The unfolded protein response (UPR) or endoplasmic reticulum (ER) stress response is a physiological process enabling cells to cope with altered
protein synthesis demands. However, under conditions of
obesity, prolonged activation of the UPR has been shown to have deteriorating effects on different metabolic pathways. Here we identify Bax inhibitor-1 (BI-1), an evolutionary conserved ER-
membrane protein, as a novel modulator of the
obesity-associated alteration of the UPR. BI-1 partially inhibits the UPR by interacting with IRE1alpha and inhibiting IRE1alpha
endonuclease activity as seen on the splicing of the
transcription factor Xbp-1. Because we observed a down-regulation of BI-1 expression in liver and muscle of genetically obese ob/ob and db/db mice as well as in mice with diet-induced
obesity in vivo, we investigated the effect of restoring BI-1 expression on metabolic processes in these mice. Importantly, BI-1 overexpression by adenoviral gene transfer dramatically improved
glucose metabolism in both standard diet-fed mice as well as in mice with diet-induced
obesity and, critically, reversed
hyperglycemia in db/db mice. This improvement in whole body
glucose metabolism and
insulin sensitivity was due to dramatically reduced gluconeogenesis as shown by reduction of
glucose-6-phosphatase and
phosphoenolpyruvate carboxykinase expression. Taken together, these results identify BI-1 as a critical regulator of ER stress responses in the development of
obesity-associated
insulin resistance and provide proof of concept evidence that gene transfer-mediated elevations in hepatic BI-1 may represent a promising approach for the treatment of
type 2 diabetes.