Advertisement
No access
Research Articles

Endoplasmic Reticulum Stress Links Obesity, Insulin Action, and Type 2 Diabetes

Science
15 Oct 2004
Vol 306, Issue 5695
pp. 457-461

Abstract

Obesity contributes to the development of type 2 diabetes, but the underlying mechanisms are poorly understood. Using cell culture and mouse models, we show that obesity causes endoplasmic reticulum (ER) stress. This stress in turn leads to suppression of insulin receptor signaling through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate–1 (IRS-1). Mice deficient in X-box–binding protein–1 (XBP-1), a transcription factor that modulates the ER stress response, develop insulin resistance. These findings demonstrate that ER stress is a central feature of peripheral insulin resistance and type 2 diabetes at the molecular, cellular, and organismal levels. Pharmacologic manipulation of this pathway may offer novel opportunities for treating these common diseases.

Get full access to this article

View all available purchase options and get full access to this article.

Supplementary Material

File (ozcan.som.rev.pdf)

References and Notes

1
G. S. Hotamisligil, in Diabetes Mellitus, D. LeRoith, S. I. Taylor, J. M. Olefsky, Eds. (Lippincott Williams & Wilkins, Philadelphia, 2003), pp. 953–962.
2
K. T. Uysal, S. M. Wiesbrock, M. W. Marino, G. S. Hotamisligil, Nature389, 610 (1997).
3
J. Hirosumi et al., Nature420, 333 (2002).
4
M. Yuan et al., Science293, 1673 (2001).
5
R. Y. Hampton, Curr. Biol.10, R518 (2000).
6
K. Mori, Cell101, 451 (2000).
7
H. P. Harding, M. Calfon, F. Urano, I. Novoa, D. Ron, Annu. Rev. Cell Dev. Biol.18, 575 (2002).
8
Y. Ma, L. M. Hendershot, Cell107, 827 (2001).
9
R. J. Kaufman et al., Nature Rev. Mol. Cell Biol.3, 411 (2002).
10
I. Kharroubi et al., Endocrinology (2004); published online 5 August 2004 (10.1210/en.2004-0478).
11
Y. Shi, S. I. Taylor, S. L. Tan, N. Sonenberg, Endocr. Rev.24, 91 (2003).
12
Y. Shi et al., Mol. Cell. Biol.18, 7499 (1998).
13
H. P. Harding, Y. Zhang, D. Ron, Nature397, 271 (1999).
14
F. Urano et al., Science287, 664 (2000).
15
R. P. Shiu, J. Pouyssegur, I. Pastan, Proc. Natl. Acad. Sci. U.S.A.74, 3840 (1977).
16
U. Özcan, G. S. Hotamisligil, unpublished observations.
17
B. L. Bennett et al., Proc. Natl. Acad. Sci. U.S.A.98, 13681 (2001).
18
R. K. Barr, T. S. Kendrick, M. A. Bogoyevitch, J. Biol. Chem.277, 10987 (2002).
19
M. Calfon et al., Nature415, 92 (2002).
20
X. Shen et al., Cell107, 893 (2001).
21
H. Yoshida, T. Matsui, A. Yamamoto, T. Okada, K. Mori, Cell107, 881 (2001).
22
A. H. Lee, N. N. Iwakoshi, L. H. Glimcher, Mol. Cell. Biol.23, 7448 (2003).
23
A. M. Reimold et al., Genes Dev.14, 152 (2000).
24
H. P. Harding et al., Mol. Cell7, 1153 (2001).
25
M. Delepine et al., Nature Genet.25, 406 (2000).
26
D. Scheuner et al., Mol. Cell7, 1165 (2001).
27
We thank the Hotamisligil laboratory for their contributions and J. Gound and L. Beppu for technical assistance. Supported in part by NIH grants AI32412 (L.H.G.), DK52539 (G.S.H.), American Diabetes Association (G.S.H.), PO5-CA100707 (L.H.G., A.H.L.), an Irvington Institute Postdoctoral Fellowship Award (N.I.), an NIH training grant T32-DK07703 (Q.C.), and a postdoctoral fellowship from the Iaccoca Foundation (G.T.). L.H.G. holds equity in MannKind Corporation, which has licensed the XBP-1 technology.

(0)eLetters

eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed. Please read our Terms of Service before submitting your own eLetter.

Log In to Submit a Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science
Volume 306 | Issue 5695
15 October 2004

Submission history

Received: 23 July 2004
Accepted: 9 September 2004
Published in print: 15 October 2004

Permissions

Request permissions for this article.

Notes

Supporting Online Material
www.sciencemag.org/cgi/content/full/306/5695/457/DC1
Materials and Methods
Figs. S1 to S8
References

Authors

Affiliations

Umut Özcan*
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Qiong Cao*
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Erkan Yilmaz
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Ann-Hwee Lee
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
Neal N. Iwakoshi
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
Esra Özdelen
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Gürol Tuncman
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Cem Görgün
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Laurie H. Glimcher
Department of Immunology and Infectious Diseases, Harvard School of Public Health, Harvard Medical School, Boston, MA 02115, USA.
Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
Gökhan S. Hotamisligil
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.

Notes

To whom correspondence should be addressed. E-mail: [email protected]

Metrics & Citations

Metrics

Article Usage
Altmetrics

Citations

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. The ERAD system is restricted by elevated ceramides, Science Advances, 9, 2, (2023)./doi/10.1126/sciadv.add8579
    Abstract
  2. Proteotoxicity and endoplasmic reticulum stress-mediated cell death, Mechanisms of Cell Death and Opportunities for Therapeutic Development, (119-174), (2022).https://doi.org/10.1016/B978-0-12-814208-0.00006-3
    Crossref
  3. Hepatic mTORC1 signaling activates ATF4 as part of its metabolic response to feeding and insulin, Molecular Metabolism, (101309), (2021).https://doi.org/10.1016/j.molmet.2021.101309
    Crossref
  4. Bioactive lipids and their metabolism, function, and sources, Evidence-Based Nutrition and Clinical Evidence of Bioactive Foods in Human Health and Disease, (1-19), (2021).https://doi.org/10.1016/B978-0-12-822405-2.00020-7
    Crossref
  5. On the Role of Normal Aging Processes in the Onset and Pathogenesis of Diseases Associated with the Abnormal Accumulation of Protein Aggregates, Biochemistry (Moscow), 86, 3, (275-289), (2021).https://doi.org/10.1134/S0006297921030056
    Crossref
  6. Knockout of the radical scavenger α1-microglobulin in mice results in defective bikunin synthesis, endoplasmic reticulum stress and increased body weight, Free Radical Biology and Medicine, 162, (160-170), (2021).https://doi.org/10.1016/j.freeradbiomed.2020.02.019
    Crossref
  7. Non-alcoholic fatty liver disease: An overview of risk factors, pathophysiological mechanisms, diagnostic procedures, and therapeutic interventions, Life Sciences, 271, (119220), (2021).https://doi.org/10.1016/j.lfs.2021.119220
    Crossref
  8. Combined effect of metformin and gallic acid on inflammation, antioxidant status, endoplasmic reticulum (ER) stress and glucose metabolism in fructose-fed streptozotocin-induced diabetic rats, Toxicology Reports, 8, (1419-1427), (2021).https://doi.org/10.1016/j.toxrep.2021.07.011
    Crossref
  9. Endoplasmic reticulum unfolded protein response modulates the adaptation of Trachemys scripta elegans in salinity water, Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, 248, (109102), (2021).https://doi.org/10.1016/j.cbpc.2021.109102
    Crossref
  10. Agomelatine protects against obesity-induced renal injury by inhibiting endoplasmic reticulum stress/apoptosis pathway in rats, Toxicology and Applied Pharmacology, 425, (115601), (2021).https://doi.org/10.1016/j.taap.2021.115601
    Crossref
  11. See more
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.

Log in via OpenAthens.
Log in via Shibboleth.
More options

Purchase digital access to this article

Download and print this article for your personal scholarly, research, and educational use.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media