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

Background 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 have been implicated as mediators of this phenomenon. This study aimed to investigate whether the expression of genes critical for both insulin action and neuronal metabolism (APP, SOCS3, PTPN1, PTPN2) correlates with levels of targeting them microRNAs in adipose tissue of patients with obesity, predisposing them to the development of metabolic inflammation and possibly cognitive decline. Methods The expression of mRNAs of the above-mentioned genes, selected adipokines (interleukins 1β, 6, 8, 15, tumor necrosis factor-alpha, resistin, adiponectin) and microRNAs 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. Results mRNA levels of genes promoting insulin sensitivity: APP and PTPN2, were significantly (p < 0.05) decreased in adipose tissue of obese patients, both in 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 obese diabetic patients compared to obese normoglycemic individuals, too. We also observed significant positive correlations between the mRNA levels of these genes and the expression of the above-mentioned adipokines. Finally, we analyzed the levels of microRNAs 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, while in the case of PTPN2, with hsa-miR-142-3p levels. Conclusion microRNAs may be involved in the regulation of insulin sensitivity in adipose tissue and may represent a therapeutic approach to mitigate the health effects of obesity and reduce the risk of its metabolic and possibly also neurological complications.