Arachidonic acid down-regulates the insulin-dependent glucose transporter gene (GLUT4) in 3T3-L1 adipocytes by inhibiting transcription and enhancing mRNA turnover.
Chronic exposure of fully differentiated 3T3-L1 adipocytes to 50 microM arachidonic acid (AA) resulted in an inhibition (approximately 91%) in cellular GLUT4 mRNA content after a 48-h exposure, without similarly affecting the mRNA content of the ubiquitous glucose transporter, GLUT1. Subsequent investigations revealed that transcription of the GLUT4 gene was reduced by approximately 50% in response to AA treatment and the half-life of GLUT4 mRNA decreased from 8.0 to 4.6 h. By contrast, AA increased the accumulation of GLUT1 mRNA by 65%, by a mechanism that also involved regulation at both transcriptional and mRNA stability levels. Western blot analysis revealed that AA was specifically reducing the insulin-responsive glucose transporter (GLUT4) in both plasma and intracellular membranes. Subsequently, AA was observed to alter the ability of the GLUT4 transporter to respond to insulin and mediate a significant enhancement of glucose uptake. The results presented in this study indicate that AA can partially mimic the effects of both tumor necrosis factor-alpha and insulin which, when chronically supplied to 3T3-L1 adipocytes, also down-regulate GLUT4 gene expression. Therefore, these data may have relevance to the insulin-resistance associated with non-insulin-dependent diabetes mellitus.
Tebbey
P W
PW
Department of Microbiology and Immunology, East Carolina University School of Medicine, Greenville, North Carolina 27858.
McGowan
K M
KM
Stephens
J M
JM
Buttke
T M
TM
Pekala
P H
PH
D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology*; D003847:Deoxyglucose / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000235:genetics*; D009124:Muscle Proteins; D012333:RNA, Messenger / Q000378:metabolism*; D014158:Transcription, Genetic / Q000502:physiology*
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D016718:Arachidonic Acid; D003847:Deoxyglucose