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PMID: 15486293 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.

Science (New York, N.Y.) ·Vol. 306 ·No. 5695 ·2004-10-15 ·Pages 457-61

Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS

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.

MeSH Terms

Adipose Tissue/metabolism Animals Cells, Cultured DNA-Binding Proteins/genetics,metabolism Diabetes Mellitus, Type 2/metabolism Endoplasmic Reticulum/metabolism Glucose/metabolism Homeostasis Insulin/metabolism Insulin Receptor Substrate Proteins Insulin Resistance Liver/metabolism Membrane Proteins/metabolism Mice Mice, Inbred BALB C Mice, Obese Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases/metabolism Muscle, Skeletal/metabolism Mutation Nuclear Proteins/genetics,metabolism Obesity/metabolism Phosphoproteins/metabolism Phosphorylation Protein Serine-Threonine Kinases/metabolism Rats Receptor, Insulin/metabolism Regulatory Factor X Transcription Factors Signal Transduction Transcription Factors Tunicamycin/pharmacology X-Box Binding Protein 1 eIF-2 Kinase/metabolism

Chemicals

DNA-Binding Proteins Insulin Insulin Receptor Substrate Proteins Irs1 protein, mouse Irs1 protein, rat Membrane Proteins Nuclear Proteins Phosphoproteins Regulatory Factor X Transcription Factors Transcription Factors X-Box Binding Protein 1 Xbp1 protein, mouse Xbp1 protein, rat Tunicamycin Ern2 protein, mouse Ern2 protein, rat Receptor, Insulin PERK kinase Protein Serine-Threonine Kinases eIF-2 Kinase Mitogen-Activated Protein Kinase 8 Mitogen-Activated Protein Kinases Glucose

Authors & Affiliations

10 authors, click to expand affiliations / ORCID

Ozcan Umut

Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.

Cao Qiong

Yilmaz Erkan

Lee Ann-Hwee

Iwakoshi Neal N

Ozdelen Esra

Tuncman Gürol

Görgün Cem

Glimcher Laurie H

Hotamisligil Gökhan S

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

1095-9203

DOI

10.1126/science.1103160

Published

2004-10-15

Pages

457-61

Language

English

Region

United States

NLM ID

0404511

Subset

Grants

NIAID NIH HHS · AI32412 · United States

NIDDK NIH HHS · DK52539 · United States

NCI NIH HHS · P05-CA100707 · United States

NIDDK NIH HHS · T32-DK07703 · United States

Corrections

CommentIn

PMID: 15486283

External Links

PubMed source DOI: 10.1126/science.1103160 View journal details

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