期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 6, 页码 2987-3003出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03699-1
关键词
microRNA; Adipocyte; Insulin resistance; NPR3
资金
- Projekt DEAL
- Baden-Wurttemberg Stiftung [BWST_ncRNA-027]
- German Research Association (Heisenberg program) [Fi1700/7-1, Fi1700/5-1]
- International Graduate School in Molecular Medicine Ulm (iGradU)
- Deutsche Forschungsgemeinschaft (DFG) [CRC1149]
- Boehringer Ingelheim Ulm University BioCenter [BIU-C6]
The study revealed that miR-146a regulates adipose tissue inflammation by suppressing the NPR3 gene, thereby impacting the development of obesity and insulin resistance.
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.
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