The Transcription Factor COUP-TFII Is Negatively Regulated by Insulin and Glucose via Foxo1- and ChREBP-Controlled Pathways

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 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.

ACKNOWLEDGMENTS

This work was supported by grants from Nestlé France 2007, Programme National de Recherches sur le Diabète-INSERM/ARD (PNRD-A06064KS), and Agence Nationale pour la Recherche (ANR 2005 Cardiovasculaire Obésité et Diabète, ANR-05-PCOD-088-01). A.P. is the recipient of a doctoral fellowship from the Ministère de l'Enseignement Supérieur et de la Recherche and the Fondation pour la Recherche Médicale.

We are grateful to C. Newgard for the 832/13 INS-1 cell line. We thank all the INSERM U649 team (Nantes, France) for their expertise in adenovirus preparation, T. Becker for helpful discussion of the siRNA experiments, and P. Bossard for critical reading of the manuscript.