Regulation of SYSTEMIC INSULIN SENSITIVITY by miRNA-30a



 DESCRIPTION (provided by applicant): Insulin resistance and type 2 diabetes are predicted to affect 33% of the US population by 2050. Type 2 diabetes reflects the inability to store surplus energy derived from calories in fat cells. Obese fat displays a pro-inflammatory phenotype, which is partly responsible for the metabolic dysfunction and insulin resistance that precedes type 2 diabetes. Recent work challenges the idea that the all immune response is deleterious to adipose tissue. In particular, regulatory T cells (Tregs) counteract the proinflammatory response in adipose tissue to potentiate insulin sensitivity. We have discovered that overexpression of the microRNA miR-30a in subcutaneous adipose tissue of diabetic mice promotes insulin sensitivity. Through the use of RNA-seq and flow cytometry, we observed that the metabolic effects of miR-30a overexpression in subcutaneous adipose tissue are associated with increased recruitment of Tregs, which suppress local inflammation. In addition, we found that expression of miR-30a and the master controller of Treg function, Foxp3, are reduced in subcutaneous adipose tissue from insulin resistant compared to insulin sensitive human subjects. We hypothesize miR-30a promotes insulin sensitivity by stimulating the function of Tregs in subcutaneous adipose tissue. Two specific aims are proposed to critically test our hypothesis: (1) determine the role of Tregs in mediating anti-diabetic effects of miR-30a; (2) determine how miR-30a affects Treg polarization. The rationale for the proposed research plan is that identifying the mechanism underlying the beneficial effects of miR-30a expression in subcutaneous adipose tissue will lead to therapeutic strategies to enhance metabolic flexibility in subcutaneous adipocytes and thereby prevent type 2 diabetes. If our hypothesis is true, miR-30a might be exploited in novel therapies to manage insulin resistance and type 2 diabetes. We anticipate that our studies will provide new clues into the complex regulatory networks controlling energy balance in subcutaneous adipose tissue.