Anti-inflammatory microRNA-146a protects mice from diet-induced metabolic disease.
Marah C RuntschMorgan C NelsonSoh-Hyun LeeWarren VothMargaret AlexanderRuozhen HuJared WallaceCharisse PetersenVanja PanicClaudio J VillanuevaKimberley J EvasonKaylyn M BauerTimothy MosbrugerSihem BoudinaMary BronnerJune L RoundMicah J DrummondRyan M O'ConnellPublished in: PLoS genetics (2019)
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.
Keyphrases
- high fat diet induced
- cell proliferation
- insulin resistance
- weight gain
- long non coding rna
- high fat diet
- adipose tissue
- weight loss
- long noncoding rna
- metabolic syndrome
- oxidative stress
- type diabetes
- wild type
- blood glucose
- body mass index
- bariatric surgery
- skeletal muscle
- gene expression
- genome wide
- glycemic control
- birth weight
- anti inflammatory
- immune response
- blood pressure
- dna methylation
- transcription factor
- mass spectrometry
- single cell
- obese patients
- physical activity
- inflammatory response
- toll like receptor