Essential Role of Chicken Ovalbumin Upstream Promoter-Transcription Factor II in Insulin Secretion and Insulin Sensitivity Revealed by Conditional Gene Knockout

  1. Pascale Bardoux1,
  2. Pili Zhang1,
  3. Daisy Flamez2,
  4. Anaïs Perilhou1,
  5. Tiphaine Aguirre Lavin1,
  6. Jean-François Tanti3,
  7. Karine Hellemans4,
  8. Emmanuel Gomas1,
  9. Cécile Godard1,
  10. Fabrizio Andreelli5,
  11. Maria Antonietta Buccheri1,
  12. Axel Kahn1,
  13. Yannick Le Marchand-Brustel3,
  14. Rémy Burcelin6,
  15. Frans Schuit4 and
  16. Mireille Vasseur-Cognet1
  1. 1Department of Genetic Development and Molecular Biology, Université René Descartes, Institut Cochin, INSERM U567 (Institut National de la Santé et de la Recherche Médicale), Centre National de la Recherche Scientifique-UMR 8104, Paris, France
  2. 2Diabetes Research Center, Faculty of Medicine, Vrije Universiteit Brussel Laarbeeklaan, Brussels, Belgium
  3. 3Faculté de Médecine, INSERM U568, Nice, France
  4. 4Gene Expression Unit, Afdeling Biochemie, Campus Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium
  5. 5Service de Diabétologie-Nutrition, Centre Hospitalier Universitaire de Bichat-Claude Bernard, Paris, France
  6. 6Unité Mixte de Recherche 5018, Centre National de la Recherche Scientifique-UPS, IFR 31, Paul Sabatier University, Toulouse, France
  1. Address correspondence and reprint requests to M. Vasseur-Cognet, Institut Cochin, U.567/INSERM, UMR8104/Centre National de la Recherche Scientifique, Laboratoire de l’Université René Descartes, Département GDPM, 24 rue du Faubourg Saint-Jacques 75014 Paris, France. E-mail: vasseur{at}cochin.inserm.fr

Abstract

Chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) has been implicated in the control of blood glucose by its potent effect on expression and signaling of various nuclear receptors. To understand the role of COUP-TFII in glucose homeostasis, conditional COUP-TFII-deficient mice were generated and crossed with mice expressing Cre under the control of rat insulin II gene promoter, resulting in deletion of COUP-TFII in pancreatic β-cells. Homozygous mutants died before birth for yet undetermined reasons. Heterozygous mice appeared healthy at birth and showed normal growth and fertility. When challenged intraperitoneally, the animals had glucose intolerance associated with reduced glucose-stimulated insulin secretion. Moreover, these heterozygous mice presented a mild increase in fasting and random-fed circulating insulin levels. In accordance, islets isolated from these animals exhibited higher insulin secretion in low glucose conditions and markedly decreased glucose-stimulated insulin secretion. Their pancreata presented normal microscopic architecture and insulin content up to 16 weeks of study. Altered insulin secretion was associated with peripheral insulin resistance in whole animals. It can be concluded that COUP-TFII is a new, important regulator of glucose homeostasis and insulin sensitivity.

Footnotes

  • P.Z. is currently affiliated with the Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, Louisiana. M.A.B. is currently affiliated with the Dipartimento di Biologia Animale, Laboratorio di Genetica Molecolare, Universita deggli Studi di Catania, Catania, Italy.

    P.B. and P.Z. contributed equally to this report.

    COUP-TFII, chicken ovalbumin upstream promoter-transcription factor II; HNF, hepatocyte nuclear factor.

    • Accepted February 15, 2005.
    • Received August 16, 2004.
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