Altered Expression of miR-181a-5p and miR-23a-3p Is Associated With Obesity and TNFα-Induced Insulin Resistance
Altered Expression of miR-181a-5p and miR-23a-3p Is Associated With Obesity and TNFα-Induced Insulin Resistance
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DOI：
10.1210/jc.2017-01909
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发表时间：
2018-04-01
影响因子：
5.8
通讯作者：
Chacon, Matilde R.
中科院分区：
文献类型：
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作者：
Lozano-Bartolome, Javier;Llaurado, Gemma;Chacon, Matilde R.
背景：促炎细胞因子TNF α是胰岛素抵抗（IR）的关键参与者。目的：研究肥胖者中miR-181 a-5 p和miR-23 a-3 p的表达谱，并研究它们在脂肪细胞中TNF α诱导的IR中的作用。队列1用于脂肪组织（AT）表达研究，包括28名体重指数（BMI）≥ 30 kg/m2的受试者（2）。队列2用于循环血清miRNA研究，包括101名随访4年的受试者（48名病例受试者和53名对照受试者）。在皮下和内脏AT中评估miR-181 a-5 p和miR-23 a-3 p表达。使用miRNA模拟物和抑制剂在脂肪细胞中进行功能分析。胰岛素途径的关键分子AKT，PTEN，AS 160和S6K.Results：miR-181 a-5 p和miR-23 a-3 p的表达在肥胖和糖尿病受试者的脂肪组织中减少，并且与肥胖和IR指数的稳态模型评估呈负相关。在脂肪细胞中过表达miR-181 a-5 p和miR-23 a-3 p上调胰岛素刺激的AKT活化，降低TNF α诱导的IR，调节PTEN和S6 K表达。基线时，病例组与对照组受试者的血清miR-181 a-5 p水平降低，提示其具有预后价值。结论：miR-181 a-5 p和miR-23 a-3 p可能通过调节PTEN和S6 K的表达，抑制TNF α诱导的脂肪细胞IR。
Context: The proinflammatory cytokine TNFa is a key player in insulin resistance (IR). The role of miRNAs in inflammation associated with IR is poorly understood.Objective: To investigate miR-181a-5p and miR-23a-3p expression profiles in obesity and to study their role in TNF alpha-induced IR in adipocytes.Design: 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/m(2). 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.Results: 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 TNFa-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.Conclusion: miR-181a-5p and miR-23a-3p may prevent TNFa-induced IR in adipocytes through modulation of PTEN and S6K expression.