title: Impaired clearance of influenza A virus in obese, leptin receptor deficient mice is independent of leptin signaling in the lung epithelium and macrophages.
abstract: BACKGROUND
  During 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.
  
  
  METHODS
  We 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/LepR fl/fl) or macrophages and alveolar type II cells (LysM-Cre/Lepr fl/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.
  
  
  RESULTS
  The 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+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/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+/+/LepR fl/fl and LysM-Cre+/+/LepR fl/fl mice exhibited improved survival.
  
  
  CONCLUSIONS
  Global 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.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Radigan
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Luisa
authors.initials: L
authors.lastname: Morales-Nebreda
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Saul
authors.initials: S
authors.lastname: Soberanes
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Trevor
authors.initials: T
authors.lastname: Nicholson
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Recep
authors.initials: R
authors.lastname: Nigdelioglu
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Takugo
authors.initials: T
authors.lastname: Cho
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Monica
authors.initials: M
authors.lastname: Chi
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Hamanaka
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Misharin
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Harris
authors.initials: H
authors.lastname: Perlman
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.
authors.forename: Gökhan M
authors.initials: GM
authors.lastname: Mutlu
mesh_terms: D056809:Alveolar Epithelial Cells / Q000502:physiology* / Q000821:virology; D000818:Animals; D004285:Dogs; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D020738:Leptin / Q000502:physiology*; D008168:Lung / Q000276:immunology / Q000473:pathology / Q000821:virology; D016676:Macrophages, Alveolar / Q000502:physiology / Q000821:virology*; D061985:Madin Darby Canine Kidney Cells; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009504:Neutrophils / Q000276:immunology / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism
chemical_list: D020738:Leptin; D054411:Receptors, Leptin