MicroRNAs in metabolism

Abstract

MicroRNAs (miRNAs) have within the past decade emerged as key regulators of metabolic homoeostasis. Major tissues in intermediary metabolism important during development of the metabolic syndrome, such as β-cells, liver, skeletal and heart muscle as well as adipose tissue, have all been shown to be affected by miRNAs. In the pancreatic β-cell, a number of miRNAs are important in maintaining the balance between differentiation and proliferation (miR-200 and miR-29 families) and insulin exocytosis in the differentiated state is controlled by miR-7, miR-375 and miR-335. MiR-33a and MiR-33b play crucial roles in cholesterol and lipid metabolism, whereas miR-103 and miR-107 regulates hepatic insulin sensitivity. In muscle tissue, a defined number of miRNAs (miR-1, miR-133, miR-206) control myofibre type switch and induce myogenic differentiation programmes. Similarly, in adipose tissue, a defined number of miRNAs control white to brown adipocyte conversion or differentiation (miR-365, miR-133, miR-455). The discovery of circulating miRNAs in exosomes emphasizes their importance as both endocrine signalling molecules and potentially disease markers. Their dysregulation in metabolic diseases, such as obesity, type 2 diabetes and atherosclerosis stresses their potential as therapeutic targets. This review emphasizes current ideas and controversies within miRNA research in metabolism.

Keywords: adipocytes; metabolism; microRNA; non-alcoholic hepato-steatosis; type 2 diabetes mellitus; β-cells.

Figure 1

The canonical miRNA biogenesis pathway (a) and the average precursor miRNA (b). (a): The miRNA genes lies either intronic, intergenic or polycistronic. The primary miRNA (Pri‐miRNA) is transcribed by polymerase II (or polymerase III). The Pri‐miRNA is cleaved by the microprocessor complex Drosha‐DGCR8 in the nucleus. The precursor miRNA (pre‐miRNA) is transported out in the cytoplasm by Exportin 5. In the cytoplasm, the pre‐miRNA is further cleaved to its mature length (approx. 22 nt) by the RNase III Dicer in complex with the double‐stranded RNA‐binding protein TRBP. Argonaute (AGO2) proteins unwind the miRNA duplex and facilitate incorporation of the guide strand (red) into the RNA‐induced silencing complex (RISC). AGO2 then guides the RISC miRNA assembly to target mRNAs, whereas the passenger strand (blue) is degraded. Some miRNA bind mRNA with perfect complementarity and induce degradation of mRNA. miRNA also bind to targets with imperfect complementarity and block translation. (b): An average precursor miRNA with a hairpin stem of 33 base pairs, a terminal loop and two flanking region, where 5′ end are capped and a polyadenylated 3′ end.

Figure 2

(a) Translational aspects of miRNAs. For therapy, miRNAs may be used as antagonists (antagomiR) or agonists (microRNA mimics). Specific methods, such as next‐generation sequencing of small RNAs and qPCR‐based miRNA arrays are used to identify possible miRNA biomarkers from patient specimens, but may also be used to monitor therapeutic effects or unintended side effects by treatment. Integral to the translational use of miRNAs are improved and consistent data analysis strategies of qPCR results with special focus on using optimal data normalization and identification of proper reference genes or miRNAs. For these purposes, current techniques and analysis strategies need to be adjusted and optimized. The figure was assembled with the help of Servier Medical Art (http://www.servier.com/Powerpoint-image-bank). (b) Table of Web‐tools commonly used for prediction of miRNA‐target mRNAs.