PROJECT SUMMARY Obesity is the major pathology underlying the development of insulin resistance and type 2 diabetes. Despite extensive research, identifying the molecular link between obesity and type 2 diabetes has been a big challenge and it still remains elusive. Currently, there is no cure for type 2 diabetes and no therapeutic treatment methods for obesity. In order to find a therapeutic target, it is important to understand the pathophysiology of obesity and the molecular mechanism by which insulin resistance develops. Recently, it has been reported that the expression levels of a protein called bromodomain-containing protein 7 (BRD7) are significantly reduced in the liver of obese mice. Furthermore, it has been shown that restoration of BRD7 in the liver of obese and diabetic mice reduces blood glucose levels and improves glucose tolerance. Therefore, it is evident that BRD7 is involved in the regulation of glucose homeostasis. This proposal aims to investigate a novel molecular mechanism by which BRD7 improves glucose tolerance and insulin sensitivity. The ultimate goal of this project is to understand whether BRD7 can serve as a novel target to treat type 2 diabetes in obese individuals. This project addresses several novel mechanistic pathways in insulin signaling. These include understanding how BRD7 leads to the alteration of insulin receptor signaling in response to insulin, and how hepatic glucose production and blood glucose levels are regulated by BRD7. In Aim 1, genetically engineered mouse models will be used to define the role of BRD7 in the insulin signaling pathway. The outcome of these experiments will reveal a novel mechanism by which insulin receptor signaling is controlled. In Aim 2, several mouse models and cell lines will be utilized to understand the regulation of glycogen and lipids by BRD7. The results of experiments under Aim 3 will provide a better understanding of the regulation of BRD7. Successful outcomes of this proposal will improve scientific knowledge in the field of type 2 diabetes, and also suggest an alternative way to not only treat type 2 diabetes, but also prevent the development of insulin resistance and glucose intolerance in obese patients.