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

by Marah C. Runtsch, Morgan C. Nelson, Soh-Hyun Lee, Warren Voth, Margaret Alexander, Ruozhen Hu, Jared Wallace, Charisse Petersen, Vanja Panic, Claudio J. Villanueva, Kimberley J. Evason, Kaylyn M. Bauer, Timothy Mosbruger, Sihem Boudina, Mary Bronner, June L. Round, Micah J. Drummond, Ryan M. O ’Connell 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 patient s 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 r ole 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, cel lular respiration and glycolysis in macrophages through a mechanism involving its direct targetTraf6. 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-14...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research