高卵泡刺激素经PPARgamma途径在绝经女性胰岛素抵抗发生中的作用机制研究

Insulin resistance (IR) in postmenopausal women as a risk factor of metabolic diseases, has been the focus of research, and the mechanism is still unknown. We found that follicle stimulating hormone (FSH) might play an important role in the occurrence of IR in postmenopausal women. Our previous study showed the postmenopausal women with higher serum FSH levels (≥80.63 IU/L at baseline)had higher HOMA-IR than those women with FSH levels of 40 IU/L to 80.63 IU/L (p < 0.01). The present study was then designed to investigate influences of postmenopausal high FSH levels on IR and the underlying mechanisms. Firstly, we investigate the correlation between serum FSH levels and the fasting blood glucose, insulin and HOMA-IR, and improvement of HOMA-IR after treatment with hormone replacement therapy. Secondly, we used ovariectomized mice and provided GnRHa treatment to mimic higher or lower FSH levels, respectively, which would serve as a model to deduce the connection between FSH and hepactic IR in vivo. Thirdly, we use the HepG2 to explore the molecular mechanism the FSH induce the hepatic IR through PPARgamma signaling pathway. This founding may indicate a novel mechanism of postmenopausal IR and may provide a rationale for MHT inhibition of FSH levels targeted approaches for the clinical treatment.

绝经后胰岛素抵抗（IR）作为多种代谢疾病的危险因素，是研究的热点，其机制不明。绝经后高卵泡刺激素（FSH）在IR发生中的重要作用将成为IR发生研究的新切入点。我们前期临床发现血清FSH更高的绝经女性其胰岛素抵抗指数更高，拟在此基础上，进一步在临床、动物和细胞水平纵行研究：扩大临床数据收集，明确FSH水平对于绝经后IR发生的直接作用，经激素补充治疗后FSH改善水平与IR改善的相关性；采用动物模型模拟绝经后内分泌状态，利用促性腺激素释放激素激动剂（GnRHa）和反向添加FSH造成单一高FSH模型，在体检测IR发生关键因子变化，探究FSH对于肝脏IR发生的可能机制；在细胞水平，根据FSH刺激下相关通路蛋白磷酸化水平结果，分别加用上述通路特异抑制物，寻找出在FSH作用下经PPARgamma途径影响肝脏细胞IR发生的信号传导通路。本课题将为预防，治疗绝经后IR提供科学依据，具有很高创新性及临床意义。

绝经后胰岛素抵抗（IR）作为多种代谢疾病的危险因素，目前机制不明。绝经后高卵泡刺激素(FSH)在IR发生中的重要作用成为IR发生研究的新切入点。首先，流行病学调查显示相比绝经前期，绝经后女性空腹血糖无明显变化，但空腹胰岛素以及胰岛素抵抗HOMA-IR指数增加，血糖异常的发生率增加。更进一步对于绝经后女性随访发现，绝经后期女性 FSH 水平和空腹血糖、胰岛素以及 HOMA-IR 指数存在相关性，而这种影响可能是独立于绝经后低雌二醇水平的影响。在体外实验中，高浓度的 FSH 处理 HepG2 细胞后进行代谢相关的基因检测，发现 FSH 可以调控 HepG2 细胞多个生理活动，包括转录调控、脂质代谢、细胞信号转导、细胞分化等过程，FSH可以调控 HepG2 细胞的胰岛素信号通路，提示 FSH 可能参于调控肝脏细胞的葡萄糖代谢过程，阐明FSH参与胰岛素抵抗的发生机制。本研究为预防、治疗绝经后IR提供科学依据，具有很高的创新性及临床意义。