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

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.