INSULIN-LIKE-GROWTH-FACTOR-I REDUCES THYROID-HORMONE RECEPTORS IN THERAT-LIVER - EVIDENCE FOR A FEEDBACK LOOP REGULATING THE PERIPHERAL THYROID-HORMONE ACTION

Tri-iodothyronine (T-3) is known to be involved in the regulation of t he growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. In p revious studies we demonstrated that IGF-I and GH reduced the metaboli c response to T-3 measured as the activity of two T-3-dependent enzyme s, mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) and cytosolic malic enzyme (ME) in cultured rat liver cells. In this study we analysed in vivo the effect of IGF-I administered to rats on the a ctivity of alpha-GPD and ME. IGF-I (240 mu g/100 g body weight (BW) ev ery 12 h for 48 h) significantly diminished alpha-GPD (P<0.01) and ME (P<0.05) activities. Serum basal glucose concentration was not signifi cantly modified 12 h after the administration of recombinant human IGF -I (240 and 480 mu g/100 g BW every 12 h for 48 h). Under similar cond itions, no significant change in serum total thyroxine (TT4) concentra tion was observed, although free thyroxine (FT4) was diminished (P<0.0 2) and total T-3 (TT3) was increased (P<0.03). To explore the particip ation of the nuclear thyroid hormone receptor (THR) in the mechanism o f IGF-I action we measured the maximal binding capacity and the affini ty constant (K-a) of THR by Scatchard analysis, and concentrations of messenger RNAs (mRNAs) that code for the isoforms of THR present in th e liver (beta(1), alpha(1) and alpha(2)) by Northern blot. IGF-I (240 mu g/100g BW every 12 h for 48 h) significantly reduced maximal bindin g capacity to 37% of the control value (P<0.01) without changes in the K-a. beta(1), alpha(1) and alpha(2) THR mRNAs were significantly redu ced (P<0.01) by 120-480 mu g/100 g BW IGF-I administration every 12 h for 48 h. Time-course studies indicated that this effect was obtained 12 h after the administration of 240 mu g/100 g BW IGF-I (P<0.05). The se results indicate that IGF-I administration to rats diminishes the m etabolic thyroid hormone action in the liver by a mechanism that invol ves, at least in part, a reduction in the number of THRs and in their level of expression.