Transcriptional repression of the mouse insulin-responsive glucose transporter (GLUT4) gene by cAMP.
Glucose uptake by adipose tissue is mediated by two glucose transporters: GLUT4, which is most abundant, and GLUT1. While GLUT1 is expressed in many tissues, GLUT4 is unique to tissues that exhibit insulin-stimulated glucose uptake (heart and skeletal muscle and adipose tissue). In the diabetic state and during starvation, insulin-stimulated glucose uptake and GLUT4 expression are decreased in tissue adipocytes. Using 3T3-L1 adipocytes in culture, we investigated the possibility that these effects are mediated by elevated cellular cAMP. When 3T3-L1 adipocytes were treated for 16 hr with forskolin or 8-Br-cAMP, GLUT4 mRNA and protein were decreased by approximately 70%, while expression of GLUT1 mRNA and protein was increased 3-fold. These changes were accompanied by an increased basal rate of 2-deoxyglucose uptake and a loss of acute responsiveness of hexose uptake to insulin. The magnitude of GLUT4 mRNA depletion/GLUT1 mRNA accumulation was dependent upon the concentration of 8-Br-cAMP. The decrease of GLUT4 mRNA caused by 8-Br-cAMP was the result of a decreased transcription rate, while the half-life of the message was unaffected. The increase in GLUT1 mRNA caused by 8-Br-cAMP was the result of both transient transcriptional activation and mRNA stabilization. We suggest that down-regulation of GLUT4 mRNA in adipose tissue in the diabetic state and during starvation is the result of repression of transcription of the GLUT4 gene caused by cAMP.
Kaestner
K H
KH
Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Flores-Riveros
J R
JR
McLenithan
J C
JC
Janicot
M
M
Lane
M D
MD
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D016375:Antisense Elements (Genetics); D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D003847:Deoxyglucose / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014158:Transcription, Genetic / Q000187:drug effects
D016375:Antisense Elements (Genetics); D009004:Monosaccharide Transport Proteins; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D012313:RNA; D005934:Glucagon; D003847:Deoxyglucose; D000242:Cyclic AMP; D007545:Isoproterenol