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Gottmann, P.* ; Ouni, M.* ; Sausenthaler, S.* ; Roos, J.* ; Stirm, L. ; Jähnert, M.* ; Kamitz, A.* ; Hallahan, N.* ; Jonas, W.* ; Fritsche, A. ; Häring, H.-U. ; Staiger, H. ; Blüher, M.* ; Fischer-Posovszky, P.* ; Vogel, H.* ; Schürmann, A.*

A computational biology approach of a genome-wide screen connected miRNAs to obesity and type 2 diabetes.

Mol. Metab. 11, 145-159 (2018)

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Objective: Obesity and type 2 diabetes (T2D) arise from the interplay between genetic, epigenetic, and environmental factors. The aim of this study was to combine bioinformatics and functional studies to identify miRNAs that contribute to obesity and T2D.Methods: A computational framework (miR-QTL-Scan) was applied by combining QTL, miRNA prediction, and transcriptomics in order to enhance the power for the discovery of miRNAs as regulative elements. Expression of several miRNAs was analyzed in human adipose tissue and blood cells and miR-31 was manipulated in a human fat cell line.Results: In 17 partially overlapping QTL for obesity and T2D 170 miRNAs were identified. Four miRNAs (miR-15b, miR-30b, miR-31, miR-744) were recognized in gWAT (gonadal white adipose tissue) and six (miR-491, miR-455, miR-423-5p, miR-132-3p, miR-365-3p, miR-30b) in BAT (brown adipose tissue). To provide direct functional evidence for the achievement of the miR-QTL-Scan, miR-31 located in the obesity QTL Nob6 was experimentally analyzed. Its expression was higher in gWAT of obese and diabetic mice and humans than of lean controls. Accordingly, 10 potential target genes involved in insulin signaling and adipogenesis were suppressed. Manipulation of miR-31 in human SGBS adipocytes affected the expression of GLUT4, PPARg, IRS1, and ACACA. In human peripheral blood mononuclear cells (PBMC) miR-15b levels were correlated to baseline blood glucose concentrations and might be an indicator for diabetes.Conclusion: Thus, miR-QTL-Scan allowed the identification of novel miRNAs relevant for obesity and T2D.

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