mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice
mTORC1 pathway mediates beta cell compensatory proliferation in 60 % partial-pancreatectomy mice
复制标题
mTORC1%20通路%20介导%20β%20细胞%20代偿性%20增殖%20in%2060%20%%20%20%20%20%20%20部分胰腺切除术%20小鼠。
DOI：
10.1007/s12020-016-0861-5
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发表时间：
2016-07-01
期刊：
影响因子：
3.7
通讯作者：
Wang, Qidi
中科院分区：
文献类型：
--
作者：
Li, Wenyi;Zhang, Hongli;Wang, Qidi
β细胞复制是维持成年啮齿动物β细胞群的主要组成部分;然而，人们对启动啮齿动物β细胞增殖的最早信号知之甚少。mTORC 1通路整合来自生长因子和营养素的信号，并调节细胞生长和存活。在这里，我们使用血糖正常的60%部分胰腺切除术（60%Px）小鼠模型来确定mTORC 1通路是否是代偿性β细胞增殖所必需的。对C57 BL/6 J雄性小鼠进行60%Px或假手术，随后用雷帕霉素或载体处理7天。检查代谢特征、胰腺β细胞质量和增殖，并测定细胞周期调节剂的表达水平。β细胞增殖增加了2.5倍，并且在Px后的胰岛中激活了mTORC 1信号传导。雷帕霉素治疗损害60%Px小鼠的葡萄糖耐量和葡萄糖刺激胰岛素分泌，但不影响其外周组织的胰岛素敏感性。在60%Px小鼠中，雷帕霉素抑制β细胞中的mTORC 1活性，抑制代偿性β细胞增殖和生长，并降低β细胞质量和胰岛素含量。Px在蛋白水平上引起cyclin D2的表达增加，并以mTOR依赖的方式促进cyclin D2的核定位。破坏mTORC 1信号转导抑制细胞增殖，同时减少RINm 5 F细胞中的细胞周期蛋白D2蛋白丰度。我们的数据表明，mTORC 1在β细胞适应60%Px模型中显著的β细胞质量损失和通过细胞周期蛋白D2途径在早期代偿性β细胞增殖中起重要作用。
Beta cell replication is the major component for maintenance of beta cell mass in adult rodents; however, little is known about what is the earliest signals that initiate rodent beta cell proliferation. The mTORC1 pathway integrates signals from growth factors and nutrients and regulates cell growth and survival. Here, we used normoglycemic 60 % partial-pancreatectomy (60 % Px) mouse model to determine whether mTORC1 pathway was required for compensatory beta cell proliferation. C57BL/6 J male mice were subjected to 60 % Px or sham operation, and subsequently treated with either rapamycin or vehicle for 7 days. Metabolic profile, pancreatic beta cell mass, and proliferation were examined, and expression levels of cell cycle regulators were determined. Beta cell proliferation was increased by 2.5-fold, and mTORC1 signaling was activated in islets post-Px. Rapamycin treatment impaired glucose tolerance and glucose stimulating insulin secretion in 60 % Px mice, but did not affect their insulin sensitivity in peripheral tissue. Rapamycin inhibited mTORC1 activity in beta cells, suppressed compensatory beta cell proliferation and growth, and reduced beta cell mass and insulin content in 60 % Px mice. Px caused an increase of the cyclin D2 at protein level and promoted cyclin D2 nuclear localization in an mTOR-dependent manner. Disrupting mTORC1 signaling suppressed cell proliferation and simultaneously diminished cyclin D2 protein abundance in RINm5F cells. Our data demonstrated that mTORC1 plays an essential role in beta cell adaption to significant beta cell mass loss in 60 % Px model and in early compensatory beta cell proliferation via cyclin D2 pathway.