肥胖导致胰岛素抵抗，诱发Ⅱ型糖尿病；但约25%~40%的肥胖者代谢正常（MHO），不伴有胰岛素抵抗。Brd2作为转录调控因子，Brd2基因敲除的小鼠肥胖，但不发生胰岛素抵抗和Ⅱ型糖尿病，这与MHO情况相似。前期研究发现，Brd2能够促进脂肪细胞炎症反应，抑制胰岛素受体信号通路。因此Brd2可能在肥胖与胰岛素抵抗、Ⅱ型糖尿病发生中发挥重要作用。本课题拟开展以下研究：1）构建脂肪组织特异性Brd2过表达/沉默小鼠模型，研究Brd2对小鼠糖代谢、胰岛素敏感性的调控作用；2）在脂肪细胞中，研究Brd2对胰岛素信号通路、炎症反应等调节机制；3）构建Brd2蛋白结构域缺失突变体，揭示Brd2对上述信号通路及关键分子的调控机制；4）收集临床标本，分析Brd2表达与肥胖、胰岛素抵抗和Ⅱ型糖尿病的相关性。通过此研究，我们明确Brd2对机体胰岛素抵抗、糖代谢的调控作用，为Ⅱ型糖尿病提供治疗依据。

Obesity induces insulin resistance and type 2 diabetes, but around 25%~40% obese subpopulation are metabolically normal (MHO) and without insulin resistance.As an important transcription regulatory factor,disruption of Brd2 in mice caused severe obesity without insulin resistance and type 2 diabetes, the phenotype is similar to MHO. In previous study, we detected Brd2 could improve inflammatory response and block insulin receptor signaling pathway in adipocytes.Therefore, Brd2 is functionally required in vivo to couple obesity to insulin resistance and eventual type 2 diabetes. This project will include :1) Effects of Brd2 over-express/silence in adipose tissue specifically on metabolism and insulin sensitivity of mice. 2)The role of Brd2 in insulin receptor signaling pathway, inflammatory response in adipocytes.3) Identifying the function of different domain in Brd2 protein structure, to reveal the mechanism of Brd2 in regulating signaling pathway and key signal molecules. 4) Collecting the specimens of different population of patients with obesity with or without type 2 diabetes, and analyzing the association of Brd2 with obesity,insulin resistance and type 2 diabetes. The objective of this study is to establish the basis for clarifying the mechanism of Brd2 in regulating insulin sensitivity and glucose metabolism , which may provide important insights and new treatment avenues for insulin resistance and type 2 diabetes.