Targeting Peroxisome Proliferator-Activated Receptor-Gamma Decreases Host Mortality After Influenza Infection in Obese Mice

Obesity is an independent risk factor for severe influenza infection. However, the underlying cellular and molecular mechanisms are still incompletely understood. In this study, we have utilized a murine influenza infection model in genetic-induced obese (db/db) mice to explore the mechanisms by which obesity increases host susceptibility to influenza infection. We find that db/db mice have enhanced viral replication, exaggerated inflammatory responses, and dysregulated lung repair process after influenza infection, and consequently increased host mortality. Furthermore, we demonstrate that the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma), an important inflammation regulator, was downregulated in the lung macrophages of db/db mice after influenza infection. Strikingly, the treatment of 15-deoxy-Delta 12, 14-prostaglandin J2 (15d-PGJ2), a PPAR-gamma agonist, largely rescued the survival of db/db mice after influenza infection. Interestingly, macrophage PPAR-gamma-deficient mice exhibited enhanced mortality after influenza infection and 15d-PGJ2 fails to rescue host mortality in macrophage PPAR-gamma-deficient mice, suggesting that PPAR-gamma expression in macrophages is critical for the action of 15d-PGJ2. These data indicate that obesity attenuates lung antiviral immunity and hampers host recovery through the modulation of macrophage PPAR-gamma expression. Furthermore, modalities targeting macrophage PPAR-gamma expression and/or function may serve as promising therapeutics to treat severe influenza infection in obese patients.