Insulin receptor substrate-1 inhibits high-fat diet-induced obesity by browning of white adipose tissue through miR-503

FASEB J. 2020 Sep;34(9):12308-12323. doi: 10.1096/fj.201903283RR. Epub 2020 Jul 28.


Genetic variation of insulin receptor substrate 1 (IRS-1) was found to modulate the insulin resistance of adipose tissues, but the underlying mechanism was not clear. To investigate how the IRS-1 was involved in the browning of white adipose tissue through miRNA, we identified a mutated Irs-1 (Irs-1-/- ) mice model and found that this mice had a reduced subcutaneous WAT (sWAT) and increased brown adipose tissue (BAT) in the interscapular region. So we isolated the bone marrow stromal cells and analyzed differentially expressed miRNAs and adipogenesis-related genes with miRNA arrays and PCR arrays. Irs-1-/- mice showed decreased miR-503 expression, but increased expression of its target, bone morphogenetic protein receptor type 1a (BMPR1a). Overexpression of miR-503 in preadipocytes downregulated BMPR1a and impaired adipogenic activity through the phosphotidylinositol 3-kinase (PI3K/Akt) pathway, while the inhibitor had the opposite effect. In both Irs-1-/- and cold-induced models, sWAT exhibited BAT features, and showed tissue-specific increased BMPR1a expression, PI3K expression, and Akt phosphorylation. Thus, our results showed that IRS-1 regulated brown preadipocyte differentiation and induced browning in sWAT through the miR-503-BMPR1a pathway, which played important roles in high-fat diet-induced obesity.

Keywords: BMPR1a; IRS-1; PI3K/Akt pathway; brown adipogenesis; miR-503.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, White / metabolism*
  • Animals
  • Bone Morphogenetic Protein Receptors, Type I / genetics
  • Cell Differentiation
  • Diet, High-Fat*
  • Insulin Receptor Substrate Proteins / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / physiology*
  • Obesity / prevention & control*
  • Phosphatidylinositol 3-Kinases / physiology
  • Proto-Oncogene Proteins c-akt / metabolism


  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • MicroRNAs
  • Mirn503 microRNA, mouse
  • Proto-Oncogene Proteins c-akt
  • Bmpr1a protein, mouse
  • Bone Morphogenetic Protein Receptors, Type I