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Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes
Umut Özcan,1*
Qiong Cao,1*
Erkan Yilmaz,1
Ann-Hwee Lee,2
Neal N. Iwakoshi,2
Esra Özdelen,1
Gürol Tuncman,1
Cem Görgün,1
Laurie H. Glimcher,2,3
Gökhan S. Hotamisligil1
Abstract:
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.
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B. P. Cummings, A. Bettaieb, J. L. Graham, K. L. Stanhope, R. Dill, G. J. Morton, F. G. Haj, and P. J. Havel (2011)
PNAS
108, 14670-14675
|Abstract »|Full Text »|PDF »
Paracrine and Endocrine Effects of Adipose Tissue on Cancer Development and Progression.
Apoptosis inhibitor of macrophage (AIM) is required for obesity-associated recruitment of inflammatory macrophages into adipose tissue.
J. Kurokawa, H. Nagano, O. Ohara, N. Kubota, T. Kadowaki, S. Arai, and T. Miyazaki (2011)
PNAS
108, 12072-12077
|Abstract »|Full Text »|PDF »
Increased Adipose Tissue Oxygen Tension in Obese Compared With Lean Men Is Accompanied by Insulin Resistance, Impaired Adipose Tissue Capillarization, and Inflammation.
G. H. Goossens, A. Bizzarri, N. Venteclef, Y. Essers, J. P. Cleutjens, E. Konings, J. W. E. Jocken, M. Cajlakovic, V. Ribitsch, K. Clement, et al. (2011)
Circulation
124, 67-76
|Abstract »|Full Text »|PDF »
N. S. Kalupahana, K. J. Claycombe, and N. Moustaid-Moussa (2011)
Adv Nutr
2, 304-316
|Abstract »|Full Text »|PDF »
Endoplasmic Reticulum Oxidoreductin-1-Like {beta} (ERO1l{beta}) Regulates Susceptibility to Endoplasmic Reticulum Stress and Is Induced by Insulin Flux in {beta}-Cells.
C. Khoo, J. Yang, G. Rajpal, Y. Wang, J. Liu, P. Arvan, and D. A. Stoffers (2011)
Endocrinology
152, 2599-2608
|Abstract »|Full Text »|PDF »
Bidirectional Interaction Between Unfolded-Protein-Response Key Protein HSPA5 and Estrogen Signaling in Human Endometrium.
E. Guzel, M. Basar, N. Ocak, A. Arici, and U. A. Kayisli (2011)
Biol Reprod
85, 121-127
|Abstract »|Full Text »|PDF »
Sirtuin 1 (SIRT1) Protein Degradation in Response to Persistent c-Jun N-terminal Kinase 1 (JNK1) Activation Contributes to Hepatic Steatosis in Obesity.
Z. Gao, J. Zhang, I. Kheterpal, N. Kennedy, R. J. Davis, and J. Ye (2011)
J. Biol. Chem.
286, 22227-22234
|Abstract »|Full Text »|PDF »
Haploid Insufficiency of Suppressor Enhancer Lin12 1-like (SEL1L) Protein Predisposes Mice to High Fat Diet-induced Hyperglycemia.
A. B. Francisco, R. Singh, H. Sha, X. Yan, L. Qi, X. Lei, and Q. Long (2011)
J. Biol. Chem.
286, 22275-22282
|Abstract »|Full Text »|PDF »
Constitutive Role for IRE1{alpha}-XBP1 Signaling Pathway in the Insulin-Mediated Hepatic Lipogenic Program.
J. Ning, T. Hong, A. Ward, J. Pi, Z. Liu, H.-Y. Liu, and W. Cao (2011)
Endocrinology
152, 2247-2255
|Abstract »|Full Text »|PDF »
Oleate Blocks Palmitate-Induced Abnormal Lipid Distribution, Endoplasmic Reticulum Expansion and Stress, and Insulin Resistance in Skeletal Muscle.
G. Peng, L. Li, Y. Liu, J. Pu, S. Zhang, J. Yu, J. Zhao, and P. Liu (2011)
Endocrinology
152, 2206-2218
|Abstract »|Full Text »|PDF »
Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.
J. R. Garbow, J. M. Doherty, R. C. Schugar, S. Travers, M. L. Weber, A. E. Wentz, N. Ezenwajiaku, D. G. Cotter, E. M. Brunt, and P. A. Crawford (2011)
Am J Physiol Gastrointest Liver Physiol
300, G956-G967
|Abstract »|Full Text »|PDF »
Endoplasmic-Reticulum Calcium Depletion and Disease.
D. Mekahli, G. Bultynck, J. B. Parys, H. De Smedt, and L. Missiaen (2011)
Cold Spring Harb Perspect Biol
3, a004317
|Abstract »|Full Text »|PDF »
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