Department of Pediatrics - HMS
Department of Medicine - Children's Hospital
3 Blackfan Circle
CLS Building, 16th floor, Rm. 024
Boston, MA 02115
The research in our laboratory focuses on three main topics. Our first focus area is the crosstalk between Endoplasmic Reticulum (ER) stress/unfolded protein response (UPR) and insulin receptor signaling systems. The second area is the relation between ER stress and development of leptin resistance in obesity. Final area of investigation is to develop small molecule chemical chaperones to reduce ER stress to treat type 2 diabetes and obesity.
In recent years, we have demonstrated that perturbations in endoplasmic reticulum system in obesity activates a complex signaling cascade, which is defined as UPR, in liver and adipose tissues. Activation of UPR plays a crucial role in development of insulin resistance and type 2 diabetes in obesity. Following these initial observations, we have shown that agents, which have ability to decrease ER stress (chemical chaperones), increase insulin sensitivity in obesity and reverses type 2 diabetes. In this context, we have demonstrated that, 4-PBA and TUDCA, which are two different chemical structures but, which have chemical chaperone activity in common, relieve ER stress in obesity, greatly enhance insulin sensitivity, and maintain euglycemia in a severe mouse model of obesity (ob/ob) and type 2 diabetes. These observations constitute an important proof of principle that manipulation of the ER system to decrease ER stress by chemical agents may have therapeutic implications for insulin resistance and type 2 diabetes. We are currently trying to identify the underlying pathologies for development of ER stress in obesity and had several publications that brought new insights for the pathological mechanisms that lead to ER stress in obesity. We documented that loss of X-Box Binding Protein 1 (XBP1s) function in obesity is a major contributor to development of ER stress in obesity. Furthermore, we have recently identified that reduced Sarco(endo)plasmic reticulum calcium ATPase 2b (SERCA2b) is reduced in obesity leading to perturbed Ca2+ homeostasis and development of ER stress. We have several ongoing projects in these areas to understand the molecular mechanisms that are leading to both XBP1s and SERCA2b dysfunction in obesity.
Furthermore, we have also demonstrated that increased ER stress and activated UPR signaling in the hypothalamus is a crucial signaling network for development of leptin resistance. By reducing hypothalamic ER stress with chemical chaperones, for the first time, we succeeded to sensitize the obese-leptin resistant mice to leptin. One of our main aims is to investigate the signaling mechanisms that are leading to development of insulin resistance and leptin resistance through activation of UPR in obesity. We are using genetically modified cellular systems, knockout and transgenic mouse models to be able to understand the details of these pathways.
Our final investigation area is developing more potent chemical chaperones to treat insulin and leptin resistance and consequently type 2 diabetes and obesity, respectively. By using system biology approaches we have made important progress in this area and already identified much more potent chemical chaperones and have shown that these new agents are indeed very strong anti-obesity agents. Currently we are trying to identify the targets of these new agents and understand detailed mechanism of action.
Ozcan L, Ergin AS, Sarkar S, Lu A, Chung J, Nie D, Myers MG, Jr., Ozcan U. Endoplasmic Reticulum Stress Plays A Central Role in Development of Leptin Resistance. Cell Metabolism. 2009 Jan 7;9(1):35-51.
Park S, Zhou Y, Lee J, Lu A, Sun C, Chung J, Ueki K, Ozcan U. Regulatory Subunits of PI3K, P85α and P85β, Interact With XBP1 and Increase Its Nuclear Translocation. Nature Medicine, 2010 Apr;16(4):429.
Park S, Zhou Y, Lee J, Lee J, Ozcan U. Sarco(endo)plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. PNAS, 2010 Nov 9;107(45):19320-5. Epub 2010 Oct 25.
Zhou Y, Lee J, Reno CM, Chung J, Sun C, Park SW, Chung J, Lee J, White MF, Biddinger S, Fisher SJ, Ozcan U. Regulation of Glucose Homeostasis Through XBP1-FoxO1 interaction. Nature Medicine, 2011 Mar;17(3):356-65. Epub 2011 Feb 13.
For a complete listing of publications click here.
Last Update: 8/1/2012