Integrated miRNA – mRNA Analysis Reveals Obesity‐Driven Regulatory Networks in Human Visceral Adipose Tissue With and Without Type 2 Diabetes

AIMS: Obesity is characterised by pathological alterations in visceral white adipose tissue (vWAT) that may contribute to the development of type 2 diabetes (T2D). While microRNAs (miRNAs) are key post-transcriptional regulators, comprehensive human vWAT profiling across metabolic states remains limited. This study characterised vWAT miRNA expression in lean, obese and obese+T2D individuals to identify obesity-driven regulatory networks associated with metabolic dysfunction. METHODS: Deep miRNA sequencing was performed on vWAT samples from a discovery cohort comprising lean controls and individuals with obesity (with and without T2D). Findings were validated via RT-qPCR in an independent replication cohort. Differentially expressed miRNAs were bioinformatically integrated with matched mRNA transcriptomic data to construct putative functional regulatory associations and identify enriched pathways underlying metabolic impairment. RESULTS: The dominant transcriptomic signal was driven by obesity rather than T2D status, with substantial overlap between obese subgroups in principal component analyses. miR-141-3p, miR-200b-3p, miR-12 136 and miR-585-3p showed consistent differential expression associated with obesity. miR-141-3p and miR-200b-3p were upregulated and inversely associated with metabolic stress-related genes, including TF and FBXO32. Integrated miRNA-mRNA analyses revealed putative regulatory associations involving inflammation, lipid metabolism, insulin signalling and iron homeostasis. These associations were robust across progressive covariate adjustment models for age and sex. CONCLUSIONS: This study provides a comprehensive characterisation of the vWAT miRNA landscape predominantly shaped by obesity, with T2D contributing comparatively subtle additional variation. We identified putative miRNA-mRNA regulatory associations that may contribute to pathological adipose tissue dysfunction. These findings highlight candidate molecular regulators worthy of further functional investigation in the context of obesity and T2D.