Mechanism for down-regulation of GLUT4 by high-fat diet

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GLUT4, the insulin responsive-glucose transporter, mediates the rate limiting step of glucose metabolism in skeletal muscles and adipose tissues. High-fat feeding downregulates GLUT4 mRNA and decreases in insulin-stimulated glucose uptake in white adipose tissues (WAT). By using 5 -deleted mouse GLUT4 minigene transgenic mice, we have demonstrated that adipocyte specific element (s) of mouse GLUT4 are located within 45 bps between -551 and -506 relative to transcription initiation site, while high fat responsive element (s) is located within 150 bps between -701 and -551.DNase I footprinting analysis revealed that nuclear extract in WAT from both high-carbohydrate and high-fat diet fed mice protected the region from -705 to 682 (correspond to NF-1 site) and from -673 to 651 from DNase I digestion. This result showed that nuclear proteins bind to these regions regardless diet. Transgenic animal study indicated that mutation of NF-1 site near 701 abolished GLUT4 expression specially in white adipose tissues. These data suggest that a putative adipocyte specific enhancer binds both NF-1 and 45 bps between 551 and 506, while high-fat diet responsive enhancer binds 150 bps between 701 and 551 with some interaction to adipocyte specific enhancer.