It is well known that triiodothyronine (T3) activates the growth hormone (GH)-insulin like growth factor I (IGF-I) axis in the rat, by increasing the synthesis and secretion of pituitary GH, as well as hepatic IGF-I. In turn, IGF-I inhibits GH in vitro and in vivo. The impact of IGF-I on thyroid hormone (TH) action in different tissues has not been fully explored. We have presented evidence that IGF-I feeds back to limit some specific metabolic action of T3 in rat liver and pituitary, through a down regulation of nuclear T3 receptor (T3R) protein and mRNA, effects not found in other tissues such as brain and thyroid. T3Rs bind mainly as heterodimers with retinoid-X-receptors (RXRs) to TH response elements in target genes. Current evidence suggests that T3R/RXR heterodimer plays a major role in mediating transcriptional activation of target genes. In this study we further explored the molecular mechanism of the reduction of T3-specific metabolic action in liver and pituitary induced by IGF-I. For that purpose we evaluated the effect of IGF-I administration to adult male Wistar rats (rhIGF-I: 240 µg/100 g BW every 12 h for 48 h) on: 1) transcriptional rate of T3R gene (run-on assay) in liver nuclei; and 2) RXR levels (Western blot) from liver, pituitary, brain and thyroid. The transcriptional rate of T3R gene was reduced to 54% of control values by IGF-I administration in the liver (arbitrary units, mean±SEM: control= 0.273±0.021, IGF-I treated= 0.148±0.018, p<0.05, n=3, Student "t" test). On the other hand, a significant increase in total RXR from liver and pituitary tissues was registered after IGF-I treatment (% of control, mean±SEM: liver= 132±6, pituitary= 125±3, p<0.01, n:6, Student "t" test). In contrast, no significant differences in total RXR levels from thyroid and brain were attained. In conclusion, our results suggest that IGF-I reduced T3R mRNA in the liver by a mechanism that involves, at least in part, a reduction of T3R gene transcriptional rate. The increase in RXR levels in tissues where IGF-I reduced T3R, could also account for the reduced T3 specific action.
