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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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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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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DOI: https://doi.org/10.1038/82565
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