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

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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Female
  • Gene Expression
  • Humans
  • Hyperglycemia / genetics
  • Hyperglycemia / metabolism
  • Hyperglycemia / prevention & control
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Insulin / blood
  • Intra-Abdominal Fat / metabolism
  • Intra-Abdominal Fat / pathology
  • Macrophages / metabolism
  • Male
  • Metabolic Diseases / genetics
  • Metabolic Diseases / metabolism
  • Metabolic Diseases / prevention & control*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • NF-kappa B / metabolism
  • Obesity / genetics
  • Obesity / metabolism
  • Obesity / prevention & control
  • Proto-Oncogene Proteins c-akt / genetics
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • Weight Gain / drug effects
  • Weight Gain / genetics

Substances

  • Blood Glucose
  • Insulin
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • NF-kappa B
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Sirolimus