FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells.
FTO Inhibits Insulin Secretion and Promotes NF-κB Activation through Positively Regulating ROS Production in Pancreatic β cells.
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DOI：
10.1371/journal.pone.0127705
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Fan HQ;He W;Xu KF;Wang ZX;Xu XY;Chen H
FTO（脂肪量与肥胖相关）与肥胖和2型糖尿病发病风险增加有关。胰岛β细胞功能障碍和胰岛素抵抗是2型糖尿病的主要原因。然而，FTO是否在胰腺β细胞中发挥重要的功能作用以及相关的分子机制尚不清楚。本研究首次采用定量PCR和western blot技术检测了FTO的组织表达谱。FTO在各种组织中广泛表达，在胰腺组织中表达量较高，尤其是在内分泌胰腺中。FTO在慢病毒介导的MIN6细胞中过表达，在葡萄糖刺激和KCl存在下显著抑制胰岛素分泌。FTO沉默对MIN6细胞胰岛素分泌无影响。而FTO过表达不影响胰岛素基因的转录。此外，FTO过表达可显著促进活性氧（ROS）的产生和NF-κB的活化。n -乙酰- l-半胱氨酸（NAC）抑制细胞内ROS生成，可减轻NF-κB活化，恢复FTO过表达介导的胰岛素分泌。利用全转录芯片分析FTO过表达介导的差异基因表达。FTO调控的基因参与了g蛋白偶联受体信号转导和NF-κB信号转导等许多重要的生物学通路。因此，我们的研究表明，FTO可能有助于胰岛β细胞功能障碍，抑制FTO活性是治疗糖尿病的潜在靶点。
FTO (Fat mass and obesity-associated) is associated with increased risk of obesity and type 2 diabetes incurrence. Pancreas islet β cells dysfunction and insulin resistance are major causes of type 2 diabetes. However, whether FTO plays an important functional role in pancreatic β cells as well as the related molecular mechanism is still unclear. In the present study, the tissue expression profile of FTO was firstly determined using quantitative PCR and western blot. FTO is widely expressed in various tissues and presented with relative high expression in pancreas tissue, especially in endocrine pancreas. FTO overexpression in MIN6 cells achieved by lentivirus delivery significantly inhibits insulin secretion in the presence of glucose stimulus as well as KCl. FTO silence has no effect on insulin secretion of MIN6 cells. However, FTO overexpression doesn’t affect the transcription of insulin gene. Furthermore, reactive oxygen species (ROS) production and NF-κB activation are significantly promoted by FTO overexpression. Inhibition of intracellular ROS production by N-acetyl-L-cysteine (NAC) can alleviate NF-κB activation and restore the insulin secretion mediated by FTO overexpression. A whole transcript-microarray is employed to analyze the differential gene expression mediated by FTO overexpression. The genes which are modulated by FTO are involved in many important biological pathways such as G-protein coupled receptor signaling and NF-κB signaling. Therefore, our study indicates that FTO may contribute to pancreas islet β cells dysfunction and the inhibition of FTO activity is a potential target for the treatment of diabetes.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
8.2
作者：
Holmkvist, J.;Tojjar, D.;Groop, L.
通讯作者：
Groop, L.
DOI：
10.1126/science.1151710
发表时间：
2007-11-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gerken T;Girard CA;Tung YC;Webby CJ;Saudek V;Hewitson KS;Yeo GS;McDonough MA;Cunliffe S;McNeill LA;Galvanovskis J;Rorsman P;Robins P;Prieur X;Coll AP;Ma M;Jovanovic Z;Farooqi IS;Sedgwick B;Barroso I;Lindahl T;Ponting CP;Ashcroft FM;O'Rahilly S;Schofield CJ
通讯作者：
Schofield CJ
影响因子：
3.7
作者：
Gao X;Shin YH;Li M;Wang F;Tong Q;Zhang P
通讯作者：
Zhang P
影响因子：
56.9
作者：
Frayling, Timothy M.;Timpson, Nicholas J.;McCarthy, Mark I.
通讯作者：
McCarthy, Mark I.