Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes.
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.
Ozcan
Umut
U
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Cao
Qiong
Q
Yilmaz
Erkan
E
Lee
Ann-Hwee
AH
Iwakoshi
Neal N
NN
Ozdelen
Esra
E
Tuncman
Gürol
G
Görgün
Cem
C
Glimcher
Laurie H
LH
Hotamisligil
Gökhan S
GS
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008820:Mice, Obese; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction; D014157:Transcription Factors; D014415:Tunicamycin / Q000494:pharmacology; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000378:metabolism
D004268:DNA-Binding Proteins; D005947:Glucose; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008565:Membrane Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011972:Receptor, Insulin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D014415:Tunicamycin; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C526295:Irs1 protein, mouse; C526296:Irs1 protein, rat; C000605544:Xbp1 protein, mouse; C000605545:Xbp1 protein, rat; C486556:Ern2 protein, mouse; C486557:Ern2 protein, rat