Leptin mediates the pathogenesis of severe 2009 pandemic influenza A(H1N1) infection associated with cytokine dysregulation in mice with diet-induced obesity

J Infect Dis. 2013 Apr 15;207(8):1270-80. doi: 10.1093/infdis/jit031. Epub 2013 Jan 16.


Background: Obesity is associated with a high circulating leptin level and severe 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) infection. The mechanism for severe lung injury in obese patients and the specific treatment strategy remain elusive.

Method: We studied the pathogenesis of A(H1N1)pdm09 infection in a mouse model of diet-induced obesity.

Results: Obese mice had significantly higher initial pulmonary viral titer and mortality after challenge with A(H1N1)pdm09, compared with age-matched lean mice. Compared with lean mice, obese mice had heightened proinflammatory cytokine and chemokine levels and more severe pulmonary inflammatory damage. Furthermore, obese mice had a higher preexisting serum leptin level but a lower preexisting adiponectin level. Recombinant mouse leptin increased the interleukin 6 (IL-6) messenger RNA expression in mouse single-lung-cell preparations, mouse macrophages, and mouse lung epithelial cell lines infected with A(H1N1)pdm09. Administration of anti-leptin antibody improved the survival of infected obese mice, with associated reductions in pulmonary levels of the proinflammatory cytokines IL-6 and interleukin 1β but not the pulmonary viral titer.

Conclusions: Our findings suggest that preexisting high levels of circulating leptin contribute to the development of severe lung injury by A(H1N1)pdm09 in mice with diet-induced obesity. The therapeutic strategy of leptin neutralization for the reduction of proinflammatory responses and pulmonary damage in obese patients warrants further investigations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / administration & dosage
  • Antibodies / immunology
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Epithelium / immunology
  • Epithelium / pathology
  • Female
  • Influenza A Virus, H1N1 Subtype / pathogenicity*
  • Interleukin-1beta / immunology
  • Interleukin-6 / genetics
  • Interleukin-6 / immunology*
  • Kaplan-Meier Estimate
  • Leptin / immunology*
  • Leptin / metabolism
  • Leptin / pharmacology
  • Lung / immunology
  • Lung / pathology
  • Lung / virology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / virology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Obesity / immunology*
  • Obesity / virology
  • Orthomyxoviridae Infections / immunology
  • Orthomyxoviridae Infections / pathology*
  • Orthomyxoviridae Infections / virology
  • Pandemics
  • Pneumonia / immunology
  • Pneumonia / pathology
  • Pneumonia / virology
  • RNA, Messenger / analysis
  • RNA, Messenger / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • Viral Load


  • Antibodies
  • Interleukin-1beta
  • Interleukin-6
  • Leptin
  • RNA, Messenger
  • Recombinant Proteins
  • interleukin-6, mouse