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Circ Res:增加miR-181b水平或可抵抗肥胖和糖尿病

来源:生物谷 2016-03-17 10:09

2016年3月17日/生物谷BIOON/--肥胖与低水平炎症相关联,它在糖尿病和心血管疾病产生中发挥着重要作用。尽管包括脂肪组织在内的几种组织与炎症过程相关联,但是促进这种过程的细胞类型和因子仍不清楚。在一项新的研究中,来自美国布莱根妇女医院的研究人员利用一种临床前肥胖症模型开展研究,发现一种小片段的被称作miR-181b的非编码RNA分子通过控制脂肪组织中的血管功能而在肥胖诱导的脂肪组织变化中发挥着重要的决定性作用。这些发现可能指出一种新的靶标用于开发治疗肥胖症和糖尿病的方法。相关研究结果2016年3月4日那期Circulation Research期刊上,论文标题为“MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue”。

研究人员鉴定出仅仅在一周时间给小鼠喂食高脂肪食物,miR-181b在脂肪组织内皮细胞而不是脂肪细胞中表达较低。他们猜测在肥胖小鼠体内还原这种microRNA水平可能阻止胰岛素耐受性/糖尿病产生。确实,他们发现将一种miR-181b类似物注射进肥胖小鼠体内显著性地改善胰岛素敏感性、葡萄糖水平和降低脂肪组织中的炎症。

研究人员发现蛋白磷酸酶PHLPP2是miR-181b的直接作用靶标,而且抑制这种蛋白也会改善小鼠体内的胰岛素敏感性、葡萄糖水平,并降低炎症,从而提供另一种新的治疗靶标。

最后,研究人员注意到相比于健康人,来自糖尿病病人脂肪组织内皮细胞中的PHLPP2水平更高,这提示着这些在小鼠体内获得的新发现也与人类疾病相关联。

论文通信作者、布莱根妇女医院副主任医师Mark W. Feinberg说,“我们发现一种microRNA的功能在于它通过靶向脂肪组织周围的内皮细胞和一种导致一氧化氮水平增加的途径,从而削弱脂肪组织血管系统中的炎症反应。这种microRNA的有益作用可能是冰山一角,这是因为在一系列慢性炎症中,过度炎症是一种普遍的现象。”(生物谷 Bioon.com)

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MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose TissueNovelty and Significance

doi:10.1161/CIRCRESAHA.115.308166

Rationale: The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function.

Objective: To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity.

Methods and Results: MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b’s effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression.

Conclusions: Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or Pleckstrin homology domain leucine-rich repeat protein phosphatase inhibitors may represent a new therapeutic approach to ameliorate insulin resistance by improving adipose tissue endothelial Akt–endothelial nitric oxide synthase–nitric oxide signaling.

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