Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 25 August 2006:
Vol. 313. no. 5790, pp. 1137 - 1140
DOI: 10.1126/science.1128294
Prev | Table of Contents | Next

Reports

Chemical Chaperones Reduce ER Stress and Restore Glucose Homeostasis in a Mouse Model of Type 2 Diabetes

Umut Özcan, Erkan Yilmaz, Lale Özcan, Masato Furuhashi, Eric Vaillancourt, Ross O. Smith, Cem Z. Görgün, Gökhan S. Hotamisligil*

Endoplasmic reticulum (ER) stress is a key link between obesity, insulin resistance, and type 2 diabetes. Here, we provide evidence that this mechanistic link can be exploited for therapeutic purposes with orally active chemical chaperones. 4-Phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviated ER stress in cells and whole animals. Treatment of obese and diabetic mice with these compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in liver, muscle, and adipose tissues. Our results demonstrate that chemical chaperones enhance the adaptive capacity of the ER and act as potent antidiabetic modalities with potential application in the treatment of type 2 diabetes.

Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA 02115, USA.

* To whom correspondence should be addressed. E-mail: ghotamis{at}hsph.harvard.edu

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The chemical chaperone 4-phenylbutyrate inhibits adipogenesis by modulating the unfolded protein response.
S. Basseri, S. Lhotak, A. M. Sharma, and R. C. Austin (2009)
J. Lipid Res. 50, 2486-2501
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress in Diabetic Hearts Abolishes Erythropoietin-Induced Myocardial Protection by Impairment of Phospho-Glycogen Synthase Kinase-3{beta}-Mediated Suppression of Mitochondrial Permeability Transition.
T. Miki, T. Miura, H. Hotta, M. Tanno, T. Yano, T. Sato, Y. Terashima, A. Takada, S. Ishikawa, and K. Shimamoto (2009)
Diabetes 58, 2863-2872
   Abstract »    Full Text »    PDF »
Fenofibrate and PBA prevent fatty acid-induced loss of adiponectin receptor and pAMPK in human hepatoma cells and in hepatitis C virus-induced steatosis.
S. M. Rahman, I. Qadri, R. C. Janssen, and J. E. Friedman (2009)
J. Lipid Res. 50, 2193-2202
   Abstract »    Full Text »    PDF »
Degradation of IRS1 leads to impaired glucose uptake in adipose tissue of the type 2 diabetes mouse model TALLYHO/Jng.
Y. Wang, P. M Nishina, and J. K Naggert (2009)
J. Endocrinol. 203, 65-74
   Abstract »    Full Text »    PDF »
Bile acids: regulation of apoptosis by ursodeoxycholic acid.
J. D. Amaral, R. J. S. Viana, R. M. Ramalho, C. J. Steer, and C. M. P. Rodrigues (2009)
J. Lipid Res. 50, 1721-1734
   Abstract »    Full Text »    PDF »
Autophagy-Mediated Insulin Receptor Down-Regulation Contributes to Endoplasmic Reticulum Stress-Induced Insulin Resistance.
L. Zhou, J. Zhang, Q. Fang, M. Liu, X. Liu, W. Jia, L. Q. Dong, and F. Liu (2009)
Mol. Pharmacol. 76, 596-603
   Abstract »    Full Text »    PDF »
Chronic Endoplasmic Reticulum Stress Activates Unfolded Protein Response in Arterial Endothelium in Regions of Susceptibility to Atherosclerosis.
M. Civelek, E. Manduchi, R. J. Riley, C. J. Stoeckert Jr, and P. F. Davies (2009)
Circ. Res. 105, 453-461
   Abstract »    Full Text »    PDF »
Correction of the Disease Phenotype of Myocilin-Causing Glaucoma by a Natural Osmolyte.
L.-Y. Jia, B. Gong, C.-P. Pang, Y. Huang, D. S.-C. Lam, N. Wang, and G. H.-F. Yam (2009)
Invest. Ophthalmol. Vis. Sci. 50, 3743-3749
   Abstract »    Full Text »    PDF »
Adipose Tissue Inflammation: Developmental Ontogeny and Consequences of Gestational Nutrient Restriction in Offspring.
D. Sharkey, M. E. Symonds, and H. Budge (2009)
Endocrinology 150, 3913-3920
   Abstract »    Full Text »    PDF »
Individual Stearoyl-CoA Desaturase 1 Expression Modulates Endoplasmic Reticulum Stress and Inflammation in Human Myotubes and Is Associated With Skeletal Muscle Lipid Storage and Insulin Sensitivity In Vivo.
A. Peter, C. Weigert, H. Staiger, F. Machicao, F. Schick, J. Machann, N. Stefan, C. Thamer, H.-U. Haring, and E. Schleicher (2009)
Diabetes 58, 1757-1765
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress Regulates Adipocyte Resistin Expression.
M. I. Lefterova, S. E. Mullican, T. Tomaru, M. Qatanani, M. Schupp, and M. A. Lazar (2009)
Diabetes 58, 1879-1886
   Abstract »    Full Text »    PDF »
Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.
Y. Liu, Y. Wang, C. Wu, Y. Liu, and P. Zheng (2009)
Hum. Mol. Genet. 18, 2622-2631
   Abstract »    Full Text »    PDF »
Taurine: Red Bull or Red Herring?.
S. Wesseling, M. P. Koeners, and J. A. Joles (2009)
Hypertension 53, 909-911
   Full Text »    PDF »
Impact of Early Onset Obesity and Hypertension on the Unfolded Protein Response in Renal Tissues of Juvenile Sheep.
D. Sharkey, H. P. Fainberg, V. Wilson, E. Harvey, D. S. Gardner, M. E. Symonds, and H. Budge (2009)
Hypertension 53, 925-931
   Abstract »    Full Text »    PDF »
High Dietary Taurine Reduces Apoptosis and Atherosclerosis in the Left Main Coronary Artery: Association With Reduced CCAAT/Enhancer Binding Protein Homologous Protein and Total Plasma Homocysteine but not Lipidemia.
A. Zulli, E. Lau, B. P.P. Wijaya, X. Jin, K. Sutarga, G. D. Schwartz, J. Learmont, P. J. Wookey, A. Zinellu, C. Carru, et al. (2009)
Hypertension 53, 1017-1022
   Abstract »    Full Text »    PDF »
Maternal nutrient restriction during pregnancy differentially alters the unfolded protein response in adipose and renal tissue of obese juvenile offspring.
D. Sharkey, D. S. Gardner, H. P. Fainberg, S. Sebert, P. Bos, V. Wilson, R. Bell, M. E. Symonds, and H. Budge (2009)
FASEB J 23, 1314-1324
   Abstract »    Full Text »    PDF »
Nicotinamide Mononucleotide Adenylyl Transferase-Mediated Axonal Protection Requires Enzymatic Activity But Not Increased Levels of Neuronal Nicotinamide Adenine Dinucleotide.
Y. Sasaki, B. P. S. Vohra, F. E. Lund, and J. Milbrandt (2009)
J. Neurosci. 29, 5525-5535
   Abstract »    Full Text »    PDF »
SCAMP5 Links Endoplasmic Reticulum Stress to the Accumulation of Expanded Polyglutamine Protein Aggregates via Endocytosis Inhibition.
J.-Y. Noh, H. Lee, S. Song, N. S. Kim, W. Im, M. Kim, H. Seo, C.-W. Chung, J.-W. Chang, R. J. Ferrante, et al. (2009)
J. Biol. Chem. 284, 11318-11325
   Abstract »    Full Text »    PDF »
Insulin Regulates TRB3 and Other Stress-Responsive Gene Expression through Induction of C/EBP{beta}.
K. Du and J. Ding (2009)
Mol. Endocrinol. 23, 475-485
   Abstract »    Full Text »    PDF »
Asymmetrical dimethylarginine triggers lipolysis and inflammatory response via induction of endoplasmic reticulum stress in cultured adipocytes.
Q. G. Zhou, M. Zhou, F. F. Hou, and X. Peng (2009)
Am J Physiol Endocrinol Metab 296, E869-E878
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress Is Reduced in Tissues of Obese Subjects After Weight Loss.
M. F. Gregor, L. Yang, E. Fabbrini, B. S. Mohammed, J. C. Eagon, G. S. Hotamisligil, and S. Klein (2009)
Diabetes 58, 693-700
   Abstract »    Full Text »    PDF »
GRP78, but Not Protein-disulfide Isomerase, Partially Reverses Hyperglycemia-induced Inhibition of Insulin Synthesis and Secretion in Pancreatic {beta}-Cells.
L. Zhang, E. Lai, T. Teodoro, and A. Volchuk (2009)
J. Biol. Chem. 284, 5289-5298
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response and Autophagy: Herpesviruses Rule!.
D. Y. Lee, J. Lee, and B. Sugden (2009)
J. Virol. 83, 1168-1172
   Full Text »    PDF »
Implication of nitric oxide in the increased islet-cells vulnerability of adult progeny from protein-restricted mothers and its prevention by taurine.
K Goosse, T Bouckenooghe, M Balteau, B Reusens, and C Remacle (2009)
J. Endocrinol. 200, 177-187
   Abstract »    Full Text »    PDF »
Imatinib Mesylate Reduces Endoplasmic Reticulum Stress and Induces Remission of Diabetes in db/db Mice.
M. S. Han, K. W. Chung, H. G. Cheon, S. D. Rhee, C.-H. Yoon, M.-K. Lee, K.-W. Kim, and M.-S. Lee (2009)
Diabetes 58, 329-336
   Abstract »    Full Text »    PDF »
Saturated Fatty Acids Produce an Inflammatory Response Predominantly through the Activation of TLR4 Signaling in Hypothalamus: Implications for the Pathogenesis of Obesity.
M. Milanski, G. Degasperi, A. Coope, J. Morari, R. Denis, D. E. Cintra, D. M. L. Tsukumo, G. Anhe, M. E. Amaral, H. K. Takahashi, et al. (2009)
J. Neurosci. 29, 359-370
   Abstract »    Full Text »    PDF »
Positive and Negative Regulation of Insulin Signaling by Reactive Oxygen and Nitrogen Species.
N. Bashan, J. Kovsan, I. Kachko, H. Ovadia, and A. Rudich (2009)
Physiol Rev 89, 27-71
   Abstract »    Full Text »    PDF »
Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death.
N. Bouvier, J. P. Flinois, J. Gilleron, F.-L. Sauvage, C. Legendre, P. Beaune, E. Thervet, D. Anglicheau, and N. Pallet (2009)
Am J Physiol Renal Physiol 296, F160-F169
   Abstract »    Full Text »    PDF »
Antioxidants reduce endoplasmic reticulum stress and improve protein secretion.
J. D. Malhotra, H. Miao, K. Zhang, A. Wolfson, S. Pennathur, S. W. Pipe, and R. J. Kaufman (2008)
PNAS 105, 18525-18530
   Abstract »    Full Text »    PDF »
Overexpressed cyclophilin B suppresses apoptosis associated with ROS and Ca2+ homeostasis after ER stress.
J. Kim, T. G. Choi, Y. Ding, Y. Kim, K. S. Ha, K. H. Lee, I. Kang, J. Ha, R. J. Kaufman, J. Lee, et al. (2008)
J. Cell Sci. 121, 3636-3648
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress Markers Are Associated with Obesity in Nondiabetic Subjects.
N. K. Sharma, S. K. Das, A. K. Mondal, O. G. Hackney, W. S. Chu, P. A. Kern, N. Rasouli, H. J. Spencer, A. Yao-Borengasser, and S. C. Elbein (2008)
J. Clin. Endocrinol. Metab. 93, 4532-4541
   Abstract »    Full Text »    PDF »
Cytokine-Induced {beta}-Cell Death Is Independent of Endoplasmic Reticulum Stress Signaling.
M. C. Akerfeldt, J. Howes, J. Y. Chan, V. A. Stevens, N. Boubenna, H. M. McGuire, C. King, T. J. Biden, and D. R. Laybutt (2008)
Diabetes 57, 3034-3044
   Abstract »    Full Text »    PDF »
Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue.
A. Sobolewski, N. Rudarakanchana, P. D. Upton, J. Yang, T. K. Crilley, R. C. Trembath, and N. W. Morrell (2008)
Hum. Mol. Genet. 17, 3180-3190
   Abstract »    Full Text »    PDF »
Effect of pioglitazone treatment on endoplasmic reticulum stress response in human adipose and in palmitate-induced stress in human liver and adipose cell lines.
S. K. Das, W. S. Chu, A. K. Mondal, N. K. Sharma, P. A. Kern, N. Rasouli, and S. C. Elbein (2008)
Am J Physiol Endocrinol Metab 295, E393-E400
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum stress and unfolded protein response in renal pathophysiology: Janus faces.
M. Kitamura (2008)
Am J Physiol Renal Physiol 295, F323-F334
   Abstract »    Full Text »    PDF »
ATF4-dependent transcription is a key mechanism in VEGF up-regulation by oxidized phospholipids: critical role of oxidized sn-2 residues in activation of unfolded protein response.
O. V. Oskolkova, T. Afonyushkin, A. Leitner, E. von Schlieffen, P. S. Gargalovic, A. J. Lusis, B. R. Binder, and V. N. Bochkov (2008)
Blood 112, 330-339
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response: A Pathway That Links Insulin Demand with {beta}-Cell Failure and Diabetes.
D. Scheuner and R. J. Kaufman (2008)
Endocr. Rev. 29, 317-333
   Abstract »    Full Text »    PDF »
TRB3 suppresses adipocyte differentiation by negatively regulating PPAR{gamma} transcriptional activity.
Y. Takahashi, N. Ohoka, H. Hayashi, and R. Sato (2008)
J. Lipid Res. 49, 880-892
   Abstract »    Full Text »    PDF »
Inhibition of Foxo1 Protects Pancreatic Islet {beta}-Cells Against Fatty Acid and Endoplasmic Reticulum Stress-Induced Apoptosis.
S. C. Martinez, K. Tanabe, C. Cras-Meneur, N. A. Abumrad, E. Bernal-Mizrachi, and M. A. Permutt (2008)
Diabetes 57, 846-859
   Abstract »    Full Text »    PDF »
The PKC{delta} -Abl complex communicates ER stress to the mitochondria - an essential step in subsequent apoptosis.
X. Qi and D. Mochly-Rosen (2008)
J. Cell Sci. 121, 804-813
   Abstract »    Full Text »    PDF »
Differential activation of ER stress and apoptosis in response to chronically elevated free fatty acids in pancreatic {beta}-cells.
E. Lai, G. Bikopoulos, M. B. Wheeler, M. Rozakis-Adcock, and A. Volchuk (2008)
Am J Physiol Endocrinol Metab 294, E540-E550
   Abstract »    Full Text »    PDF »
Role of Mitochondrial Dysfunction in Insulin Resistance.
J.-a Kim, Y. Wei, and J. R. Sowers (2008)
Circ. Res. 102, 401-414
   Abstract »    Full Text »    PDF »
Adapting Proteostasis for Disease Intervention.
W. E. Balch, R. I. Morimoto, A. Dillin, and J. W. Kelly (2008)
Science 319, 916-919
   Abstract »    Full Text »    PDF »
ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones.
H. Wei, S.-J. Kim, Z. Zhang, P.-C. Tsai, K. E. Wisniewski, and A. B. Mukherjee (2008)
Hum. Mol. Genet. 17, 469-477
   Abstract »    Full Text »    PDF »
BAX Inhibitor-1 Modulates Endoplasmic Reticulum Stress-mediated Programmed Cell Death in Arabidopsis.
N. Watanabe and E. Lam (2008)
J. Biol. Chem. 283, 3200-3210
   Abstract »    Full Text »    PDF »
HSP72 protects against obesity-induced insulin resistance.
J. Chung, A.-K. Nguyen, D. C. Henstridge, A. G. Holmes, M. H. S. Chan, J. L. Mesa, G. I. Lancaster, R. J. Southgate, C. R. Bruce, S. J. Duffy, et al. (2008)
PNAS 105, 1739-1744
   Abstract »    Full Text »    PDF »
The Role for Endoplasmic Reticulum Stress in Diabetes Mellitus.
D. L. Eizirik, A. K. Cardozo, and M. Cnop (2008)
Endocr. Rev. 29, 42-61
   Abstract »    Full Text »    PDF »
Essential Role of Mitochondrial Function in Adiponectin Synthesis in Adipocytes.
E. H. Koh, J.-Y. Park, H.-S. Park, M. J. Jeon, J. W. Ryu, M. Kim, S. Y. Kim, M.-S. Kim, S.-W. Kim, I. S. Park, et al. (2007)
Diabetes 56, 2973-2981
   Abstract »    Full Text »    PDF »
p53 Is a Key Molecular Target of Ursodeoxycholic Acid in Regulating Apoptosis.
J. D. Amaral, R. E. Castro, S. Sola, C. J. Steer, and C. M. P. Rodrigues (2007)
J. Biol. Chem. 282, 34250-34259
   Abstract »    Full Text »    PDF »
HIV-1 Protease Inhibitors Nelfinavir and Atazanavir Induce Malignant Glioma Death by Triggering Endoplasmic Reticulum Stress.
P. Pyrko, A. Kardosh, W. Wang, W. Xiong, A. H. Schonthal, and T. C. Chen (2007)
Cancer Res. 67, 10920-10928
   Abstract »    Full Text »    PDF »
Conditional Intestinal Lipotoxicity in Apobec-1-/- Mttp-IKO Mice: A SURVIVAL ADVANTAGE FOR MAMMALIAN INTESTINAL APOLIPOPROTEIN B mRNA EDITING.
Y. Xie, J. Luo, S. Kennedy, and N. O. Davidson (2007)
J. Biol. Chem. 282, 33043-33051
   Abstract »    Full Text »    PDF »
In and Out of the ER: Protein Folding, Quality Control, Degradation, and Related Human Diseases.
D. N. Hebert and M. Molinari (2007)
Physiol Rev 87, 1377-1408
   Abstract »    Full Text »    PDF »
Dose-Dependent Effects of Alcohol on Insulin Signaling: Partial Explanation for Biphasic Alcohol Impact on Human Health.
L. He, J. C. Marecki, G. Serrero, F. A. Simmen, M. J. J. Ronis, and T. M. Badger (2007)
Mol. Endocrinol. 21, 2541-2550
   Abstract »    Full Text »    PDF »
Chemical Chaperones Reduce Endoplasmic Reticulum Stress and Prevent Mutant HFE Aggregate Formation.
S. F. de Almeida, G. Picarote, J. V. Fleming, M. Carmo-Fonseca, J. E. Azevedo, and M. de Sousa (2007)
J. Biol. Chem. 282, 27905-27912
   Abstract »    Full Text »    PDF »
Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome: A Balancing Act Between Plaque Stability and Rupture.
J. G. Dickhout, S. M. Colgan, S. Lhotak, and R. C. Austin (2007)
Circulation 116, 1214-1216
   Full Text »    PDF »
Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease.
M. F. Gregor and G. S. Hotamisligil (2007)
J. Lipid Res. 48, 1905-1914
   Abstract »    Full Text »    PDF »
Defects in the Leptin Axis Reduce Abundance of the ABCG5-ABCG8 Sterol Transporter in Liver.
N. S. Sabeva, E. J. Rouse, and G. A. Graf (2007)
J. Biol. Chem. 282, 22397-22405
   Abstract »    Full Text »    PDF »
A Developmentally Regulated Chaperone Complex for the Endoplasmic Reticulum of Male Haploid Germ Cells.
M. van Lith, A.-R. Karala, D. Bown, J. A. Gatehouse, L. W. Ruddock, P. T.K. Saunders, and A. M. Benham (2007)
Mol. Biol. Cell 18, 2795-2804
   Abstract »    Full Text »    PDF »
Activating Transcription Factor 6 Polymorphisms and Haplotypes Are Associated with Impaired Glucose Homeostasis and Type 2 Diabetes in Dutch Caucasians.
S. J. R. Meex, M. M. J. van Greevenbroek, T. A. Ayoubi, R. Vlietinck, J. V. van Vliet-Ostaptchouk, M. H. Hofker, V. M. M.-J. Vermeulen, C. G. Schalkwijk, E. J. M. Feskens, J. M. A. Boer, et al. (2007)
J. Clin. Endocrinol. Metab. 92, 2720-2725
   Abstract »    Full Text »    PDF »
Mechanisms of obesity-associated insulin resistance: many choices on the menu.
M. Qatanani and M. A. Lazar (2007)
Genes & Dev. 21, 1443-1455
   Abstract »    Full Text »    PDF »
Innate Immune Pathway Links Obesity to Insulin Resistance.
P. K. Shah (2007)
Circ. Res. 100, 1531-1533
   Full Text »    PDF »
The Macrophage at the Crossroads of Insulin Resistance and Atherosclerosis.
C.-P. Liang, S. Han, T. Senokuchi, and A. R. Tall (2007)
Circ. Res. 100, 1546-1555
   Abstract »    Full Text »    PDF »
Perturbation of Endoplasmic Reticulum Homeostasis Facilitates Prion Replication.
C. Hetz, J. Castilla, and C. Soto (2007)
J. Biol. Chem. 282, 12725-12733
   Abstract »    Full Text »    PDF »
Activating Transcription Factor 6 (ATF6) Sequence Polymorphisms in Type 2 Diabetes and Pre-Diabetic Traits.
W. S. Chu, S. K. Das, H. Wang, J. C. Chan, P. Deloukas, P. Froguel, L. J. Baier, W. Jia, M. I. McCarthy, M. C.Y. Ng, et al. (2007)
Diabetes 56, 856-862
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)