Metabolic Disease Biology Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam, India.
Computational Biophysics Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur 784028, Assam, India.
Biochem J. 2019 Aug 30;476(16):2371-2391. doi: 10.1042/BCJ20190251.
Saturated free fatty acid-induced adipocyte inflammation plays a pivotal role in implementing insulin resistance and type 2 diabetes. Recent reports suggest A adenosine receptor (AAR) could be an attractive choice to counteract adipocyte inflammation and insulin resistance. Thus, an effective AAR agonist devoid of any toxicity is highly appealing. Here, we report that indirubin-3'-monoxime (I3M), a derivative of the bisindole alkaloid indirubin, efficiently binds and activates AAR which leads to the attenuation of lipid-induced adipocyte inflammation and insulin resistance. Using a combination of virtual screening of potential anti-diabetic candidates and study on insulin-resistant model of 3T3-L1 adipocytes, we determined I3M through AAR activation markedly prevents lipid-induced impairment of the insulin signaling pathway in adipocytes without any toxic effects. While I3M restrains lipid-induced adipocyte inflammation by inhibiting NF-κB dependent pro-inflammatory cytokines expression, it also augments cAMP-mediated CREB activation and anti-inflammatory state in adipocytes. However, these attributes were compromised when cells were pretreated with the AAR antagonist, SCH 58261 or siRNA mediated knockdown of AAR. I3M, therefore, could be a valuable option to intervene adipocyte inflammation and thus showing promise for the management of insulin resistance and type 2 diabetes.
饱和游离脂肪酸诱导的脂肪细胞炎症在引发胰岛素抵抗和 2 型糖尿病中起着关键作用。最近的报告表明，A 腺苷受体（AAR）可能是对抗脂肪细胞炎症和胰岛素抵抗的一个有吸引力的选择。因此，一种没有任何毒性的有效 AAR 激动剂非常有吸引力。在这里，我们报告说，靛玉红-3'-单肟（I3M），双吲哚生物碱靛玉红的衍生物，能够有效地结合和激活 AAR，从而减轻脂质诱导的脂肪细胞炎症和胰岛素抵抗。我们通过虚拟筛选有潜力的抗糖尿病候选物和研究 3T3-L1 脂肪细胞胰岛素抵抗模型的结合，确定 I3M 通过激活 AAR 显著防止了脂肪细胞中脂质诱导的胰岛素信号通路损伤，而没有任何毒性作用。虽然 I3M 通过抑制 NF-κB 依赖性促炎细胞因子的表达来抑制脂质诱导的脂肪细胞炎症，但它也增强了脂肪细胞中环磷酸腺苷（cAMP）介导的 CREB 激活和抗炎状态。然而，当细胞用 AAR 拮抗剂 SCH 58261 预处理或用 AAR siRNA 介导的敲低时，这些特性就会受到损害。因此，I3M 可能是干预脂肪细胞炎症的一个有价值的选择，从而为胰岛素抵抗和 2 型糖尿病的治疗提供了希望。
