Strain, Diet, and Gender Influence the Role of miR155 in Diabetes Mellitus.

Sir,

An integrated view of genetic background, gender, and the tissues studied is essential to decipher the role of miR155 in diabetes mellitus.

MicroRNAs (miRNAs) are increasingly being discovered to mediate several physiological and pathological processes. miRNAs are secreted in vesicles in exosomes and are thought to have paracrine or endocrine effects by suppressing the expression of genes in different tissues. One of the miRNAs, namely miR155, has been extensively studied in immunological and metabolic diseases. miR155 has been shown to be expressed in immune cells and other tissues including adipose tissue and are thought to be involved in several diseases including diabetes mellitus.[123]miR155 regulates a number of genes involved in adipogenesis and those involved in carbohydrate and lipid metabolism.[2]Adipocyte-derived miR155 has been demonstrated to take part in the polarization of M1 macrophages and influence diet-induced obesity.[4]In this article, we analyze the role of miR155 in mediating insulin resistance, nonalcoholic steatohepatitis, and diabetes in studies done in mice. Two studies have analyzed the role of miR155 in diet-induced obesity and hepatic steatosis in C57BL/6 strain.[56]Miller et al. found that miR155 knockout mice in C57BL/6 background developed increased hepatic steatosis in comparison to wild-type mice when they were fed high-fat diet.[5]This study was done only in male mice. Another study by Gaudet et al. reported that miR155 knockout female mice in C57BL/6 background were protected from high-fat diet-induced obesity but not male mice.[6]In addition, they also showed that there was less increase in white adipose tissue weight in both male and female mice fed high-fat diet. With respect to glucose metabolism, it was found that female mice with miR155 knockout had improved responses. There was no such improvement noticed in male mice with miR155 knockout in both these studies. It can be summarized from these two studies that in C57BL/6 strain, knockout of miR155 in female mice is associated with protection from obesity and dysfunctional glucose metabolism, a decrease in adipose tissue weight in both male and female miR155 knockout mice, and increased liver steatosis in male miR155 knockout mice. These findings highlight the differential role of miR155 in different gender and tissues analyzed in this particular strain. Similar results have been reported in another recent study done in this strain.[7]

In another recent study, Ying et al. explored the miRNAs secreted by adipose tissue macrophages and found that miR155 expression was higher in exosomes from obese mice in comparison to lean mice.[8]They further demonstrated that administration of exosomes from obese mice to lean mice made them insulin resistant by affecting the signaling in muscle, liver, and adipose tissue. In contrast, exosomes from lean mice were protective when administered to obese mice and improved insulin resistance. The same authors studied the effect of high-fat diet in miR155 knockout animals (in C57BL/6 background) and found that insulin sensitivity was better among these mice compared to control mice fed with high-fat diet. This is in stark contrast to another report where the authors found that the deficiency of miR155 led to hyperglycemia and insulin resistance compared to wild-type mice.[9]However, these mice were not fed with high-fat diet. These authors also studied the effects of overexpression of miR155 on insulin resistance and found that global transgenic overexpression of miR155 led to improvement in insulin sensitivity and glucose tolerance. However, this study was done in FVB/N strain which is different in immunological responses as well as susceptibility to diet-induced obesity than C57BL/6 strain. They also found that overexpression of miR155 led to improved insulin signaling in liver, muscle, and adipose tissue, contrary to the findings of Ying et al.[8]These findings highlight the importance of the influence of genetic background in metabolic studies.

The comparative analysis of studies reporting on the role of miR155 in metabolic diseases presented in this article suggests the importance of considering the influence of background strain, gender of mice, and the tissues analyzed in various studies.[10]It is, therefore, important that the findings are interpreted by considering these variables [Figure 1] which may influence outcomes in these types of studies to have an impact on translational medicine.

Figure 1

Factors affecting the levels of miR155 in serum and tissues and their role in the causation of insulin resistance and diabetes mellitus can be influenced by a concerted action of strain, diet, and gender. Dotted lines represent the effects mediated through changes in miR155 levels

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