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.
Insulin resistance and impaired energy metabolism are central defects in type 2 diabetes mellitus affecting nearly 100 million children and adults in the U.S. Insulin sensitivity is improvd by enhancing energy metabolism in subcutaneous fat. Our research will establish the therapeutic potential of a novel microRNA that enhances insulin sensitivity by augmenting the function of subcutaneous fat
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