LncRNA-p3134通过NAMPT靶向调控AMPK/Sirt1通路影响脂肪组织能量消耗及胰岛素抵抗的机制研究

The imbalance of energy metabolism and insulin resistance are the key to obesity, but the mechanism is still unknown. Recent research found that long non-coding RNA (lncRNA) involved in regulating AMPK signaling pathway, which is correlated with the energy metabolism. Our pilot study show that lncRNA-p3134 significantly up-regulated in obese patients, and co-expressed with Sirt1, involving in regulating AMPK signaling pathway, and targeting NAMPT protein. Therefore, we propose the hypothesis that lncRNA-p3134 may regulate NAMPT to induce the imbalance of energy metabolism and insulin resistance in adipose tissue through AMPK/SIRT1 signaling pathway. To test this hypothesis, we will explore the regulation of lncRNA-p3134 and AMPK/Sirt1 signaling pathway in 3T3-L1 adipose cells and high-fat-diet induced C57BL/6 mice by using adenovirus transfection and molecular biology methods. We will take the new perspective of lncRNA to clarify the mechanism of the imbalance of energy metabolism and insulin resistance in adipose tissue, and provide new ideas and new methods for the prevention and treatment of obesity.

机体能量代谢失衡及胰岛素抵抗是肥胖发生发展的关键环节,但机制尚未明确。最新研究表明长链非编码RNA(lncRNA)参与调控AMPK信号通路,该信号通路与能量代谢密切相关。申请者前期发现lncRNA-p3134在肥胖人群中表达显著升高,与Sirt1基因共表达,参与调控AMPK信号通路,并进一步发现NAMPT蛋白是lncRNA-p3134的调控靶标。为此我们提出假说:lncRNA-p3134靶向调控NAMPT,通过AMPK/Sirt1通路,引起脂肪组织能量代谢失衡及胰岛素抵抗。为验证这一假说,我们将从lncRNA这个新视点,通过3T3-L1前脂肪细胞、高脂喂养C57BL/6小鼠,采用腺病毒转染及分子生物学等手段,从分子、细胞、组织以及动物整体水平等多方面探讨lncRNA-p3134对AMPK/Sirt1信号通路的调控,明确肥胖状态下脂肪组织能量代谢失衡及胰岛素抵抗的分子机制。

机体能量代谢失衡及胰岛素抵抗是肥胖发生发展的关键环节,而长链非编码 RNA（lncRNA）在众多疾病的发生发展过程中起重要的调控作用。本课题组研究中应用lncRNA基因芯片发现lncRNA-p3134在肥胖人群的表达水平较正常人群显著升高，与患者BMI、腰围和胰岛素抵抗水平（HOMA-IR值）显著正相关。脂肪细胞中过表达lncRNA-p3134干扰了脂肪细胞的葡萄糖的摄取，降低了脂肪细胞对胰岛素的敏感性。课题组研究发现并验证PASK是LncRNA-p3134调节脂肪细胞分化和功能的潜在作用靶点。探讨了lncRNA-p3134可引起脂肪组织能量代谢失衡及胰岛素抵抗，参与肥胖发生发展的调控机制。

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