MicroRNAs as regulators of metabolic disease: pathophysiologic significance and emerging role as biomarkers and therapeutics

Abstract

The prevalence of overweight and obesity in developed and developing countries has greatly increased the risk of insulin resistance and type 2 diabetes mellitus. It is evident from human and animal studies that obesity alters microRNA (miRNA) expression in metabolically important organs, and that miRNAs are involved in changes to normal physiology, acting as mediators of disease. miRNAs regulate multiple pathways including insulin signaling, immune-mediated inflammation, adipokine expression, adipogenesis, lipid metabolism, and food intake regulation. Thus, miRNA-based therapeutics represent an innovative and attractive treatment modality, with non-human primate studies showing great promise. In addition, miRNA measures in plasma or bodily fluids may be used as disease biomarkers and predictors of metabolic disease in humans. This review analyzes the role of miRNAs in obesity and insulin resistance, focusing on the miR-17/92, miR-143-145, miR-130, let-7, miR-221/222, miR-200, miR-223, miR-29 and miR-375 families, as well as miRNA changes by relevant tissue (adipose, liver and skeletal muscle). Further, the current and future applications of miRNA-based therapeutics and diagnostics in metabolic disease are discussed.

Figure 1

microRNA biogenesis and ADAR-mediated editing during miRNA maturation. ADAR, family of adenosine deaminase; miRISC, miRNA-induced silencing complex.

Figure 2

Obesity/insulin resistance-related miRNA expression changes in humans and in murine models. miRNAs in red font were differentially expressed in human and murine obesity with arrow indicating up- or downregulation. Gene symbols or conventional gene synonyms are used to show miRNA–mRNA repression. Gene symbol in red font indicates conserved miRNA-targeting between species. The image is published with the permission of Mr Massimiliano Crespi, medical illustrator.