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Mol. Cell. Biol. doi:10.1128/MCB.02211-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

The transcription factor COUP-TFII is negatively regulated by insulin and glucose via Foxo1 and ChREBP controlled pathways

Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Department of Endocrinology, Metabolism and Cancer, Paris, France; Inserm, U567, Paris, France; Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Gunma, 371-8512, Japan; Université Paris-Diderot, CNRS UMR 7059, Paris, France

^* To whom correspondence should be addressed. Email: vasseur{at}cochin.inserm.fr; mireille.vasseur@inserm.fr.

	Abstract

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 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.