PERINATAL HYPOTHYROIDISM IMPAIRS THE NORMAL TRANSITION OF GLUT4 AND GLUT1 GLUCOSE TRANSPORTERS FROM FETAL TO NEONATAL LEVELS IN HEART AND BROWN ADIPOSE-TISSUE - EVIDENCE FOR TISSUE-SPECIFIC REGULATION OF GLUT4 EXPRESSION BY THYROID-HORMONE

GLUT1 and GLUT4 glucose transporter expression is highly regulated in muscle and adipose tissue during perinatal life. Here we have investigated the role of thyroid hormones in the regulation of GLUT4 induction and GLUT1 repression associated to neonatal development. Perinatal hypothyroidism markedly impaired GLUT4 protein induction in heart. This effect was heart specific, and a greater expression of GLUT4 was detected in brown adipose tissue from neonatal hypothyroid rats compared with controls. These changes in GLUT4 protein expression were not detected in brown adipose tissue or heart when hypothyroidism was induced in adult rats. These results indicate that GLUT4 induction during perinatal life is highly sensitive to thyroid hormones in both heart and adipose tissue. Perinatal hypothyroidism was characterized by decreased cardiac GLUT4 mRNA concentrations. T-3 injection caused a marked increase in cardiac levels of GLUT4 mRNA in hypothyroid neonates. Thus, in 18-day-old hypothyroid rats, GLUT4 mRNA levels increased 3-fold 1 h after T-3 injection. Under these conditions, retinoic acid also caused a rapid increase in cardiac GLUT4 mRNA levels from hypothyroid neonates. In addition, cardiac levels of GLUT4 protein markedly increased in fetuses and in neonates 24 h after T-3 injection. These findings suggest that a direct effect of thyroid hormones is the promotion of cardiac GLUT4 gene expression. GLUT1 protein expression was markedly enhanced in brown adipose tissue and heart during neonatal hypothyroidism as well, as in hypothyroidism induced in adult rats. This was concomitant to greater levels of GLUT1 mRNA in hearts from hypothyroid neonates, Immunofluorescence analysis indicated that cardiomyocytes from hypothyroid pups contained an enhanced level of GLUT1 protein. Furthermore, T-3 injection caused a decrease in cardiac levels of GLUT1 mRNA in hypothyroid neonates. These results indicate that thyroid hormone manipulation leads to inverse regulation of GLUT1 and GLUT4 glucose transporter gene expression in the neonatal heart. We conclude that thyroid hormones play a pivotal role controlling the transition of glucose transporter carriers from fetal to neonatal levels in heart and brown adipose tissue.