Perilhou Anaïs, Tourrel-Cuzin Cécile, Kharroubi Ilham, Henique Carole, Fauveau Véronique, Kitamura Tadahiro, Magnan Christophe, Postic Catherine, Prip-Buus Carina, Vasseur-Cognet Mireille
Department of Endocrinology, Metabolism, and Cancer, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
Mol Cell Biol. 2008 Nov;28(21):6568-79. doi: 10.1128/MCB.02211-07. Epub 2008 Sep 2.
COUP-TFII has an important role in regulating metabolism in vivo. We showed this previously by deleting COUP-TFII from pancreatic beta cells in heterozygous mutant mice, which led to abnormal insulin secretion. Here, we report that COUP-TFII expression is reduced in the pancreas and liver of mice refed with a carbohydrate-rich diet and in the pancreas and liver of hyperinsulinemic and hyperglycemic mice. In pancreatic beta cells, COUP-TFII gene expression is repressed by secreted insulin in response to glucose through Foxo1 signaling. Ex vivo COUP-TFII reduces insulin production and secretion. Our results suggest that beta cell insulin secretion is under the control of an autocrine positive feedback loop by alleviating COUP-TFII repression. In hepatocytes, both insulin, through Foxo1, and high glucose concentrations repress COUP-TFII expression. We demonstrate that this negative glucose effect involves ChREBP expression. We propose that COUP-TFII acts in a coordinate fashion to control insulin secretion and glucose metabolism.
COUP-TFII在体内调节代谢中发挥着重要作用。我们之前通过在杂合突变小鼠的胰腺β细胞中删除COUP-TFII证明了这一点，这导致胰岛素分泌异常。在此，我们报告，在重新喂食富含碳水化合物饮食的小鼠的胰腺和肝脏中，以及在高胰岛素血症和高血糖小鼠的胰腺和肝脏中，COUP-TFII的表达降低。在胰腺β细胞中，分泌的胰岛素通过Foxo1信号通路响应葡萄糖抑制COUP-TFII基因表达。体外实验中，COUP-TFII减少胰岛素的产生和分泌。我们的结果表明，β细胞胰岛素分泌受自分泌正反馈回路的控制，该回路通过减轻COUP-TFII的抑制作用来实现。在肝细胞中，胰岛素通过Foxo1以及高葡萄糖浓度都会抑制COUP-TFII的表达。我们证明这种负性葡萄糖效应涉及ChREBP的表达。我们提出，COUP-TFII以协同方式发挥作用，以控制胰岛素分泌和葡萄糖代谢。
