Grant: Project Grant

Metabolic diseases, including diabetes and obesity, are reaching epidemic levels in the Western world. Chronic activation of the glucocorticoid receptor signaling pathway by stress hormones can contribute to diabetes and metabolic dysfunction. Diabetes is characterized by elevated blood glucose levels (hyperglycemia) caused by the body's inability to properly secrete insulin and/or respond to increasing insulin levels. A high-fat diet and long-term therapeutic use of glucocorticoid drugs can cause obesity and type 2 diabetes. These negative effects are due in part to the glucose production pathway being strongly induced by glucocorticoid drugs in the liver and by the increased delivery of glucose precursors from other tissues, such as fat. We have a strong interest in understanding the molecular connections between high-fat diet, stress hormones (glucocorticoids) and the ultimate response obtained in tissues such as the liver and adipose tissue. We have identified a new protein called ARGLU1 that is important for transmitting the stress hormone signals to the liver to increase glucose production and does not appear to impact the role of glucocorticoids on the immune system. In this proposal, we will assess the importance of high-fat diet and glucocorticoid drugs on metabolism using in vivo mouse models that have ARGLU1 deleted from either the liver or the fat tissue. We will use new proteomic and sequencing technologies to uncover the different signaling mechanisms involved, and in the process, identify new determinants of glucocorticoid specificity. This project has high public relevance because it will allow us to identify new drug targets to benefit patients with metabolic disease and potentially identify pathways that can be targeted to allow safer glucocorticoid drug use for the future.