The Effects of Retinoic Acid on the Expression of Glucose Transporter 4 in Differentiating L6 Myocytes and 3T3-L1 CARΔ1 Adipose Cells

The epidemicity of metabolic diseases such as obesity and diabetes globally has become a public health concern. Therefore, understanding interactions of macronutrients such as glucose and micronutrients such as vitamin A (VA) has become urgent. Both skeletal muscle and adipose tissues are critical for the regulation of glucose homeostasis. Retinoid acid (RA) is an active metabolite of retinol which mediates the major functions of VA. RA and insulin signals have been shown to regulate glucose metabolism. However, their roles in glucose metabolism in skeletal muscle and adipocytes remain to be revealed. We postulate that insulin and RA signals may work together to regulate glucose metabolism in skeletal muscle cells and adipocytes. In the first study, the glucose transporter 4 (GLUT4) expression were measured in L6 myocyes treated with increasing doses of RA in the absence or presence of insulin for 6 days. RA and insulin were found to inhibit the expression levels of GLUT4 in L6 cells after 4 and 6 days of treatment. The synergy inhibition effects of RA and insulin on GLUT4 can be observed at Day 4 with RA at 1 μM RA. To study the RA effects on adipocytes, recombinant adenoviruses were used to overexpress retinoid X receptor α (RXRα) and chicken ovalbumin upstream transcription factor II (COUP-TFII), two transcription factors with the potential to mediate RA signaling. 3T3-L1 CARΔ1 cells were transfected with ad-β-gal, ad-RXRα or ad-COUPTFII and treated with increasing RA doses during differentiation. Lipid accumulation and GLUT4 protein level were examined. Interestingly, overexpression of RXRα enhanced the inhibitory effects of RA on lipid accumulation. Moreover, the inhibitory effect of RA on GLUT4 expression can be attenuated in the presence of RXRα overexpression. The overexpression of COUPTFII may enhance the inhibitory effects of RA on the expression of GLUT4. The fact that RA and insulin synergized to inhibit the GLUT4 expression in L6 cells seems to indicate that cautions should be taken when VA supplement is recommended for patients with diabetes or obesity.