Abstract
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.
Highlights
The prevalence of obesity steadily increases worldwide [1]
These results identify Bax Inhibitor-1 (BI-1) as a critical regulator of endoplasmic reticulum (ER) stress responses in the development of obesityassociated 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
BI-1 in Obesity-associated Insulin Resistance stress were found in liver and adipose tissue of genetically obese mice and mice exposed to a high fat diet, indicating that the metabolic abnormalities associated with obesity cause ER stress in vivo [3]
Summary
Animals—All animal procedures were conducted in compliance with protocols approved by local government authorities (Bezirksregierung Koln) and were in accordance with National Institutes of Health guidelines. Adenovirus-mediated Gene Transfer in Vivo—The adenoviral vector expressing BI-1 (Ad BI-1) was generated using the Gateway system (Invitrogen). Glucose and Insulin Tolerance Tests—Glucose tolerance tests were performed on animals that had been fasted overnight for 16 h. After determination of fasted blood glucose levels, each animal received an intraperitoneal injection of 2 mg/g of body weight of glucose (20% glucose; Delta Select). Insulin tolerance tests were performed on random-fed animals. After determination of random fed blood glucose levels, each animal received an intraperitoneal injection of 0.75 milliunits/g of body weight of insulin (Actrapid; Novo Nordisk). The abdominal cavity of the mice was opened, and 100-l samples containing 13 milliunits of regular human insulin (Actrapid; Novo Nordisk) diluted in 0.9% saline were injected. Samples of liver were harvested 2 min performed by a comparative cycle threshold (Ct) method; the after injection and snap-frozen in liquid nitrogen.
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