Joan XXIII University Hospital, IISPV, Tarragona, Spain.
Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Madrid, Spain.
J Clin Endocrinol Metab. 2018 Apr 1;103(4):1447-1458. doi: 10.1210/jc.2017-01909.
The proinflammatory cytokine TNFα is a key player in insulin resistance (IR). The role of miRNAs in inflammation associated with IR is poorly understood.
To investigate miR-181a-5p and miR-23a-3p expression profiles in obesity and to study their role in TNFα-induced IR in adipocytes.
Two separate cohorts were used. Cohort 1 was used in adipose tissue (AT) expression studies and included 28 subjects with body mass index (BMI) <30 kg/m2 and 30 with BMI ≥30 kg/m2. Cohort 2 was used in circulating serum miRNA studies and included 101 subjects with 4 years of follow-up (48 case subjects and 53 control subjects). miR-181a-5p and miR-23a-3p expression was assessed in subcutaneous and visceral AT. Functional analysis was performed in adipocytes, using miRNA mimics and inhibitors. Key molecules of the insulin pathway, AKT, PTEN, AS160, and S6K, were analyzed.
Expression of miR-181a-5p and miR-23a-3p was reduced in adipose tissue from obese and diabetic subjects and was inversely correlated to adiposity and homeostasis model assessment of IR index. Overexpression of miR-181a-5p and miR-23a-3p in adipocytes upregulated insulin-stimulated AKT activation and reduced TNFα-induced IR, regulating PTEN and S6K expression. Serum levels of miR-181a-5p were reduced in case vs control subjects at baseline, suggesting a prognostic value. Variable importance in projection scores revealed miR-181a-5p had more effect on the model than insulin or glucose at 120 minutes.
miR-181a-5p and miR-23a-3p may prevent TNFα-induced IR in adipocytes through modulation of PTEN and S6K expression.
促炎细胞因子 TNFα 是胰岛素抵抗（IR）的关键因素。miRNA 在与 IR 相关的炎症中的作用尚未完全阐明。
研究肥胖症中 miR-181a-5p 和 miR-23a-3p 的表达谱，并研究其在脂肪细胞中 TNFα 诱导的 IR 中的作用。
使用了两个独立的队列。队列 1 用于脂肪组织（AT）表达研究，包括 28 名 BMI<30kg/m2 的受试者和 30 名 BMI≥30kg/m2 的受试者。队列 2 用于循环血清 miRNA 研究，包括 101 名有 4 年随访的受试者（48 例病例组和 53 例对照组）。评估了皮下和内脏 AT 中 miR-181a-5p 和 miR-23a-3p 的表达。在脂肪细胞中进行了功能分析，使用 miRNA 模拟物和抑制剂。分析了胰岛素通路的关键分子 AKT、PTEN、AS160 和 S6K。
肥胖和糖尿病受试者的脂肪组织中 miR-181a-5p 和 miR-23a-3p 的表达降低，且与肥胖和胰岛素抵抗评估的稳态模型评估指数呈负相关。在脂肪细胞中过表达 miR-181a-5p 和 miR-23a-3p 可上调胰岛素刺激的 AKT 激活，并减少 TNFα 诱导的 IR，调节 PTEN 和 S6K 的表达。病例组受试者的血清 miR-181a-5p 水平在基线时低于对照组受试者，提示具有预后价值。投影分数的重要性表明，miR-181a-5p 在 120 分钟时对模型的影响比胰岛素或葡萄糖更大。
miR-181a-5p 和 miR-23a-3p 可能通过调节 PTEN 和 S6K 的表达来防止 TNFα 诱导的脂肪细胞中的 IR。
