Differential Modulation of Liver and Pituitary Triiodothyronine and 9- cis Retinoid Acid Receptors by Insulin-Like Growth Factor I in Rats

Abstract

Triiodothyronine (T₃) exerts most of its effects through nuclear thyroid hormone receptors (TRs) that bind mainly as heterodimers with retinoid-X receptors (RXRs) to thyroid hormone response elements in target genes. It is well known that T₃ activates the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis in rats. In turn, IGF-I inhibits the T₃-induced GH production in cell cultures. The impact of IGF-I on T₃ action has only been partially explored. We have presented evidence that IGF-I feeds back to limit specific metabolic actions of T₃ in rat liver through a downregulation of nuclear TR number and its mRNA expression. We have also found that IGF-I injected to rats inhibited pituitary GH production. In this study we aimed at exploring whether the IGF-I-induced feedback loop on T₃-action in the liver also operates in the pituitary gland. The mechanism of the liver TR mRNA reduction induced by IGF-I was also studied. We evaluated the effect of recombinant human (rh) IGF-I administration (240 μg/100 g of body weight subcutaneously every 12 hours for 48 hours) to adult male Wistar rats on TR and RXR proteins (Western blot) from pituitary, liver, brain, and thyroid and TR mRNA (Northern blot) from pituitary and liver. The transcriptional rate of liver TR gene (run-on assay) was also determined. In pituitary, TR protein and TR mRNA isoforms were reduced by rhIGF-I. No changes in TR proteins in brain and thyroid were observed. Nuclear run-on assay revealed that IGF-I reduced the TR gene transcriptional rate in liver. A significant increase in RXR proteins in liver and pituitary without changes in thyroid and brain was induced by IGF-I. In conclusion, these results indicate that in pituitary, IGF-I downregulates TR expression, similarly as previously found in liver. A reduced transcriptional rate of TR gene is implicated in the IGF-I effect on the liver. The increase in RXR protein levels may be also involved in the expression of T₃ specific actions in liver and pituitary.