Obesity reprograms the pulmonary polyunsaturated fatty acid-derived lipidome, transcriptome, and gene-oxylipin networks

• Type of Material: Article
• Authors: Rafia Virk, University of North Carolina Chapel Hill; Nicole Buddenbaum, University of North Carolina Chapel Hill; Abrar Al-Shaer, University of North Carolina Chapel Hill; Michael Armstrong, University of Colorado Denver; Jonathan Manke, University of Colorado Denver; Nichole Reisdorph, University of Colorado Denver; Selin Sergin, Michigan State University; Jenifer I Fenton, Michigan State University; Diane E Wallace, University of North Carolina Chapel Hill; Brandie M Ehrmann, University of North Carolina Chapel Hill; Hannah B Lovins, Ohio State University; Kymberly M Gowdy, Ohio State University; Ryan M Smith, Emory University; Gregory J Smith, University of North Carolina at Chapel Hill; Samir NP Kelada, University of North Carolina Chapel Hill; Saame Raza Shaikh, University of North Carolina Chapel Hill
• Language: English
• Date: 2022-10-01
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jlr.2022.100267
• Title of Journal or Parent Work: JOURNAL OF LIPID RESEARCH
• Volume: 63
• Issue: 10
• Start Page: 100267
• End Page: 100267
• Grant/Funding Information: This work was supported by NIH R01AT008375 (S. R. S.), NIH R01ES031378 (K. M. G., S. R. S.), NIH P30DK05635 (S. R. S.), and NIH S10 RR026522-01 (N. R.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
• Keywords: transcriptional regulation; Biochemistry & Molecular Biology; MEDIATORS; Science & Technology; inflammation; INFLAMMATION; triglycerides; arachidonic acid; omega-3 fatty acids; prostaglandins; PROMOTE INSULIN-RESISTANCE; nutrition; high-fat diet; LUNG; INFLUENZA-VIRUS; OZONE; MICE; CELLS; 17-HDHA; Life Sciences & Biomedicine; oxylipins; glycerophospholipid metabolism
• Research Categories: Health Sciences, Medicine and Surgery; Chemistry, General

Abstract

Obesity exacerbates inflammation upon lung injury; however, the mechanisms by which obesity primes pulmonary dysregulation prior to external injury are not well studied. Herein, we tested the hypothesis that obesity dysregulates pulmonary PUFA metabolism that is central to inflammation initiation and resolution. We first show that a high-fat diet (HFD) administered to C57BL/6J mice increased the relative abundance of pulmonary PUFA-containing triglycerides and the concentration of PUFA-derived oxylipins (particularly prostaglandins and hydroxyeicosatetraenoic acids), independent of an increase in total pulmonary PUFAs, prior to onset of pulmonary inflammation. Experiments with a genetic model of obesity (ob/ob) generally recapitulated the effects of the HFD on the pulmonary oxylipin signature. Subsequent pulmonary next-generation RNA sequencing identified complex and unique transcriptional regulation with the HFD. We found the HFD increased pathways related to glycerophospholipid metabolism and immunity, including a unique elevation in B cell differentiation and signaling. Furthermore, we conducted computational integration of lipidomic with transcriptomic data. These analyses identified novel HFD-driven networks between glycerophospholipid metabolism and B cell receptor signaling with specific PUFA-derived pulmonary oxylipins. Finally, we confirmed the hypothesis by demonstrating that the concentration of pulmonary oxylipins, in addition to inflammatory markers, were generally increased in mice consuming a HFD upon ozone-induced acute lung