GSE123938
Impact of Diet Induced Obesity on Hyperoxic Lung Injury
Background: Obesity has become a worldwide concern. Acute respiratory distress syndrome (ARDS) comprises 10.4% of total intensive care unit admissions and is associated with very high mortality. ARDS incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the clinical and pathologic features observed in patients with ARDS. The aim of this study was to determine the impact of high fat diet-induced obesity on the susceptibility to hyperoxic acute lung injury in mice. Methods: Male C57BL/6 mice received 60% fat versus ingredient matched 10% fat diet. Mice were exposed to >95% oxygen to induce lung damage. RNA was isolated from lung homogenates and by comparing RNA sequencing results with mouse Mitocarta, an inventory of genes encoding proteins with mitochondrial localization, we identified fatty acid synthase (FASN), an enzyme catalyzing de novo fatty acid synthesis, as one of the mitochondrial genes significantly changed with diet and with hyperoxia. We generated mice deficient in FASN in alveolar epithelial cells by using a tamoxifen inducible Cre recombinase construct (FASNflox/flox SPC Cre+/-) and subjected them to hyperoxia and high fat diet. Results: Mice receiving 60% fat diet had significantly higher weight, serum cholesterol and fasting glucose. High fat diet mice had significantly reduced survival and increased lung damage, as assessed by BAL protein and LDH, histology and TUNEL staining. By RNA sequencing of lung homogenates we identified FASN as one of the mitochondrial genes significantly reduced in mice receiving 60% compared to 10% fat diet and further reduced with hyperoxia. We confirmed that FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. After 48 hours of hyperoxia FASNflox/flox SPC Cre+/- mice displayed increased levels of BAL protein and LDH and more severe histologic lung injury. FASNflox/flox SPC Cre+/- mice remained more prone to lung injury after hyperoxic exposure even when they received 60% fat diet. Conclusions: These results demonstrate that obesity increases the severity of hyperoxia induced acute lung injury in mice by altering FASN levels in the lung of high fat diet fed rodents. To our knowledge, this is the first study to show that high fat diet leads to altered FASN expression in the lung and that both high fat diet and reduced FASN in alveolar epithelial cells lead to increased lung injury under hyperoxic conditions. Overall design: Lung RNA profiles of mice that received 12 weeks of 60% fat and 10% fat diet after exposure to >95% oxygen or room air were generated