miR-146a regulates insulin sensitivity via NPR3
Julian Roos, Meike Dahlhaus, Jan‐Bernd Funcke, Monika Kustermann, Gudrun Strauß, Daniel Halbgebauer, Elena Boldrin, Karlheinz Holzmann, Peter Möller, Bernadette M. Trojanowski, Bernd Baumann, Klaus‐Michael Debatin, Martin Wabitsch, Pamela Fischer‐Posovszky
Abstract
Abstract The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a −/− mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson–Golabi–Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a −/− mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.