1747-P: MicroRNA-30a Exerts Antifibrotic Effects in Subcutaneous White Adipose Tissue to Preserve Insulin Sensitivity in Obesity Free

White adipose tissue (WAT) is an endocrine organ that dynamically expands and contracts to meet the metabolic demands of the organism. However, prolonged excessive caloric intake overwhelms WAT depots, resulting in peripheral fat deposition, systemic glucose dysregulation, tissue fibrosis, insulin resistance, and type 2 diabetes mellitus. The chronic triggers that degrade WAT function remain undefined, hindering the development of effective strategies to treat obesity and prevent its co-morbidities. We have identified a microRNA, miR-30a, that potently stimulates subcutaneous adipose tissue metabolic flexibility and enhances systemic insulin sensitivity. In follow-up studies, we created a genetically engineered mouse model to conclusively show miR-30a expression in white adipocytes is antidiabetic. Obese mice modified to express miR-30a at elevated levels in adipose tissues maintain insulin sensitivity coupled with reduced hepatic steatosis. Proteomic profiling indicated that miR-30a targets Plasminogen Activator Inhibitor-1 (PAI-1) to limit pro-fibrotic programs that would otherwise restrict subcutaneous WAT expansion and decrease insulin sensitivity. While visceral WAT depots remain a site of significant fibrosis in mice, subcutaneous WAT fibrosis is epidemiologically linked to metabolic disease risk in adult humans. In obese humans, miR-30a expression negatively correlates with PAI-1 levels in subcutaneous WAT, supporting an anti-fibrotic role for miR-30a that ultimately defends insulin sensitivity. Collectively, our observations linking miR-30a expression to insulin sensitivity suggest a new method that restores WAT homeostasis.