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PLoS Genet. 2019 Feb 15;15(2):e1007970. doi: 10.1371/journal.pgen.1007970. eCollection 2019 Feb.

Anti-inflammatory microRNA-146a protects mice from diet-induced metabolic disease.

Author information

1
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
2
Department of Biochemistry, University of Utah, Salt Lake City, Utah, United States of America.
3
Bioinformatics, Huntsman Cancer Institute and University of Utah, Salt Lake City, Utah, United States of America.
4
Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, Utah, United States of America.
5
Department of Physical Therapy and Athletic Training, University of Utah, Salt Lake City, Utah, United States of America.

Abstract

Identifying regulatory mechanisms that influence inflammation in metabolic tissues is critical for developing novel metabolic disease treatments. Here, we investigated the role of microRNA-146a (miR-146a) during diet-induced obesity in mice. miR-146a is reduced in obese and type 2 diabetic patients and our results reveal that miR-146a-/- mice fed a high-fat diet (HFD) have exaggerated weight gain, increased adiposity, hepatosteatosis, and dysregulated blood glucose levels compared to wild-type controls. Pro-inflammatory genes and NF-κB activation increase in miR-146a-/- mice, indicating a role for this miRNA in regulating inflammatory pathways. RNA-sequencing of adipose tissue macrophages demonstrated a role for miR-146a in regulating both inflammation and cellular metabolism, including the mTOR pathway, during obesity. Further, we demonstrate that miR-146a regulates inflammation, cellular respiration and glycolysis in macrophages through a mechanism involving its direct target Traf6. Finally, we found that administration of rapamycin, an inhibitor of mTOR, was able to rescue the obesity phenotype in miR-146a-/- mice. Altogether, our study provides evidence that miR-146a represses inflammation and diet-induced obesity and regulates metabolic processes at the cellular and organismal levels, demonstrating how the combination of diet and miRNA genetics influences obesity and diabetic phenotypes.

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