GSE194403
Obesity reprograms the pulmonary polyunsaturated fatty acid-derived lipidome prior to injury in a diet-dependent manner
Obesity exacerbates inflammation upon lung injury; however, the mechanisms by which obesity primes pulmonary dysregulation prior to injury are not well studied.  Notably, little is known about how obesity dysregulates pulmonary polyunsaturated fatty acid (PUFA) metabolism that is central to inflammation initiation and resolution.  Herein, we first show that a high fat diet (HFD) administered to C57BL/6J mice increases the relative abundance of pulmonary PUFA-containing triglycerides and the concentration of PUFA-derived oxylipins, independent of an increase in total pulmonary PUFAs, prior to onset of pulmonary inflammation. Experiments with a genetic model of obesity did not recapitulate the effects of the HFD on the pulmonary oxylipin signature, revealing a diet-driven effect.  Subsequent pulmonary next-generation RNA sequencing identified complex and unique transcriptional regulation with the HFD.  The HFD increased pathways related to glycerophospholipid metabolism and immunity, including an elevation in B cell differentiation and signaling.  Finally, computational integration of lipidomic with transcriptomic data revealed novel HFD-driven networks between glycerophospholipid metabolism and B cell receptor signaling with specific PUFA-derived oxylipins. Collectively, these data show obesity dysregulates pulmonary PUFA metabolism prior to lung injury, which may be a mechanism by which obesity primes the lungs to respond poorly upon infectious and/or inflammatory challenges. Overall design: Lung lipidomic and transcriptomic profile of mice fed a high fat diet versus mice fed a lean diet.