Circulating miRNA signatures reveal metabolic dysfunction beyond obesity

To identify circulating microRNA (miRNA) signatures associated with metabolic health status independent of body mass index (BMI) and to characterize their underlying regulatory pathways. Plasma samples from 240 Qatari adults were classified as metabolically healthy people with obesity (MHO), metabolically unhealthy people with obesity (MUHO), metabolically healthy normal-weight (MHNW), or metabolically unhealthy normal-weight (MUHNW) (n = 60/group). Differential miRNA expression was assessed using chemometric analyses, followed by target-gene and pathway enrichment analyses. Distinct circulating miRNA profiles differentiated metabolic phenotypes. Key miRNAs distinguishing MHO from MUHO included hsa-miR-122-5p, hsa-miR-195-5p, among others, differentiated MHNW from MUHNW. Predicted targets of MUHO-associated miRNAs were enriched in pathways related to lipid metabolism, insulin signaling, inflammation, oxidative stress, and apoptosis. In contrast, MUHNW-associated miRNAs were linked to immune regulation, inflammatory signaling, leukocyte migration, and lipid transport. Several miRNAs and miRNA ratios showed strong discriminatory performance across metabolic phenotypes. Circulating miRNA signatures distinguish metabolic health phenotypes independent of BMI and highlight distinct molecular pathways associated with metabolic dysfunction in people with obesity and normal weight.