New developments in microRNAs and metabolism: biomarkers and adipokines

Biogenesis

Metabolic syndrome and Type II diabetes (T2D) are major diseases with a wide impact; metabolic syndrome increased in prevalence in the United States from the period of 1988–1994 to the period of 2007–2012 by greater than 35% (1), while diabetes was the 7th leading cause of death in the US in 2013. 90–95% of all diabetes cases are Type II (2). microRNAs, small noncoding RNAs that regulate gene expression, are well-known to be involved in metabolism, and a full understanding of their impact on gene expression and their presence as biomarkers has great potential in translational research for metabolic disorders. What do we currently know about microRNA in metabolic disorders, and how can we discover their full effects?

Multiple recent studies have explored the potential of microRNA biomarkers in diabetes and metabolic disease. One promising candidate is also a known modulator of metabolism, miR-122. A recent study by Willeit and colleagues revealed that circulating miR-122 had a positive association with both metabolic syndrome and Type II diabetes in biobanked human samples, and inhibiting it in mice led to lower circulating cholesterol, as well as alteration in levels of lipid metabolism proteins in the liver (3–4).

Other studies have looked at specific complications, such as patients with Type II diabetic nephropathy. Al-Kafaji and colleagues, noting existing reports of an association of miR-126 with T2D and diabetic nephropathy (DN), showed that circulating miR-126 levels were lower in individuals with T2D, and even more so in individuals with DN. In peripheral blood, miR-126 was effective at distinguishing DN from T2D, and DN from non-diabetic controls (5).

A meta-analysis by Villard et al., conducted via PubMed, sought to identify differentially expressed miRNA in the blood of T2D individuals, obese indivduals, or both that were noted in two separate studies as being altered, and in the same direction. They identified 10 in T2D blood, 6 that increased and 4 that decreased. These included miR-320a, miR-142-3p, miR-222, miR-29a, miR-27a and miR-375 on the “increased” side, and miR-197, miR-20b, miR-17 and miR-652 among those that decreased in T2D individuals. In blood from obese individuals, miR-142-3p, miR-140-5p and miR-222 increased, while miR-21-5p, miR-221-3p, miR-125-5p and miR103-5p decreased. From these lists, miR-142-3p and miR-222 were increased in both conditions (6).

While not directly related to biomarker discovery, another interesting development has recently taken place with regard to microRNAs in metabolism; specifically, the discovery that circulating exosomal miRNAs released from adipocytes can modulate gene expression in distant locations, acting in a way as adipokines. miRNAs are stable in circulation due to their association with proteins like Ago2 or HDL, or by being carried in exosomes released by other cells. Thomou and colleagues explored the role of adipose tissue miRNAs by specifically deleting Dicer, a miRNA-processing enzyme, from the adipose tissue.

The team found that adipose tissue is a major source of exosomal miRNAs in mice (the knockout mice had decreases in 419 miRNAs and increases in only 3), and to a lesser extent, to total serum miRNA as well. Glucose tolerance was reduced and insulin resistance increased in the knockout mice, which could only be partially ameliorated by transplantation of normal brown adipose tissue (BAT). Further investigation showed potential regulation of Fgf21 in the liver by exosome-delivered miRNA, and then provided evidence via 2 reporter systems, using BAT-specific expression of a human miRNA and liver-specific expression of its 3’ UTR reporter, that exosomal miRNAs from adipose tissue were able to affect gene expression in the liver. In this way, exosomal miRNAs from fat tissue could be considered novel adipokines, influencing distant gene expression (7).

What’s the best way to discover microRNA biomarkers? microRNA sequencing enables quick profiling of the whole miRNome from high numbers of samples, as well as the potential for novel miRNA discovery, and the new QIAseq miRNA Library Kit incorporates Unique Molecular Index technology for accurate quantification. The low sample input requirement also means that it’s optimal for the sample types most frequently tested for biomarkers, such as biofluids.

Want to learn more? Join our 2-part webinar series in July! Our microRNA expert Jonathan Shaffer, Ph.D. will discuss microRNA sequencing technology in Part I, and in Part II he will explore miRNA-seq in biofluids for liquid biopsy.

Watch the recordings:

Part 1: Introduction to miRNA-seq using unique molecular indices and gel-free library construction

 

Part 2: miRNA-seq from liquid biopsy: robust detection from the lowest sample amounts

 

References:

  1. 1. Metabolic Syndrome Prevalence by Race/Ethnicity and Sex in the United States, National Health and Nutrition Examination Survey, 1988–2012. CDC Original Research 14, March 16 2017. Link
  2. 2. Chronic Disease Prevention and health Promotion, At A Glance Fact Sheet, Diabetes. Link
  3. 3. Dumas, M-E. and Emanueli, C. (2017) Circulating microRNAs to predict the risk for metabolic diseases in the general population? Diabetes 66, 565. Link
  4. 4. Willeit, P. et al. (2016) Circulating microRNA-122 is associated with the risk of new-onset metabolic syndrome and Type-2-diabetes. Diabetes 66, 247. Link
  5. 5. Al-Kafaji, G., Al-Mahroos, G., Al-Muhtaresh, H.A., Skrypnyk, C., Sabry, M.A., and Ramadan, A.R. (2016) Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: a potential blood-based biomarker. Exp. Ther. Med. 12, 815. Link
  6. 6. Villard, A., Marchand, L., Thivolet, C., and Rome, S. (2015) Diagnostic value of cell-free circulating microRNAs for obesity and Type II diabetes: a meta-analysis. J. Mol. Biomark. Diagn. 6, 251. Link
  7. 7. Thomou, T. et al. (2017) Adipose-derived circulation miRNAs regulate gene expression in other tissues. Nature 542, 450. Link
Ali Bierly

Ali Bierly, PhD is a Global Market Manager in Translational Sciences at QIAGEN, and has written on a number of scientific topics in the biotech industry as the author of QIAGEN's Reviews Online. She received her PhD from Cornell University in 2009, studying the immune response to a protozoan parasite, Toxoplasma gondii. Ali has a keen interest in the emerging importance of microRNA and other circulating nucleic acids as biomarkers for disease.

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