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A Novel Long Non‐coding RNA Modulates Macrophage Phenotype During Diet‐Induced Obesity
Author(s) -
Stapleton Kenneth,
Chen Zhou,
Reddy Marpadga,
Lanting Linda,
Leung Amy,
Dieuliis Jeffrey,
Natarajan Rama
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.757.10
Subject(s) - gene knockdown , proinflammatory cytokine , inflammation , biology , diabetes mellitus , fatty acid binding protein , gene expression , phenotype , macrophage , macrophage polarization , insulin resistance , endocrinology , medicine , gene , immunology , biochemistry , in vitro
Systemic low‐grade inflammation associated with obesity is a strong risk factor for the development of metabolic syndrome, which in turn raises the risk of diabetes and cardiovascular complications. This inflammatory state is primarily caused by the release of proinflammatory cytokines by macrophages in response to excess lipid levels. Macrophage phenotypic changes are associated with a shift in global gene expression profiles, which includes long non‐coding RNAs (lncRNAs). Although the misregulation of lncRNAs have been implicated in the development of many human diseases, including diabetic complications, their role in directing macrophage phenotype during diet‐induced obesity and pre‐diabetes has been largely unexplored. We assembled transcriptomes de novo from macrophages of high fat diet (HFD)‐ and control diet‐fed mice and identified novel lncRNAs that were differentially expressed. One of the top lncRNA candidates was termed lnc‐Fabp5, due to its proximity to Fabp5 , a fatty acid transporter with known roles in insulin resistance and diabetes. HFD caused decreased expression of both lnc‐Fabp5 and Fabp5. We hypothesized that lnc‐Fabp5 affects macrophage dysfunction during obesity and diabetes. Gain‐ and loss‐of‐function studies were performed to evaluate the effect of lnc‐Fabp5 on macrophage gene expression and phenotype. A reduction in lnc‐Fabp5 transcripts with gapmers decreased Fabp5 levels, increased expression of immune response and inflammatory genes, and increased acetylated LDL uptake. Many of those changes were not replicated by Fabp5 knockdown, indicating that lnc‐Fabp5 knockdown‐induced changes are not simply a result of altered Fabp5 expression. Lnc‐Fabp5 overexpression caused inverse expression changes and partially blunted the inflammatory response to endotoxin. lnc‐Fabp5 levels were measured in human adipose tissue macrophages from obese and healthy donors, and expression was inversely correlated with patient BMI and fasting insulin levels. This previously uncharacterized lncRNA appears to have a functional role in macrophage response to environmental changes caused by high‐fat diet. Support or Funding Information NIH: DK065073