The Link Between Nutritional Status and Insulin Sensitivity Is Dependent on the Adipocyte-Specific Peroxisome Proliferator–Activated Receptor-γ2 Isoform

  1. Gema Medina-Gomez1,
  2. Sam Virtue1,
  3. Christopher Lelliott1,
  4. Romina Boiani2,
  5. Mark Campbell1,
  6. Constantinos Christodoulides1,
  7. Christophe Perrin3,
  8. Mercedes Jimenez-Linan1,
  9. Margaret Blount1,
  10. John Dixon4,
  11. Dirk Zahn4,
  12. Rosemary R. Thresher4,
  13. Sam Aparicio4,
  14. Mark Carlton4,
  15. William H. Colledge1,
  16. Mikko I. Kettunen5,
  17. Tuulikki Seppänen-Laakso6,
  18. Jaswinder K. Sethi1,
  19. Stephen O’Rahilly1,
  20. Kevin Brindle5,
  21. Saverio Cinti2,
  22. Matej Orešič6,
  23. Remy Burcelin3 and
  24. Antonio Vidal-Puig1
  1. 1Department of Clinical Biochemistry, Histopathology, Physiology and Oncology, University of Cambridge/Addenbrooke’s Hospital, Cambridge, U.K.
  2. 2Institute of Normal Human Morphology, Faculty of Medicine, Ancona University, Ancona, Italy
  3. 3Centre National de la Recherche Scientifique-UMR 5018, Paul Sabatier University, Toulouse, France
  4. 4Paradigm Therapeutics, Cambridge, U.K.
  5. 5Department of Biochemistry, University of Cambridge, Cambridge, U.K.
  6. 6VTT: Technical Research Centre of Finland, VTT Biotechnology, Espoo, Finland
  1. Address correspondence and reprint requests to Antonio Vidal-Puig, Department of Clinical Biochemistry, University of Cambridge/Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QR, U.K. E-mail: ajv22{at}cam.ac.uk

Abstract

The nuclear receptor peroxisome proliferator–activated receptor-γ (PPARγ) is critically required for adipogenesis. PPARγ exists as two isoforms, γ1 and γ2. PPARγ2 is the more potent adipogenic isoform in vitro and is normally restricted to adipose tissues, where it is regulated more by nutritional state than PPARγ1. To elucidate the relevance of the PPARγ2 in vivo, we generated a mouse model in which the PPARγ2 isoform was specifically disrupted. Despite similar weight, body composition, food intake, energy expenditure, and adipose tissue morphology, male mice lacking the γ2 isoform were more insulin resistant than wild-type animals when fed a regular diet. These results indicate that insulin resistance associated with ablation of PPARγ2 is not the result of lipodystrophy and suggests a specific role for PPARγ2 in maintaining insulin sensitivity independently of its effects on adipogenesis. Furthermore, PPARγ2 knockout mice fed a high-fat diet did not become more insulin resistant than those on a normal diet, despite a marked increase in their mean adipocyte cell size. These findings suggest that PPARγ2 is required for the maintenance of normal insulin sensitivity in mice but also raises the intriguing notion that PPARγ2 may be necessary for the adverse effects of a high-fat diet on carbohydrate metabolism.

Footnotes

  • Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted February 21, 2005.
    • Received November 22, 2004.
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