Expression of the insulin-responsive glucose transporter GLUT4 in adipocytes is dependent on liver X receptor α

The insulin-responsive glucose transporter GLUT4 plays a crucial role in insulin-mediated facilitated glucose uptake into adipose tissue and muscle, and impaired expression of GLUT4 has been linked to obesity and diabetes. In this study, we demonstrate that liver X receptors (LXRs) regulate the expression of GLUT4 through direct interaction with a conserved LXR response element in the GLUT4 promoter. The expression of GLUT4 in WAT is induced by a potent LXR agonist in wild type, LXRalpha(-/-), and LXRbeta(-/-) mice but not in LXRalpha(-/-) beta(-/-) mice, demonstrating that both LXRs are able to mediate ligand activated transcription of the GLUT4 gene. However, basal and insulin stimulated expression of GLUT4 in epididymal WAT is reduced only in mice carrying ablation of the LXRalpha isoform. The expression of GLUT4 is furthermore correlated to the induction of LXRalpha during mouse and human adipocyte differentiation. LXRbeta is thus apparently not able to rescue basal expression of GLUT4 in the absence of LXRalpha. We have previously demonstrated that LXRalpha is downregulated in animal models of obesity and diabetes, thus revealing a striking correlation between GLUT4 and LXRalpha expression in insulin-resistant conditions. This suggests that the LXRalpha isoform has a unique role in adipose expression of GLUT4 and suggests that alteration of adipose tissue expression of LXRalpha might be a novel tool to normalize the expression of a gene that is dysregulated in diabetic and insulin-resistant conditions.