Adipose tissue-derived microRNAs as epigenetic modulators of type 2 diabetes

White adipose tissue (WAT) dysfunction along with an aberrant expression of miRNAs are strongly associated with the risk of developing type 2 diabetes (T2D) with limited evidence linking early changes in the WAT-derived miRNAs and T2D. The present study aims to identify early miRNome changes prognostic for T2D in mice and humans. Gonadal (g) WAT of diabetes-resistant and -prone mice were subjected to multi-omics analyses (transcriptome, miRNome, methylome, proteome). Metabolic phenotypes linked with T2D were correlated with adipose tissue miRNA expression and DNA methylation from 14 monozygotic twin pairs discordant for T2D. Plasma miRNA levels from females at high risk of developing T2D (TÜF study) were included. Adipose tissue of the diabetes-susceptible mice was less insulin sensitive with 150 differentially expressed miRNAs compared to diabetes-resistant mice. Integrative analysis of miRNome-transcriptome-proteome identified 61 proteins involved in actin cytoskeleton, amino acid and sphingolipid metabolism. More than 20 miRNAs are located in the imprinted region Dlk1-Gtl2 and miR-335 in Mest and regulated by DNA methylation. Imprinted miRNAs also exhibited similar alteration in monozygotic twin pairs discordant for T2D with miR-335 expression altered only in females. Moreover, plasma levels of miR-335-5p were negatively correlated with fasting blood glucose in female individuals at high risk of developing T2D. Early alterations of WAT-derived miRNAs such as miR-335-5p could contribute to systemic metabolic changes associated with the risk of developing T2D.