虫草素上调促脂肪褐化关键因子irisin表达的分子机制研究

Irisin is a newly identified hormone which promotes the white adipose tissue generating heat just like the brown adipose tissue (i.e. adipose browning) and thus became a new target for the treatment of obesity and diabetes. Our recent work showed that cordycepin (also known as 3’-deoxyadenosine) can promote 3T3-L1 adipocyte browning and significantly increased the expression of FNDC5, the precursor of irisin. To further investigate the novel biological action of cordycepin, this project aims to systemically evaluate the stimulating effect of cordycepin on adipocyte browning in primary and 3T3-L1 adipocytes and confirm the central role of irisin in cordycepin-induced adipocyte browning. A combined method of gene and protein expression analysis, drug intervention and RNA interference will be used to investigate the relationship between cordycepin and various irisin-regulating factors, especially the relationship between cordycpein and AMPK-PGC1α-irisin pathway or PKA/p38-PGC1α-irisin pathway, in order to identify the main molecular route of cordycepin-promoted irisin expression. A mouse model will be used to verify the adipose browning role and the mechanism of cordycepin. This project will confirm the adipose browning effect of cordycepin and reveal the molecular mechanism of cordycepin-induced irisin upregulation.

新激素irisin可促使白色脂肪表现出类似褐色脂肪的产热特征（即脂肪褐化），是治疗肥胖症、糖尿病等代谢性疾病的新靶点。本课题组新近研究发现，虫草素（又名3’-脱氧腺苷）可促进脂肪细胞褐化并显著提高irisin前体蛋白FNDC5的表达。为深入研究虫草素这一新生物学功能，本项目拟以3T3-L1脂肪细胞、小鼠原代脂肪细胞和C57BL/6小鼠为模型，对虫草素促进脂肪褐化的效果进行全面评价并确认irisin在其中的关键作用；通过基因和蛋白表达分析、药物干预及RNA干扰等技术解析虫草素与各种irisin表达调控因子，特别是与AMPK-PGC1α-irisin和PKA/p38-PGC1α-irisin通路的相互作用关系，确定其上调irisin表达的主要分子途径；并在动物体内对虫草素的药效和作用机理进行验证。本项目预期确认虫草素促进脂肪褐化的新生物学功能，并阐明其上调irisin表达的分子机制。

肥胖症是世界性的流行病。促进白色脂肪组织变成米黄色脂肪组织（脂肪褐化）有助于增加能量消耗，从而抵消肥胖。我们的研究发现，腺苷类天然产物虫草素（CPN）能够显著增加能量消耗，减低体重，改善脂质代谢和葡萄糖耐量，降低皮下脂肪重量和脂肪细胞的大小，提高正常和高脂饲料喂养的小鼠的耐冷性。虫草素明显增加腹股沟白色脂肪组织的表面温度和促进腹股沟脂肪褐化。进一步的研究表明，虫草素诱导了腹股沟的棕色样脂肪细胞的发育，但不会促进附睾脂肪的褐化。虫草素还增加了白色脂肪组织和3T3-L1脂肪细胞的 UCP1和其他产热基因的表达，其功能是通过一种涉及AMP激活的蛋白激酶（AMPK）的机制。我们的研究结果为揭示虫草素调节能量代谢方面的作用机制提供了新的见解，并提出了虫草素在治疗肥胖症等方面的潜在效用。