MicroRNAs in dysfunctional adipose tissue: cardiovascular implications

Abstract

In this review, we focus on the emerging role of microRNAs, non-coding RNAs that regulate gene expression and signaling pathways, in dysfunctional adipose tissue. We highlight current paradigms of microRNAs involved in adipose differentiation and function in depots such as white, brown, and beige adipose tissues and potential implications of microRNA dysregulation in human disease such as obesity, inflammation, microvasculature dysfunction, and related cardiovascular diseases. We highlight accumulating studies indicating that adipocyte-derived microRNAs may not only serve as biomarkers of cardiometabolic disease, but also may directly regulate gene expression of other tissues. Finally, we discuss the future prospects, challenges, and emerging strategies for microRNA delivery and targeting for therapeutic applications in cardiovascular disease states associated with adipocyte dysfunction.

Keywords: Adipocytes; Brown adipose tissue; MicroRNA; White adipose tissue.

Figure 1

Example of microRNAs involved in the differentiation of white, beige, and brown adipocytes. These microRNAs are involved in regulating adipocyte differentiation through effects on their targets that control expression of metabolic genes, inflammation, or insulin resistance. Activation of brown and/or beige adipocytes may contribute to favorable effects on energy expenditure, insulin resistance, and potentially cardiovascular remodeling. Solid lines with arrows followed by (+) indicate positive regulation of the indicated adipocyte differentiation pathway. Dashed lines followed by (+) or ( ++) indicate that the adipocyte differentiation pathway may be favorably implicated in regulating cardiovascular disease.

Figure 2

MiR-181b improves endothelial dysfunction, glucose homeostasis, and insulin sensitivity in white adipose tissue by binding to the 3’-UTR of the phosphatase PHLPP2 and reducing its expression. Consequently, decreased PHLPP2 improves insulin signaling with enhanced AKT and eNOS expression in eWAT. Abbreviations: IRS, insulin receptor substrate; PI3K, phosphoinositide 3-kinase; AKT, also known as protein kinase B; PHLPP2, pleckstrin homology domain leucine-rich repeat protein 2; pSer473, phosphorylation of serine residue 473 of AKT; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; FoxO, Forkhead box O; eWAT, epididymal white adipose tissue; EC, endothelial cells; M1, pro-inflammatory macrophages; M2, anti-inflammatory macrophages.