MiR-155 Enhances Insulin Sensitivity by Coordinated Regulation of Multiple Genes in Mice

Abstract

miR-155 plays critical roles in numerous physiological and pathological processes, however, its function in the regulation of blood glucose homeostasis and insulin sensitivity and underlying mechanisms remain unknown. Here, we reveal that miR-155 levels are downregulated in serum from type 2 diabetes (T2D) patients, suggesting that miR-155 might be involved in blood glucose control and diabetes. Gain-of-function and loss-of-function studies in mice demonstrate that miR-155 has no effects on the pancreatic β-cell proliferation and function. Global transgenic overexpression of miR-155 in mice leads to hypoglycaemia, improved glucose tolerance and insulin sensitivity. Conversely, miR-155 deficiency in mice causes hyperglycemia, impaired glucose tolerance and insulin resistance. In addition, consistent with a positive regulatory role of miR-155 in glucose metabolism, miR-155 positively modulates glucose uptake in all cell types examined, while mice overexpressing miR-155 transgene show enhanced glycolysis, and insulin-stimulated AKT and IRS-1 phosphorylation in liver, adipose tissue or skeletal muscle. Furthermore, we reveal these aforementioned phenomena occur, at least partially, through miR-155-mediated repression of important negative regulators (i.e. C/EBPβ, HDAC4 and SOCS1) of insulin signaling. Taken together, these findings demonstrate, for the first time, that miR-155 is a positive regulator of insulin sensitivity with potential applications for diabetes treatment.

MiRNAs Regulating Insulin Sensitivity Are Dysregulated in Polycystic Ovary Syndrome (PCOS) Ovaries and Are Associated With Markers of Inflammation and Insulin Sensitivity

“…MiR-155 has a well-documented role in autoimmune and other chronic inflammatory diseases (28)(29)(30)(31). Furthermore, miR-155 has been demonstrated to regulate insulin sensitivity in vitro (32) and in vivo in mice (32,33). MiR-320 is currently considered as a potential target for type 2 diabetes mellitus therapy (34,35) since it regulates the expression of phosphoinositide-3-kinase (PI3K), a downstream mediator of insulin signaling.…”

miR155 deficiency aggravates high-fat diet-induced adipose tissue fibrosis in male mice

“…Furthermore, our results, as well as those of Gaudet et al (2016), suggest that miR155 deficiency in a male mouse model exposed to an HFD results in similar degree of impaired glucose metabolism and insulin resistance as WT HFD-fed mice. Lin et al (2016), however, found that miR155 deletion in male mice resulted in poorer glucose metabolism and greater insulin resistance than WT controls.…”

“…Lin et al. (), however, found that miR155 deletion in male mice resulted in poorer glucose metabolism and greater insulin resistance than WT controls.…”

“…(), on the other hand, found that miR155 deficiency in female mice led to a similar body weight gain and body fat accumulation as WT‐HFD‐fed mice and Lin et al. () discovered that miR155 −/− female mice exposed to an HFD actually displayed impaired glucose metabolism and insulin signaling compared to WT HFD‐fed controls. There are many factors which may account for the discrepancies between studies.…”

“…For example, Gaudet et al (2016) found miR155 deficiency in female mice to be effective at preventing diet-induced obesity as characterized by decreased body weight gain, increased expression of adipogenic genes, blunting of adipose tissue inflammation, and improved insulin sensitivity. Virtue et al (2016), on the other hand, found that miR155 deficiency in female mice led to a similar body weight gain and body fat accumulation as WT-HFD-fed mice and Lin et al (2016) discovered that miR155 À/À female mice exposed to an HFD actually displayed impaired glucose metabolism and insulin signaling compared to WT HFD-fed controls. There are many factors which may account for the discrepancies between studies.…”