LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice
LIM-homeodomain Transcription Factor Isl-1 Mediates the Effect of Leptin on Insulin Secretion in Mice
复制标题
LIM-同源域转录因子 Isl-1 介导瘦素对小鼠胰岛素分泌的影响
DOI：
10.1074/jbc.m113.450536
复制
发表时间：
2013-04-26
影响因子：
4.8
通讯作者：
Cui, Sheng
中科院分区：
文献类型：
--
作者：
Chen, Juan;Fu, Rui;Cui, Sheng
除了众所周知的瘦素通过中枢神经系统调节能量平衡和葡萄糖稳态的作用外，循环瘦素还通过其受体（OBRb）直接影响胰岛和胰岛素分泌。lim同源结构域转录因子il -1在所有类型的胰腺内分泌细胞中表达，并参与调节胰岛发育和胰岛素分泌。OBRb和il -1突变都会导致肥胖相关的糖尿病。然而，瘦素与胰岛中il -1的相互作用及其生理意义仍有待确定。在这里，我们发现胰岛和NIT β细胞中的大多数瘦素靶细胞表达il -1。体内和体外实验结果均表明，在高脂饮食等生理和病理生理条件下，瘦素可抑制胰岛中il -1的表达和胰岛素分泌。瘦素对胰岛素分泌的影响在瘦素受体缺陷db/db和il -1诱导敲除小鼠中消失。我们得出结论，瘦素对胰岛素分泌的作用至少部分是由il -1介导的。本研究的另一个新发现是，isl1作为瘦素信号分子STAT3的直接下游靶点，影响瘦素对胰岛素分泌的影响，而反过来，胰岛素通过JAK-STAT3通路反馈调节isl1的表达。这些发现对于理解相关疾病（如肥胖和2型糖尿病）中胰岛素分泌和代谢的调节机制至关重要。
In addition to the well known regulating effects of leptin on energy balance and glucose homeostasis through the central nervous system, circulating leptin has a direct effect on pancreatic islet and insulin secretion through its receptor (OBRb). The LIM-homeodomain transcription factor Isl-1 is expressed in all classes of pancreatic endocrine cells and is involved in regulating both islet development and insulin secretion. Both OBRb and Isl-1 mutations result in obesity-related diabetes. However, the interactions and physiological significance of leptin and Isl-1 in pancreatic islets remain to be established. Here, we show that most of leptin target cells in pancreatic islets and NIT beta cells express Isl-1. Both in vivo and in vitro results demonstrate that leptin suppresses Isl-1 expression and insulin secretion in islet in physiological and pathophysiological conditions, e. g. high fat diet. This effect of leptin on insulin secretion is lost in leptin receptor-defective db/db and Isl-1-inducible knock-out mice. We conclude that the action of leptin on insulin secretion is at least partly mediated by Isl-1. Another new finding of this study is that Isl-1 acts as a direct downstream target of leptin signaling molecule STAT3 to influence the effect of leptin on insulin secretion, whereas inversely, insulin has feedback regulating effects on Isl-1 expression through JAK-STAT3 pathway. These findings are crucial for understanding the mechanisms regulating insulin secretion and metabolism in related diseases, such as obesity and type 2 diabetes.