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 this initial observations, we have shown that agents which have the 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, despite having different chemical structures, have chaperone activity and relieve ER stress in obesity, greatly enhancing insulin sensitivity, and maintaining 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 our publications have brought new insights into the pathological mechanisms that lead to ER stress in obesity.