Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, India
Academy of Scientific and Innovative Research, CSIR-CDRI, Lucknow, India
J Endocrinol. 2018 Oct 1;239(1):1–17. doi: 10.1530/JOE-17-0387.
miRNA has been known to regulate diverse cellular and molecular functions. In the earlier study, we have reported that adipocytes differentiated from human mesenchymal stem cells (hMSC) on 72-h chronic insulin (CI) treatment exhibit insulin resistance (IR). Present study has further explored above model to investigate the role of early expressed miRNAs within human adipocytes to modulate differential adipokine expression as observed during IR. Our results highlight that miR-876-3p regulate glucose homeostasis and its dysregulation leads to IR. We found that miR-876-3p level is a critical determinant of adiponectin expression by virtue of its target within adiponectin 3′UTR. Regulatory effect of miR-876-3p impacts crosstalk between adiponectin and insulin signaling. Rosiglitazone treatment in CI-induced IR adipocytes drastically reduced miR-876-3p expression and increased adiponectin level. In line with this, lentiviral-mediated inhibition of miR-876-3p expression ameliorated CI and high-fat diet (HFD)-induced IR in adipocytes differentiated from hMSC and C57BL/6 mice, respectively. Our findings thus suggest that modulating miR-876-3p expression could provide novel opportunities for therapeutic intervention of obesity-associated metabolic syndrome.
miRNA 已被证实可调节多种细胞和分子功能。在早期研究中，我们已经报告称，在慢性胰岛素（CI）处理 72 小时后，从人间质干细胞（hMSC）分化而来的脂肪细胞表现出胰岛素抵抗（IR）。本研究进一步探索了上述模型，以研究在 IR 期间观察到的人脂肪细胞中早期表达的 miRNA 对调节差异脂肪因子表达的作用。我们的结果强调了 miR-876-3p 对葡萄糖稳态的调节作用，其失调导致 IR。我们发现，miR-876-3p 水平是通过其在脂联素 3'UTR 中的靶标来调节脂联素表达的关键决定因素。miR-876-3p 的调节作用影响脂联素和胰岛素信号之间的串扰。在 CI 诱导的 IR 脂肪细胞中，罗格列酮治疗可显著降低 miR-876-3p 的表达并增加脂联素水平。与此一致，慢病毒介导的 miR-876-3p 表达抑制分别改善了 hMSC 和 C57BL/6 小鼠来源的脂肪细胞中 CI 和高脂肪饮食（HFD）诱导的 IR。因此，我们的研究结果表明，调节 miR-876-3p 的表达可能为肥胖相关代谢综合征的治疗干预提供新的机会。
