Hepatic Bax inhibitor-1 inhibits IRE1alpha and protects from obesity-associated insulin resistance and glucose intolerance.
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.
Bailly-Maitre
Béatrice
B
Department of Mouse Genetics and Metabolism, Institute for Genetics, Center of Molecular Medicine Cologne at the University of Cologne, Cologne, Germany.
Belgardt
Bengt F
BF
Jordan
Sabine D
SD
Coornaert
Beatrice
B
von Freyend
Miriam John
MJ
Kleinridders
Andre
A
Mauer
Jan
J
Cuddy
Michael
M
Kress
Christina L
CL
Willmes
Diana
D
Essig
Manuela
M
Hampel
Brigitte
B
Protzer
Ulrike
U
Reed
John C
JC
Brüning
Jens C
JC
D000818:Animals; D004721:Endoplasmic Reticulum / Q000473:pathology; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D015316:Genetic Therapy / Q000379:methods; D005943:Gluconeogenesis / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000628:therapy*; D006943:Hyperglycemia / Q000628:therapy; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000150:complications*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D056811:Unfolded Protein Response
D008565:Membrane Proteins; C490015:Tmbim6 protein, mouse; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D005947:Glucose