miR-146a regulates insulin sensitivity via NPR3.

Cellular and molecular life sciences : CMLS 2021 Mar

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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.

Citation

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. miR-146a regulates insulin sensitivity via NPR3. Cellular and molecular life sciences : CMLS. 2021 Mar;78(6):2987-3003