miR-146a regulates insulin sensitivity via NPR3
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
miR‑146a regulates insulin sensitivity via NPR3 Julian Roos1,2 · Meike Dahlhaus1,2 · Jan‑Bernd Funcke1,2,3 · Monika Kustermann1 · Gudrun Strauss1 · Daniel Halbgebauer1,2 · Elena Boldrin1 · Karlheinz Holzmann4 · Peter Möller5 · Bernadette M. Trojanowski6 · Bernd Baumann6 · Klaus‑Michael Debatin1 · Martin Wabitsch1,2 · Pamela Fischer‑Posovszky1,2 Received: 2 June 2020 / Revised: 1 October 2020 / Accepted: 31 October 2020 © The Author(s) 2020
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. Keywords microRNA · Adipocyte · Insulin resistance · NPR3
Introduction Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03699-1) contains supplementary material, which is available to authorized users. * Pamela Fischer‑Posovszky pamela.fischer@uniklinik‑ulm.de 1
Department of Pediatrics and Adolescent Medicine, University Medical Center, Eythstr. 24, 89075 Ulm, Germany
2
Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany
3
Department of Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX, USA
4
Core Facility Genomics, Ulm University, Ulm, Germany
5
Institute of Pathology, University Medical Center, Ulm, Germany
6
Institute of Physiological Chemistry, Ulm University, Ulm, Germany
Obesity is associated with white adipose tissue (WAT) inflammation and insulin resistance [1]. It is well documented that cells of the innate as well as the adaptive immune system accumulate in expanding WAT and by virtue of their secretion products, inhibit the action of insulin in ad
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