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

作者：Xinghui Sun, Jibin Lin, Yu Zhang, Sona Kang, Nathan Belkin, Akm Khyrul Wara, Basak Icli, Naomi M. Hamburg, Dazhu Li, Mark W. Feinberg · 发表于：Circulation Research · 年份：2016 · DOI：10.1161/circresaha.115.308166 · 被引用次数：136 · 研究领域：Adipokines, Inflammation, and Metabolic Diseases、Adipose Tissue and Metabolism、MicroRNA in disease regulation

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 rep...