MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue
Rationale: The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types including endothelial cells (ECs). Posttranscriptional 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 towards an M2 anti-inflammatory phenotype in epididymal white adipose tissue (eWAT). These effects were associated with increased eNOS and FoxO1 phosphorylation as well as nitric oxide activity in eWAT. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that PHLPP2, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of PHLPP2 increased Akt phosphorylation at Ser473 in ECs, and 'phenocopied' miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of eWAT in vivo. Finally, ECs from diabetic subjects exhibited increased PHLPP2 expression.
Conclusions: Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or PHLPP2 inhibitors may represent a new therapeutic approach to ameliorate insulin resistance by improving adipose tissue endothelial Akt-eNOS-NO signaling.
- Received December 12, 2015.
- Revision received January 5, 2016.
- Accepted January 6, 2016.