Insulin secretory defects and impaired islet architecture in pancreatic β-cell-specific STAT3 knockout mice
Insulin secretory defects and impaired islet architecture in pancreatic β-cell-specific STAT3 knockout mice
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DOI：
10.1016/j.bbrc.2004.05.095
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发表时间：
2004-07-09
影响因子：
3.1
通讯作者：
Hori, M
中科院分区：
文献类型：
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作者：
Gorogawa, S;Fujitani, Y;Hori, M
正常的胰岛形成和功能取决于产前和产后发育中各种生长因子的作用;然而，每个因子的具体生理功能在很大程度上是未知的。到目前为止，小鼠功能丧失分析提供的信息很少，这可能是由于作用于胰腺的生长因子的功能冗余。本研究的重点是转录因子STAT 3在胰岛素产生细胞中的作用。STAT 3是作用于胰腺β细胞的多种生长因子的潜在下游介质之一，所述生长因子包括β细胞素、肝细胞生长因子、生长激素和肝素结合EGF样生长因子。为了阐明其在α细胞中的作用，使用cre介导的基因重组方法，在小鼠的胰岛素产生细胞中破坏STAT 3基因（STAT 3-因斯科）。出乎意料的是，STAT 3-因斯科小鼠在8周龄或更大时表现出食欲增加和肥胖。小鼠表现出部分瘦素抵抗，表明RIP（大鼠胰岛素启动子）-cre转基因在下丘脑中的表达部分抑制了食欲调节系统。在非肥胖的5周龄小鼠中进行的腹膜内葡萄糖耐量试验显示，STAT 3-因斯科小鼠是葡萄糖不耐受的。胰岛灌流实验进一步揭示了早期胰岛素分泌的不足。而胰岛胰岛素含量或胰岛质量不受影响，GLUT 2，SUR 1和VEGF-A的表达水平在STAT 3-因斯科胰岛中显著降低。有趣的是，STAT 3-因斯科小鼠显示出受损的胰岛形态：α细胞经常出现在胰岛的中心区域。我们目前的观察结果表明，STAT 3在维持葡萄糖介导的早期胰岛素分泌和正常胰岛形态中具有独特的作用。(C)2004年爱思唯尔公司All rights reserved.
Normal islet formation and function depends on the action of various growth factors operating in pre- and postnatal development; however, the specific physiological function of each factor is largely unknown. Loss-of-function analyses in mice have provided little information so far, perhaps due to functional redundancies of the growth factors acting on the pancreas. The present study focuses on the role of the transcription factor STAT3 in insulin-producing cells. STAT3 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta-cells, including betacellulin, hepatocyte growth factor, growth hormone, and heparin-binding EGF-like growth factor. To elucidate its role in the alpha-cells, the STAT3 gene was disrupted in insulin-producing cells in mice (STAT3-insKO), using a cre-mediated gene recombination approach. Unexpectedly, STAT3-insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older. The mice showed partial leptin resistance, suggesting that expression of the RIP (rat insulin promoter)-cre transgene in hypothalamus partially inhibited the appetite-regulating system. Intraperitoneal glucose tolerance tests, performed in non-obese 5-week-old mice, showed that the STAT3-insKO mice were glucose intolerant. Islet perifusion experiments further revealed a deficiency in early-phase insulin secretion. Whereas islet insulin content or islet mass was not affected, expression levels of GLUT2, SUR1, and VEGF-A were significantly reduced in STAT3-insKO islets. Interestingly, STAT3-insKO mice displayed impaired islet morphology: alpha-cells were frequently seen in central regions of islets. Our present observations demonstrate a unique role of STAT3 in maintaining glucose-mediated early-phase insulin secretion and normal islet morphology. (C) 2004 Elsevier Inc. All rights reserved.