Expression data from female C57BL/6J and B6.Cg-Mir146atm1.1Bal/J mice after 10 weeks of normal or high fat diet. Expression data from female C57BL/6J and B6.Cg-Mir146atm1.1Bal/J mice after 10 weeks of normal or high fat diet

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 sensitivityresistance . 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. Overall design: 5 samples/group; groups: C57BL/6J normal diet (ND), C57BL/6J high fat diet (HFD), B6.Cg-Mir146atm1.1Bal/J ND , B6.Cg-Mir146atm1.1Bal/J HFD