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

Abstract

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.

Endothelial FoxO proteins impair insulin sensitivity and restrain muscle angiogenesis in response to a high‐fat diet

“…However, enrichment in genes associated with M2 polarization was detected in HF-fed FoxO D compared to FoxO L/L muscles, suggesting that M2 polarization underlies the inhibition of inflammation. This shift in macrophage phenotype may occur as a consequence of FoxO-dependent changes in endothelial cell behavior, similar to the recent report that prevention of endothelial cell dysfunction promoted an M2 phenotype within local tissue-resident macrophages (35).…”

The Good Neighbor

“…Sun et al 19 also observed a reduction in macrophage infiltration into adipose tissue and a preferential polarization of adipose tissue macrophages to an M2 subtype in mice treated with miR-181b. While the reduced macrophage infiltration may be directly related to lower EC activation, it was not clear how altered EC activation could influence the polarization of infiltrated and resident macrophages in the adipose tissue.…”

“…In summary, the study by Sun et al 19 demonstrated that miR-181b expression decreases early in a diet-induced obesity animal model. This reduction results in increased PHLPP2 expression, EC activation and immune cell infiltration, as well as decreased Akt phosphorylation.…”

“…In earlier reports, the miR-181b was shown to ameliorate NFκB activation in ECs in response to atherosclerosis 18 . In this issue of Circulation Research , Sun et al 19 demonstrated a different role for miR-181b in adipose tissue ECs in the pathogenesis of diet-induced IR (Figure). They first showed that miR-181b is the predominant member of miR-181 family in adipose tissue ECs and its expression is significantly reduced early after the initiation of high-fat diet (HFD).…”

“…It was clear from the study by Sun et al 19 that EC activation is closely linked to increased macrophage infiltration and adipose tissue inflammation. However, the extent to which EC dysfunction and altered insulin sensitivity of adipocytes, independent of inflammation, contributes to the development of systemic IR remains unknown.…”