Regulation of SYSTEMIC INSULIN SENSITIVITY by miRNA-30a

 描述（由申请人提供）：预计到2050年，胰岛素抵抗和2型糖尿病将影响33%的美国人口。2型糖尿病反映了无法将来自卡路里的多余能量储存在脂肪细胞中。肥胖脂肪显示出促炎表型，这是2型糖尿病之前的代谢功能障碍和胰岛素抵抗的部分原因。最近的工作挑战了所有免疫反应对脂肪组织有害的想法。特别地，调节性T细胞（Tcells）抵消脂肪组织中的促炎反应以增强胰岛素敏感性。我们已经发现，在糖尿病小鼠皮下脂肪组织中microRNA miR-30 a的过表达促进胰岛素敏感性。通过使用RNA-seq和流式细胞术，我们观察到皮下脂肪组织中miR-30 a过表达的代谢效应与TGFAP的募集增加相关，TGFAP抑制局部炎症。此外，我们发现，与胰岛素敏感的人类受试者相比，胰岛素抵抗的皮下脂肪组织中miR-30 a和Treg功能的主控制器Foxp 3的表达减少。我们假设miR-30 a通过刺激皮下脂肪组织中TGFAP的功能来促进胰岛素敏感性。提出了两个具体的目标来严格检验我们的假设：（1）确定TcG在介导miR-30 a的抗糖尿病作用中的作用;（2）确定miR-30 a如何影响Treg极化。拟议研究计划的基本原理是，确定皮下脂肪组织中miR-30 a表达的有益作用的机制将导致治疗策略，以增强皮下脂肪细胞的代谢灵活性，从而预防2型糖尿病。如果我们的假设是正确的，那么miR-30 a可能会被用于治疗胰岛素抵抗和2型糖尿病的新疗法。我们期望我们的研究将为控制皮下脂肪组织能量平衡的复杂调控网络提供新的线索。

 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.