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.

中文翻译：

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胰岛素受体底物-1通过miR-503使白色脂肪组织褐变抑制高脂饮食诱导的肥胖

发现胰岛素受体底物 1 (IRS-1) 的遗传变异可调节脂肪组织的胰岛素抵抗，但其潜在机制尚不清楚。为了研究 IRS-1 如何通过 miRNA 参与白色脂肪组织的褐变，我们鉴定了一个突变的 Irs-1 (Irs-1-/-) 小鼠模型，发现该小鼠的皮下 WAT (sWAT) 和肩胛间区域的棕色脂肪组织（BAT）增加。因此，我们分离了骨髓基质细胞，并用 miRNA 阵列和 PCR 阵列分析了差异表达的 miRNA 和脂肪生成相关基因。Irs-1-/- 小鼠的 miR-503 表达降低，但其靶标骨形态发生蛋白受体 1a（BMPR1a）表达增加。前脂肪细胞中 miR-503 的过表达通过磷脂酰肌醇 3-激酶 (PI3K/Akt) 途径下调 BMPR1a 并损害脂肪生成活性，而抑制剂具有相反的作用。在 Irs-1-/- 和冷诱导模型中，sWAT 表现出 BAT 特征，并显示组织特异性 BMPR1a 表达、PI3K 表达和 Akt 磷酸化增加。因此，我们的结果表明，IRS-1 通过 miR-503-BMPR1a 途径调节棕色前脂肪细胞分化并诱导 sWAT 褐变，这在高脂饮食诱导的肥胖中起重要作用。