miRNA signatures of insulin resistance in obesity

OBJECTIVES: Extracellular microRNAs represent functional biomarkers for obesity and related disorders; we investigated plasma microRNAs in insulin resistance phenotypes in obesity. METHODS: 175 microRNA were analysed in females with (insulin sensitivity n=11; insulin resistance n=19; Type-II diabetes n=15) and without (n=12) obesity. Correlations between microRNA level and clinical parameters, and levels of 15 microRNA in a murine obesity model were investigated. RESULTS: 106 microRNA were significantly (adjusted P≤0.05) different between controls and at least one obesity phenotype, including microRNAs with: previously reported roles in obesity and altered circulating levels (e.g. miR-122, miR-192); known roles in obesity but no reported changes in circulating level (e.g. miR-378a); no current reported role in, or association, with obesity (e.g. miR-28-5p, miR-374b, miR-32). miRNA in the latter group were found to be associated with extracellular vesicles. 48 microRNA showed significant correlations with clinical parameters; stepwise regression retained let-7b, miR-144-5p, miR-34a, and miR-532-5p in a model predictive of insulin resistance (R(2) = 0.57, P=7.5 × 10(-8)). miR-378a and miR-122 were perturbed in metabolically relevant tissues in a murine model of obesity. CONCLUSIONS: This study expands on the role of extracellular miRNA in insulin resistant phenotypes of obesity and identifies candidate miRNA not previously associated with obesity.