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Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production

Nature Genetics volume 26, pages 435–439 (2000)Cite this article

Abstract

The gene Ucp2 is a member of a family of genes found in animals and plants, encoding a protein homologous to the brown fat uncoupling protein Ucp1 (refs 1–3). As Ucp2 is widely expressed in mammalian tissues4,5, uncouples respiration6 and resides within a region of genetic linkage to obesity4, a role in energy dissipation has been proposed. We demonstrate here, however, that mice lacking Ucp2 following targeted gene disruption are not obese and have a normal response to cold exposure or high-fat diet. Expression of Ucp2 is robust in spleen, lung and isolated macrophages4,5,7, suggesting a role for Ucp2 in immunity or inflammatory responsiveness4. We investigated the response to infection with Toxoplasma gondii in Ucp2−/− mice, and found that they are completely resistant to infection, in contrast with the lethality observed in wild-type littermates. Parasitic cysts and inflammation sites in brain were significantly reduced in Ucp2−/− mice (63% decrease, P<0.04). Macrophages from Ucp2 −/− mice generated more reactive oxygen species than wild-type mice (80% increase, P<0.001) in response to T. gondii, and had a fivefold greater toxoplasmacidal activity in vitro compared with wild-type mice (P<0.001 ), which was absent in the presence of a quencher of reactive oxygen species (ROS). Our results indicate a role for Ucp2 in the limitation of ROS and macrophage-mediated immunity.

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Figure 1: Generation of Ucp2−/− mice.
Figure 2: Survival of Ucp2−/− mice to infection by T. gondii, toxoplasmacidal activity and increased ROS production of macrophages from mutant mice.
Figure 3: Effects of LPS on the mRNA levels of Ucp2, Il1b and Sod2 in cultured peritoneal macrophages.

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Acknowledgements

We thank C. Bock and the Duke University Transgenic Core for ES cell electroporation and blastocyst injections; L. Hale for immunohistochemistry of Ucp1 expression in adipose tissue sections; and W. Wetsel, B. Haynes, J.B. Weinberg, G. Sempowski and G. Taylor for discussions, reading of the manuscript and suggestions. This work was supported by Centre National de la Recherche Scientifique, Association de Recherches sur le Cancer, Institut de Recherches Servier, and Association Française contre les Myopathies (D. Ricquier), Université Laval (D. Richard), Human Frontier Science Program organization (grant RG-307/98 to D. Richard and D. Ricquier), NIH grants R01 DK54024 (S.C.). C.P. and E.C. were supported by doctoral fellowships of Association de Recherches sur le Cancer and Servier, respectively.

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Author notes

  1. Denis Arsenijevic, Hiroki Onuma, Claire Pecqueur and Serge Raimbault: These authors contributed equally to this work.

Authors and Affiliations

  1. Centre de Recherche de Hôpital Laval et Centre de Recherche sur le Métabolisme Energétique, Université Laval, Québec, Canada

    Denis Arsenijevic & Denis Richard

  2. Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina, USA

    Hiroki Onuma, Brian S. Manning, Richard Surwit & Sheila Collins

  3. Pharmacology, Duke University Medical Center, Durham, North Carolina, USA

    Sheila Collins

  4. Centre de Recherche sur l'Endocrinologie Moléculaire et le Développement, Centre National de la Recherche Scientifique, UPR 9078, Meudon, France

    Claire Pecqueur, Serge Raimbault, Bruno Miroux, Elodie Couplan, Marie-Clotilde Alves-Guerra, Frédéric Bouillaud & Daniel Ricquier

  5. Ecole Pratique des Hautes Etudes/Institut National de la Recherche Agronomique, Jouy-en-Josas, France

    Marc Goubern

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Correspondence to Sheila Collins or Daniel Ricquier.

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Arsenijevic, D., Onuma, H., Pecqueur, C. et al. Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nat Genet 26, 435–439 (2000). https://doi.org/10.1038/82565

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