雌激素通过瘦素信号通路途径调节脂肪细胞代谢生成

雌激素通过瘦素信号通路途径调节脂肪细胞代谢生成

雌激素通过瘦素信号通路途径调节脂肪细 胞代谢生成# 李文娟，许良智，陈焱，牟丽，许文明，程萌，庄静，李婷婷，詹晶** 5 10 15 20 25 30 35 40 （四川大学华西第二医院，成都 610041） 摘要：目的：探讨雌激素是否是通过瘦素相关信号通路对女性形体改变产生影响。方法：二 月龄雌性 SD 大鼠随机为去势组及假手术组，术后 14 周收集生殖器周围脂肪、内脏脂肪和 皮下脂肪，并分别检测瘦素受体表达，同时通过 17-β雌二醇及瘦素对脂肪细胞前体细胞 MSCs 进行干预，检验瘦素受体亚型、瘦素表达及成脂分化的指标 PPARγ的变化。结果： 通过对造模期间大鼠体重的每周监测，发现去势组体重增长及术后 14 周 Lee’s 指数均明显 高于假手术组 P 0.001 。瘦素受体在去势组的脂肪组织中表达显著增加，内脏脂肪中尤为明 显。体外实验显示，随着瘦素和雌激素浓度的增加，MSCs 上瘦素长形受体和短受体的表达 均随之下降；随雌激素浓度的增加，MSCs 中瘦素表达呈下降趋势，同时，MSCs 中 PPAR γ表达也受到抑制。结论：在低雌激素的影响下，去势后大鼠发生类似绝经后女性样的形体 改变，高浓度雌激素可抑制大鼠间充质干细胞向脂肪细胞分化，雌激素对瘦素及瘦素受体的 影响可能是绝经后女性体型变化发生变化的原因。 关键词：妇产科学；雌激素；瘦素；瘦素受；脂肪；间充质干细胞 中图分类号：R339.6 Estrogen regulate adipocyte metabolism through leptin signaling pathway LI Wenjuan, XU Liangzhi, CHEN Yan, MU Li, XU Wenming, CHENG Meng, ZHUANG Jing, LI Tingting, ZHAN Jing West China Second University Hospital, Sichuan University, Chengdu 610041 Abstract: Postmenopausal women often present obvious body composition changes under the absence of estrogen, including overweight, obesity and android-like body fat distribution, therefore poses serious threaten for women’s health. Although the intimate relationship between estrogen and body appearance have been noticed, mechanism remains unclear. We assumed that estrogen may regulate fat distribution through affecting leptin signal pathway, which has been shown playing major role in energy homeostasis. To test this hypothesis, we randomized female SD rat into ovariectomy OVX and sham group, and then collected adipose tissue around genital, retroperitoneal and subcutaneous after 14 week. Leptin receptor expression in adipose tissue was measured by western blot. Results indicated that leptin receptor were significantly down-regulated in ovariectomy group, especially in fat around genital. Weight changes were observed every week, repeated measures analysis of variance showed that OVX group has higher weight gain compared with sham group during the 3 month P 0.001 , and so does the Lee’s index P 0.001 , which were calculated at the end of the study. We further used mesenchymal stem cells MSCs , the progenitor of Adipocytes as an in vitro model to figure out the effect of estrogen on leptin receptor expression. After MSCs were treated by increasingconcentration of 17-βestradiol and letpin respectively, QPCR were used to test the mRNA expression of leptin receptor subtype, OBRb long form and OBRa short form . Negative correlation was noticed between estrogen concentration and leptin receptor subtype expression. Similar tendency were also observed in leptin treatment group. Besides, the expression of leptin in MSCs was degrading accompaied with increasing concentration of estrogen, and PPARγ, the indicator of adipogenisis, was also 基金项目：高等学校博士学科点专项科研基金（201XXXXXXXXXX7）；自然科学基金（81070464） 作者简介：李文娟（1986-），女，在读博士，主要研究方向：妇产科生殖内分泌 通信联系人：许良智（1957-），女，教授，主要研究方向：妇产科生殖内分泌. E-mail: liangzxu@126 -1- 45 supressed under treatment of estrogen. Estrogen may act on leptin receptor expression to influence the body composition in postmenopausal women. And the similar molecular mechanism of estrogen and leptin shows that these two hormones probably have synergistic effects on energy metabolism. Key words: Gynecology; Estrogen; Leptin; Leptin receptor; Adipose; Mesenchymal stem cells 50 0 引言 体重增加、肥胖、男性样脂肪分布等一系列体型变化等是高血压、糖尿病、代谢综合征 等多种常见疾病的危险因素，对生命健康有显著影响，而围绝经期和绝经后女性伴随着雌激 素下降出现以上改变的比例较绝经前明显增加[1,2]。在 60 岁之前，女性的体重指数（body mess 55 60 65 70 75 80 index，BMI）随年龄增加而逐渐上升，60-64 岁时 BMI 的平均水平达到高峰，绝经后女性 的 BMI 也与血清中总胆固醇（TC）、低密度脂蛋白（LDL-C）、高密度脂蛋白（HDL-C） 存在显著相关性[3,4]。尽管雌激素对女性形体的影响已经引起了学者们的广泛关注，但具体 机制仍不清楚。 瘦素是由位于染色体 7q31.3 区肥胖基因编码的一种蛋白类激素，主要由白色脂肪细胞 分泌，脂肪分布及代谢和调节能量稳态的重要激素，与能量及糖脂代谢密切相关，具有广泛 的生物学效应，肥胖人群多伴发高瘦素血症。间充质干细胞（mesenchymal stem cell, MSC） 是脂肪细胞前体细胞，含有雌激素受体和瘦素受体，在特定条件下（如胰岛素、地塞米松、 3-异丁基-1-甲基黄嘌呤、吲哚美辛等）可以定向分化为脂肪细胞。目前研究报道雌激素在 体外有促进间充质干细胞增殖的作用[5]，但对雌激素是否能影响 MSC 向脂肪细胞的分化， 是否是通过瘦素系统引起绝经后妇女体型改变仍不清楚。为解决以上问题，本文章从动物模 型和体外实验两方面入手，对雌激素影响绝经后女性体型的机制进行研究分