Joslin Diabetes Center, Harvard Medical School, Harvard University, Boston, MA, USA; Harvard Medical School, Harvard University, Boston, MA, USA.
Joslin Diabetes Center, Harvard Medical School, Harvard University, Boston, MA, USA.
Cell Rep. 2024 Jul 23;43(7):114491. doi: 10.1016/j.celrep.2024.114491. Epub 2024 Jul 13.
Tissues release microRNAs (miRNAs) in small extracellular vesicles (sEVs) including exosomes, which can regulate gene expression in distal cells, thus acting as modulators of local and systemic metabolism. Here, we show that insulin regulates miRNA secretion into sEVs from 3T3-L1 adipocytes and that this process is differentially regulated from cellular expression. Thus, of the 53 miRNAs upregulated and 66 miRNAs downregulated by insulin in 3T3-L1 sEVs, only 12 were regulated in parallel in cells. Insulin regulated this process in part by phosphorylating hnRNPA1, causing it to bind to AU-rich motifs in miRNAs, mediating their secretion into sEVs. Importantly, 43% of insulin-regulated sEV-miRNAs are implicated in obesity and insulin resistance. These include let-7 and miR-103, which we show regulate insulin signaling in AML12 hepatocytes. Together, these findings demonstrate an important layer to insulin's regulation of adipose biology and provide a mechanism of tissue crosstalk in obesity and other hyperinsulinemic states.
组织通过小细胞外囊泡（sEVs）释放 microRNAs（miRNAs），包括外泌体，它们可以调节远端细胞中的基因表达，从而作为局部和全身代谢的调节剂。在这里，我们表明胰岛素调节 3T3-L1 脂肪细胞中 miRNA 分泌到 sEVs 中，并且该过程与细胞表达的调节不同。因此，在胰岛素上调的 53 个 miRNA 和下调的 66 个 miRNA 中，只有 12 个在细胞中平行调节。胰岛素通过磷酸化 hnRNPA1 来调节这个过程，使其与 miRNA 中的富含 AU 的基序结合，将其分泌到 sEVs 中。重要的是，43%的胰岛素调节的 sEV-miRNAs 与肥胖和胰岛素抵抗有关。其中包括 let-7 和 miR-103，我们表明它们可以调节 AML12 肝细胞中的胰岛素信号。总之，这些发现表明胰岛素调节脂肪生物学的一个重要层次，并为肥胖和其他高胰岛素血症状态下的组织串扰提供了一种机制。
