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

Abstract

Triiodothyronine (T(3)) 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 T(3) activates the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis in rats. In turn, IGF-I inhibits the T(3)-induced GH production in cell cultures. The impact of IGF-I on T(3) action has only been partially explored. We have presented evidence that IGF-I feeds back to limit specific metabolic actions of T(3) 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 T(3)-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 microg/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 T(3) specific actions in liver and pituitary.

Growth hormone treatment in children with idiopathic short stature: correlation of growth response with peripheral thyroid hormone action

“…Previously, we reported data showing that IGF‐I and GH reduced specific T3 responses in rat tissues by a down‐regulation of TR in both rat cell culture and in vivo. 9–11 In consonance, we provided evidence for a reduced peripheral TH action induced by GH treatment to Turner Syndrome (TS) girls assessed by the measurement of TR mRNA expression in peripheral blood mononuclear cells (PBMC) and serum biochemical markers of TH action at tissue level 12 . However, these results could not be extrapolated to other patients receiving GH treatment, taking into consideration the different endogenous GH secretion as well as the different GH dosage administered to patients carrying different etiopathogenic growth deficiencies 13 .…”

Growth hormone (GH) treatment reduces peripheral thyroid hormone action in girls with Turner syndrome

“…TRβ is the main pituitary isoform with a prevalence of TRβ 2 28 which is not expressed in PBMC. However, a pituitary reduction not only of TRβ 1 but also TRβ 2 induced by GH treatment to TS girls is highly probable, considering the reduction of total TRβ in pituitary, both at protein and mRNA level, induced by IGF‐I administration as shown in experiments carried out on the rat 17 . As TRβ is the most potent regulator of TSH production, 29 a decreased expression of TRβ could explain, at least in part, the increase in TSH serum concentration attained in TS patients under GH treatment.…”

“…[14][15][16] The effect of IGF-I on TR was exerted at transcriptional level. 17 According to our previous results from an animal model, the supraphysiological IGF-I levels induced by GH treatment to TS girls could reduce TR expression at tissue level, leading to an impaired peripheral thyroid signalling pathway. TR are expressed in peripheral blood mononuclear cells (PBMC) and blood represents a tissue readily accessible for studies conducted in human beings.…”

“…In turn, we reported data showing that IGF‐I and GH (through IGF‐I synthesis) reduced specific T 3 responses in rat tissues by a down‐regulation of nuclear TR in both cell culture and in vivo. 14–16 The effect of IGF‐I on TR was exerted at transcriptional level 17 …”

Identification and characterization of RanBPM, a novel coactivator of thyroid hormone receptors

“…Total cell extract concentrations were measured using a standard Bradford assay (Bio-Rad Laboratories). Immunoprecipitation was performed using a rabbit polyclonal IgG antibody raised against chicken TR 1 but recognizing all human TR isoforms (FL-408; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) (Pellizas et al 2002). The formation of immuno-complexes was made in the presence or absence of T 3 ; the positive control represents 50 µg HeLa whole cell extracts.…”