肥胖和2型糖尿病动物的脂肪可塑性变化及五甲基槲皮素促进白色脂肪棕色化的机制研究

In recent years, the adipose plasticity has been great concern, especially the browning white adipose, because of obesity has become epidemic of serious harm to human health. Obesity is an important risk factor for metabolic syndrome, type 2 diabetes, cardiovascular disease, neurodegenerative disease and certain tumors. All mammals are provided with the chemical energy-storing white adipose tissue and the energy-dissipating brown adipose tissue. Obesity is actually the excessive accumulation of white adipose tissue. View of the existing weight loss drugs are not long-term use due to adverse events. Adipose plasticity was concern and the browning white adipose was focused, hoping to find a better drug prevention and treatment of obesity and related diseases, but this area is no clear breakthrough. In the study about the mechanisms of pentamethylquercetin (PMQ) anti-metabolic syndrome, we found the PMQ significantly reduce the adipose mass. So we propose that PMQ regulate positively adipose plasticity. The pre-experimental results shown that PMQ up-regulated the expression of UCP-1, PGC-1α and Cidea in cultured 3T3-L1 adipocytes and mouse epididymal adipose. That the characteristic elements of the brown adipose were induced in white adipose suggested the white adipocyte or white adipose tissue was browned. An overall improvement in the metabolic syndrome, metabolic disorders and organ protection in view of PMQ, we intend to study fat plasticity and the mechanism of PMQ browning white adipose.

近年来，脂肪可塑性被高度关注，尤其是白色脂肪棕色化，其直接原因是肥胖已成为严重危害人类健康的流行病。肥胖是代谢综合征、2型糖尿病、心血管疾病、退行性神经病变和某些肿瘤的重要危险因素。脂肪分为储能型的白色脂肪和少量耗能产热型棕色脂肪，肥胖实际上是白色脂肪过度蓄积。鉴于现有减肥药物均因不良反应而无法长期使用，人们对脂肪可塑性和白色脂肪棕色化关注，希望能找到防治肥胖及相关疾病的更理想的药物，但此领域尚无明显突破。在研究五甲基槲皮素(PMQ)抗代谢综合征作用机制时，我们发现PMQ明显减少脂肪质量，我们设想其对脂肪可塑性产生良性调控。预实验结果表明，PMQ可使培养的3T3-L1脂肪细胞和小鼠附睾脂肪高表达棕色脂肪的特征性分子UCP-1，PGC-1α，Cidea等，即白色脂肪被棕色化。鉴于PMQ全面改善代谢综合征的代谢紊乱和器官保护作用，我们拟研究脂肪可塑性和PMQ使白色脂肪棕色化的机制。

背景：肥胖已成为严重危害人类健康的流行病，但减肥药物进展差强人意。基于对脂肪可塑性的研究进展，人们寄希望于通过对脂肪可塑性的干预，找到更好的减肥药物。主要研究内容：①肥胖及2型糖尿病动物的脂肪可塑性发生了哪些改变？包括棕色化和米色化。②PMQ对肥胖和2型糖尿病动物脂肪可塑性改变有哪些影响？③PMQ诱导白色脂肪棕色化（及米色化）的机制研究。重要结果：①在肥胖型和2型糖尿病小鼠，白色脂肪可塑性变化趋势表现为潜在的棕色化和米色化能力更趋弱化。我们在MSG-IO和HFD-IO肥胖何2型糖尿病动物，证明白色脂肪组织的棕色化基因(Ucp-1, Pgc-1α, Cidea and Cox7a1 )和米色化基因(CD137, Tbx1 and Tmem26)表达都明显降低，这些变化可能直接参与了肥胖及2型糖尿病的发病。②PMQ全面提升脂肪组织和脂肪细胞棕色化基因和米色化基因的表达。在肥胖和2型糖尿病动物，PMQ全面改善肥胖及相关代谢异常的同时，全方位矫正脂肪可塑性改变，明显上调棕色化基因和米色化基因的表达，提示PMQ对脂肪可塑性的矫正作用可能是其全面改善肥胖及相关代谢异常的重要机制。③PMQ通过AMPK/PGC-1α/FNDC5通路影响白色脂肪可塑性。在MSG-IO小鼠，骨骼肌PGC-1α/FNDC5表达明显低于正常小鼠，PMQ剂量依赖性地上调骨骼肌PGC-1α/FNDC5的表达。在培养的C2C12（骨骼肌细胞模型），PMQ上调pAMPK/ PGC-1α/FNDC5表达的作用呈明显的时间依赖性（16h-24 h达峰值）和浓度依赖性（1~10 μM）。PMQ干预的C2C12细胞化条件化培养基（PMQ-CM）可明显上调3T3-L1脂肪细胞的调棕色化基因和米色化基因的表达，此作用可被抗FNDC5抗体拮抗，提示PMQ-CM对脂肪细胞可塑性的影响是由FNDC5所中介。用选择性的AMPK抑制剂compound C 干预C2C12的培养，见PMQ上调FNDC5表达的作用被取消。结果表明，PMQ通过激活AMPK/PGC-1α/FNDC5通路，使白色脂肪棕色化和米色化。科学意义：确证了肥胖和2型糖尿并小鼠的脂肪可塑性变化的趋势是潜在的产热基因（包括棕色化和米色化）表达降低，可以作为研究治疗肥胖及相关疾病的药物靶点。PMQ全面改善脂肪可塑性，有希望发展成为防治肥胖及肥胖相关疾病的药物。