Impaired Clearance of Influenza A Virus in Obese,Leptin Receptor Deficient Mice Is Independent of Leptin Signaling in the Lung Epithelium and Macrophages |
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Authors: | Kathryn A Radigan Luisa Morales-Nebreda Saul Soberanes Trevor Nicholson Recep Nigdelioglu Takugo Cho Monica Chi Robert B Hamanaka Alexander V Misharin Harris Perlman G R Scott Budinger G?khan M Mutlu |
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Institution: | 1. Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.; 2. Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.; University of California Los Angeles, United States of America, |
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Abstract: | RationaleDuring the recent H1N1 outbreak, obese patients had worsened lung injury and increased mortality. We used a murine model of influenza A pneumonia to test the hypothesis that leptin receptor deficiency might explain the enhanced mortality in obese patients.MethodsWe infected wild-type, obese mice globally deficient in the leptin receptor (db/db) and non-obese mice with tissue specific deletion of the leptin receptor in the lung epithelium (SPC-Cre/LepRfl/fl) or macrophages and alveolar type II cells (LysM-Cre/Leprfl/fl) with influenza A virus (A/WSN/33 H1N1]) (500 and 1500 pfu/mouse) and measured mortality, viral clearance and several markers of lung injury severity.ResultsThe clearance of influenza A virus from the lungs of mice was impaired in obese mice globally deficient in the leptin receptor (db/db) compared to normal weight wild-type mice. In contrast, non-obese, SP-C-Cre+/+/LepRfl/fl and LysM-Cre+/+/LepRfl/fl had improved viral clearance after influenza A infection. In obese mice, mortality was increased compared with wild-type mice, while the SP-C-Cre+/+/LepRfl/fl and LysM-Cre+/+/LepRfl
/fl mice exhibited improved survival.ConclusionsGlobal loss of the leptin receptor results in reduced viral clearance and worse outcomes following influenza A infection. These findings are not the result of the loss of leptin signaling in lung epithelial cells or macrophages. Our results suggest that factors associated with obesity or with leptin signaling in non-myeloid populations such as natural killer and T cells may be associated with worsened outcomes following influenza A infection. |
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