ABSTRACT
Poor diets and obesity are associated with inflammation and insulin resistance (IR), but the physiological regulation of insulin sensitivity (IS) is not completely understood. We report that miR-467, induced by elevated blood glucose levels, decreases inflammation and IR in a diet-induced IR model. In Western diet-fed mice, miR-467 antagonist injections increased IR compared to mice injected with a control oligonucleotide. In mice injected with the antagonist, we detected elevated blood glucose (143 vs 121.7 mg/dL); higher plasma insulin levels (98 vs 63 ng/mL); lower insulin sensitivity; increased adipocyte size; and increased recruitment of macrophages into adipose tissue and pancreas (by 47% in adipose tissue; 44% in pancreas), without increases in weight or lipoproteins and cholesterol levels.
Lack of miR-467 antagonist effects in Thbs1−/− mice (deficient in thrombospondin-1, TSP-1, a target of miR-467 that we have experimentally confirmed elsewhere) in response to the miR-467 antagonist suggested that TSP-1 mediates some effects of miR-467 in preventing IR. Not all effects by the miR-467 antagonist were abolished in Thbs1−/− mice and their macrophages, suggesting that miR-467 employs multiple targets in regulating inflammation and IR.
Our results demonstrate that miR-467 provides a physiological feedback to prevent inflammation and IR in response to dietary signals.