Negative correlation between microRNA and insulin sensitivity gene expression in adipose tissue: potential implications for diabetes and neurodegenerative diseases.

Obesity-related adipose tissue dysfunction leads to a chronic inflammatory state affecting distant organs and tissues. This metabolic inflammation has a detrimental impact on the expression of genes related to glucose metabolism, leading to systemic insulin resistance, which also affects the central nervous system and contributes to cognitive decline. Adipose tissue-derived microRNAs (miRNAs) have been implicated in this phenomenon. This study aimed to investigate whether the expression of genes critical for both insulin action and neuronal metabolism (APP, SOCS3, PTPN1, PTPN2) is altered in the adipose tissue of patients with obesity due to miRNA interference, predisposing them directly to the development of insulin resistance and metabolic inflammation, while indirectly leading to a decline in cognitive function. The expression of mRNAs of the above-mentioned genes, selected adipokines (interleukins 1β, 6, 8, 15, tumor necrosis factor-alpha, resistin, adiponectin) and miRNAs was measured by real-time PCR in adipose tissue of 75 patients with obesity, 19 patients who successfully reduced body mass after metabolic surgery and 25 normal weight subjects, stratified by insulin sensitivity and diabetic status. The results were correlated with patients' clinical and biochemical parameters. mRNA levels of genes promoting insulin sensitivity, APP and PTPN2, were significantly (p < 0.05) decreased in adipose tissue from patients with obesity, in both visceral (VAT) and subcutaneous (SAT) depots. After stratification by the triglyceride/high-density lipoprotein ratio (an indirect marker of insulin sensitivity), we found that individuals diagnosed with insulin resistance had lower VAT and SAT APP and PTPN2 mRNA levels, whereas APP expression was significantly decreased in VAT from patients with both obesity and type 2 diabetes compared to normoglycemic individuals with obesity, too. We also observed significant positive correlations between the mRNA levels of these genes and the expression of the above-mentioned adipokines. Finally, we analysed the levels of miRNAs targeting the mRNAs of the genes studied and observed significant negative correlations between APP mRNA levels and hsa-miR-579-5p and hsa-miR-142-3p, and between PTPN2 mRNA levels and hsa-miR-142-3p. Adipose tissues of patients with obesity are characterised by altered expression of genes that are key for both insulin action and neuronal metabolism, and miRNAs may be involved in this phenomenon. However, due to the descriptive nature of our experiments, these results require verification in functional studies.