miR-146a regulates insulin sensitivity via NPR3

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.

Senescent macrophages in the human adipose tissue as a source of inflammaging

“…The abnormal level of miR-21 and miR-146a has been observed both in normal aging and in the major ARDs [14,15]. In both mice model and observational studies in humans, miR-21 and miR-146a expression levels were consistently associated with both obesity and T2DM [16][17][18][19].…”

MicroRNAs as Potential Biomarkers for Exercise-Based Cancer Rehabilitation in Cancer Survivors

“…Evidence suggested that miR-146a −/− mice exposed to a high-fat diet gained more body weight and fat mass than controls, accompanied by insulin resistance and glucose intolerance. Both adipocytes transfected with miR146a and knockout of natriuretic peptide receptor 3 (NPR3), a target gene of miR-146a, exhibited an increase in insulin-stimulated glucose intake, demonstrating that miR-146a modulated insulin sensitivity by downregulating NPR3 [86]. These results indicated miR-146a might serve as a more promising biomarker to evaluate response to antidiabetic intervention than miR-126.…”

Mechanisms contributing to adverse outcomes of COVID-19 in obesity

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