purified from 5 WT and 5 RORasg/sg (natural deletion of RORa gene in mice) mice fed with a high fat diet for 6 weeks. Then samples were applied on Agilent mouse genome chip.

本研究证实，与野生型（wild type, WT）同窝对照小鼠相比，喂食高脂饮食（high fat diet, HFD）的RORα缺陷型摇摆小鼠（RORa^sg/sg）脂肪蓄积与肝甘油三酯水平均显著降低，且可抵抗肝脂肪变性、脂肪组织相关炎症及胰岛素抵抗的发生。基因表达谱分析显示，RORa^sg/sg小鼠肝脏中，诸多参与甘油三酯合成与储存的基因（包括Cidec、Cidea及Mogat1）的表达水平显著下调。除脂质蓄积减少外，喂食高脂饮食的RORa^sg/sg小鼠白色脂肪组织（white adipose tissue, WAT）中的炎症反应亦大幅减轻。研究发现，该小鼠白色脂肪组织中巨噬细胞浸润量显著减少，且诸多免疫应答与促炎基因（包括编码各类趋化/细胞因子、Toll样受体及TNF信号蛋白的基因）的表达水平均显著降低。此外，喂食高脂饮食的RORa^sg/sg小鼠可免受胰岛素抵抗的侵扰。综上，上述结果表明RORα在代谢综合征多维度的调控中发挥关键作用。因此，RORα或可成为肥胖及相关代谢性疾病治疗的新型靶点。本研究从5只野生型小鼠与5只RORa^sg/sg小鼠（小鼠RORa基因自然缺失）中提取肝脏及白色脂肪组织总RNA，上述小鼠均喂食高脂饮食6周。随后将样本应用于安捷伦小鼠基因组芯片进行检测。