miR-31 as critical regulator of adipogenesis and insulin signaling in white adipose tissue

Background:

Obesity and T2D arise from the interplay between genetic, epigenetic, and environmental factors. In recent studies we generated a backcross population of lean B6 and obese NZO mice to determine quantitative trait loci (QTL) for obesity and diabetes. In parallel, we detected a high number of differently expressed genes (DEG) by micro array analysis of mouse strains. As most of the DEGs were located outside of QTL we hypothesized that other regulatory elements such as miRNAs must be responsible for these effects.

Methods:

A computational framework (miR-QTL-Scan) was developed by combining QTL, miRNA target prediction, and transcriptomics for the discovery of miRNAs as regulative elements responsible for QTL.

Results:

miR-QTL-scan identified eleven miRNAs in obesity QTL, among these miR-31. According to target prediction miR-31 interacts with more than 1,500 target genes of which 416 exhibited a differential expression in gWAT of B6 and NZO mice. In mice and humans, miR-31 levels were higher abundance in WAT of obese and diabetic subjects than in lean controls. These effects associated with a lower expression of 10 potential target genes involved in insulin signaling and adipogenesis. Manipulation of miR-31 in human SGBS adipocytes affected the expression of the targets GLUT4, PPARγ, IRS1, and ACACA.

Conclusion:

Thus, miR-QTL-Scan allowed the identification of novel non-coding RNAs in metabolic diseases. Further on we could confirm the role of miR-31 in adipogenesis and insulin signaling was confirmed by its manipulation in adipocytes.