Adipocyte CREB promotes insulin resistance in obesity.
Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.
Qi
Ling
L
Laboratories for Peptide Biology, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
Saberi
Maziyar
M
Zmuda
Erik
E
Wang
Yiguo
Y
Altarejos
Judith
J
Zhang
Xinmin
X
Dentin
Renaud
R
Hedrick
Susie
S
Bandyopadhyay
Gautam
G
Hai
Tsonwin
T
Olefsky
Jerry
J
Montminy
Marc
M
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005943:Gluconeogenesis / Q000502:physiology; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism
D051700:Activating Transcription Factor 3; D052242:Adiponectin; C103002:Atf3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D051275:Glucose Transporter Type 4; C495693:Slc2a4 protein, mouse; D014157:Transcription Factors; D000263:Adenylate Kinase