Estrogen-driven control of diabetogenic gene networks is associated with reduced levels of miR-224/452 circulating in extracellular vesicles [miRNA-Seq]

Women with diabetes have a higher prevalence of cardiovascular complications than men, suggesting that sex-steroid hormones like estrogen may impact on female health in diabetes. Here we demonstrate that estrogen suppletion and insulin resistance in male-to-female transgenders coincides with lower plasma levels of miR-224 and miR-452 carried in extracellular vesicles. Systemic silencing of miR-224 and miR-452 in mice triggered a prediabetic phenotype with higher plasma insulin levels, increased white adipose lipogenesis and less glucose uptake and mitochondrial respiration in brown adipose tissue. Consistent with a prediabetic metabolic state, RNA sequencing demonstrated differential expression of genes involved in lipogenesis in white adipose tissue and mitochondrial respiration and glucose uptake in brown adipose tissue. In vitro studies confirmed the estrogen-dependent lowering of miR-224 (brown adipocytes) and miR-452 (white adipocytes) and their impact on adipocyte-specific metabolic processes. Collectively, we identified novel estrogen-driven, post-transcriptional networks that could drive the progression to insulin resistance in transwomen and provide potential anti-diabetic therapeutic targets in women. Total RNA obtained from plasma of male-to-female-transgenders