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J. Biol. Chem. 284 (14): 9066-9073

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

The Circadian Clock Components CRY1 and CRY2 Are Necessary to Sustain Sex Dimorphism in Mouse Liver Metabolism*

Isabelle M. Bur{ddagger}1, Anne M. Cohen-Solal{ddagger}, Danielle Carmignac§, Pierre-Yves Abecassis, Norbert Chauvet{ddagger}, Agnès O. Martin{ddagger}, Gijsbertus T. J. van der Horst||, Iain C. A. F. Robinson§, Patrick Maurel**, Patrice Mollard{ddagger}, , and Xavier Bonnefont{ddagger}2

{ddagger}CNRS, UMR 5203, Institut de Génomique Fonctionnelle and INSERM, U661 and Université Montpellier, 34094 Montpellier, France, the §National Institute of Medical Research, Division of Molecular Neuroendocrinology, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom, Sanofi-Aventis, Discovery Metabolism and Pharmacokinetics Safety (DMPK-S), 3 Digue d'Alfortville, 94140 Alfortville, France, the ||Erasmus University Medical Center, Department of Genetics, Dr. Molewaterplein 50, 3000 CA Rotterdam, The Netherlands, and **INSERM, U632, 1919 Route de Mende, 34293 Montpellier, France

Abstract: In mammals, males and females exhibit anatomical, hormonal, and metabolic differences. A major example of such sex dimorphism in mouse involves hepatic drug metabolism, which is also a noticeable target of circadian timekeeping. However, whether the circadian clock itself contributes to sex-biased metabolism has remained unknown, although several daily output parameters differ between sexes in a number of species, including humans. Here we show that dimorphic liver metabolism is altered when the circadian regulators Cryptochromes, Cry1 and Cry2, are inactivated. Indeed, double mutant Cry1–/– Cry2–/– male mice that lack a functional circadian clock express a number of sex-specific liver products, including several cytochrome P450 enzymes, at levels close to those measured in females. In addition, body growth of Cry-deficient mice is impaired, also in a sex-biased manner, and this phenotype goes along with an altered pattern of circulating growth hormone (GH) in mutant males, specifically. It is noteworthy that hormonal injections able to mimic male GH pulses reversed the feminized gene expression profile in the liver of Cry1–/– Cry2–/– males. Altogether, our observations suggest that the 24-h clock paces the dimorphic ultradian pulsatility of GH that is responsible for sex-dependent liver activity. We thus conclude that circadian timing, sex dimorphism, and liver metabolism are finely interconnected.

Received for publication November 3, 2008. Revision received February 2, 2009.

* This work was supported by the Netherlands Organization for Scientific Research Grant ZonMW Vici 918.36.619 to G. T. J. v. d. H., a Marie Curie European Reintegration Grant from the European Community (to X. B.), a grant from the Région Languedoc-Roussillon (to P. M.), a grant from the Institut National de la Santé et de la Recherche Médicale (to P. M. and X. B.), and a grant from the Centre National de la Recherche Scientifique (to P. M. and X. B.).

1 Fellow of the Ministère de l'Enseignement Supérieur et de la Recherche.

2 To whom correspondence should be addressed: Institut de Génomique Fonctionnelle, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France. Tel.: 33-467142989; Fax: 33-467542432; E-mail: Xavier.Bonnefont{at}igf.cnrs.fr.

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