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.
Department of Genetics and Complex Diseases, Harvard Medical School, Boston, MA 02115, USA.
Umut
U
Ozcan
Qiong
Q
Cao
Erkan
E
Yilmaz
Ann-Hwee
AH
Lee
Neal N
NN
Iwakoshi
Esra
E
Ozdelen
Gürol
G
Tuncman
Cem
C
Görgün
Laurie H
LH
Glimcher
Gökhan S
GS
Hotamisligil
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