Acute inhibition of fatty acid import inhibits GLUT4 transcription in adipose tissue, but not skeletal or cardiac muscle tissue, partly through liver X receptor (LXR) signaling.
OBJECTIVE
Insulin-mediated glucose uptake is highly sensitive to the levels of the facilitative GLUT protein GLUT4. Transcription of the GLUT4 gene is repressed in states of insulin deficiency and insulin resistance and can be induced by states of enhanced energy output, such as exercise. The cellular signals that regulate GLUT4 transcription are not well understood. We hypothesized that changes in energy substrate flux regulate GLUT4 transcription.


METHODS
To test this hypothesis, we used transgenic mice in which expression of the chloramphenicol acetyltransferase (CAT) gene is driven by a functional 895-bp fragment of the human GLUT4 promoter, thereby acting as a reporter for transcriptional activity. Mice were treated with a single dose of etomoxir, which inhibits the transport of long-chain fatty acids into mitochondria and increases basal, but not insulin-mediated, glucose flux. GLUT4 and transgenic CAT mRNA were measured.


RESULTS
Etomoxir treatment significantly reduced CAT and GLUT4 mRNA transcription in adipose tissue, but did not change transcription in heart and skeletal muscle. Downregulation of GLUT4 transcription was cell autonomous, since etomoxir treatment of 3T3-L1 adipocytes resulted in a similar downregulation of GLUT4 mRNA. GLUT4 transcriptional downregulation required the putative liver X receptor (LXR) binding site in the human GLUT4 gene promoter in adipose tissue and 3T3-L1 adipocytes. Treatment of 3T3-L1 adipocytes with the LXR agonist, TO901317, partially restored GLUT4 expression in etomoxir-treated cells.


CONCLUSIONS
Our data suggest that long-chain fatty acid import into mitochondria in adipose tissue may produce ligands that regulate expression of metabolic genes.
Griesel
Beth A
BA
Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Weems
Juston
J
Russell
Robert A
RA
Abel
E Dale
ED
Humphries
Kenneth
K
Olson
Ann Louise
AL
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015500:Chloramphenicol O-Acetyltransferase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017931:DNA Primers; D004852:Epoxy Compounds / Q000494:pharmacology; D051275:Glucose Transporter Type 4 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity; D011401:Promoter Regions, Genetic
D017931:DNA Primers; D004852:Epoxy Compounds; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495692:SLC2A4 protein, human; D015500:Chloramphenicol O-Acetyltransferase; C054207:etomoxir