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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Umut Özcan,1*Qiong Cao,1*Erkan Yilmaz,1Ann-Hwee Lee,2Neal N. Iwakoshi,2Esra Özdelen,1Gürol Tuncman,1Cem Görgün,1Laurie H. Glimcher,2,3Gökhan S. Hotamisligil1
Obesity contributes to the development of type 2 diabetes, butthe underlying mechanisms are poorly understood. Using cellculture and mouse models, we show that obesity causes endoplasmicreticulum (ER) stress. This stress in turn leads to suppressionof insulin receptor signaling through hyperactivation of c-JunN-terminal kinase (JNK) and subsequent serine phosphorylationof insulin receptor substrate–1 (IRS-1). Mice deficientin X-box–binding protein–1 (XBP-1), a transcriptionfactor that modulates the ER stress response, develop insulinresistance. These findings demonstrate that ER stress is a centralfeature of peripheral insulin resistance and type 2 diabetesat the molecular, cellular, and organismal levels. Pharmacologicmanipulation of this pathway may offer novel opportunities fortreating these common diseases.
1 Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA. 2 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA. 3 Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: ghotamis{at}hsph.harvard.edu
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S. De Barros, A. Zakaroff-Girard, M. Lafontan, J. Galitzky, and V. Bourlier (2007)
J. Pharmacol. Exp. Ther.
320, 291-299
|Abstract »|Full Text »|PDF »
Amelioration of diet-induced diabetes mellitus by removal of visceral fat.
C. Pitombo, E. P Araujo, C. T De Souza, J. C Pareja, B. Geloneze, and L. A Velloso (2006)
J. Endocrinol.
191, 699-706
|Abstract »|Full Text »|PDF »
Diabetes Alters Sphingolipid Metabolism in the Retina: A Potential Mechanism of Cell Death in Diabetic Retinopathy.
T. E. Fox, X. Han, S. Kelly, A. H. Merrill Jr., R. E. Martin, R. E. Anderson, T. W. Gardner, and M. Kester (2006)
Diabetes
55, 3573-3580
|Abstract »|Full Text »|PDF »
Glucose, dexamethasone, and the unfolded protein response regulate TRB3 mRNA expression in 3T3-L1 adipocytes and L6 myotubes.
S. Z. Yacoub Wasef, K. A. Robinson, M. N. Berkaw, and M. G. Buse (2006)
Am J Physiol Endocrinol Metab
291, E1274-E1280
|Abstract »|Full Text »|PDF »
Translocable Glucose Transporters in the Brain: Where Are We in 2006?.
T. Alquier, C. Leloup, A. Lorsignol, and L. Penicaud (2006)
Diabetes
55, S131-S138
|Abstract »|Full Text »|PDF »
RNA Editing by ADAR2 Is Metabolically Regulated in Pancreatic Islets and beta-Cells.
Z. Gan, L. Zhao, L. Yang, P. Huang, F. Zhao, W. Li, and Y. Liu (2006)
J. Biol. Chem.
281, 33386-33394
|Abstract »|Full Text »|PDF »
Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates.
G. Solinas, W. Naugler, F. Galimi, M.-S. Lee, and M. Karin (2006)
PNAS
103, 16454-16459
|Abstract »|Full Text »|PDF »
Endoplasmic reticulum stress signaling in disease..
Growth retardation alters the epigenetic characteristics of hepatic dual specificity phosphatase 5.
Q. Fu, R. A. McKnight, X. Yu, C. W. Callaway, and R. H. Lane (2006)
FASEB J
20, 2127-2129
|Abstract »|Full Text »|PDF »
Nck in a Complex Containing the Catalytic Subunit of Protein Phosphatase 1 Regulates Eukaryotic Initiation Factor 2{alpha} Signaling and Cell Survival to Endoplasmic Reticulum Stress.
Polymorphisms in the Glucokinase-Associated, Dual-Specificity Phosphatase 12 (DUSP12) Gene Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes.
S. K. Das, W. S. Chu, T. C. Hale, X. Wang, R. L. Craig, H. Wang, A. R. Shuldiner, P. Froguel, P. Deloukas, M. I. McCarthy, et al. (2006)
Diabetes
55, 2631-2639
|Abstract »|Full Text »|PDF »
Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes..
U. Ozcan, E. Yilmaz, L. Ozcan, M. Furuhashi, E. Vaillancourt, R. O. Smith, C. Z. Gorgun, and G. S. Hotamisligil (2006)
Science
313, 1137-1140
|Abstract »|Full Text »|PDF »
CCAAT/Enhancer-binding Protein {alpha} Mediates Induction of Hepatic Phosphoenolpyruvate Carboxykinase by p38 Mitogen-activated Protein Kinase.
L. Qiao, O. A. MacDougald, and J. Shao (2006)
J. Biol. Chem.
281, 24390-24397
|Abstract »|Full Text »|PDF »
The Interaction of Thioredoxin with Txnip: EVIDENCE FOR FORMATION OF A MIXED DISULFIDE BY DISULFIDE EXCHANGE.
P. Patwari, L. J. Higgins, W. A. Chutkow, J. Yoshioka, and R. T. Lee (2006)
J. Biol. Chem.
281, 21884-21891
|Abstract »|Full Text »|PDF »
Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells.
Y. Wei, D. Wang, F. Topczewski, and M. J. Pagliassotti (2006)
Am J Physiol Endocrinol Metab
291, E275-E281
|Abstract »|Full Text »|PDF »
Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance.
G. Tuncman, J. Hirosumi, G. Solinas, L. Chang, M. Karin, and G. S. Hotamisligil (2006)
PNAS
103, 10741-10746
|Abstract »|Full Text »|PDF »
Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response..
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