GROWTH-HORMONE (GH) STIMULATES INSULIN-LIKE GROWTH FACTOR-I (IGF-I) AND IGF-I-BINDING PROTEIN-3, BUT NOT GH RECEPTOR GENE-EXPRESSION IN LIVERS OF JUVENILE RATS

In the adult rat, expression of the liver GH receptor, insulin-like growth factor-I (IGF-I), and IGF-I-binding protein-3 (IGFBP-3) genes has been shown to be under GH control. Additionally, hypophysectomy and GH treatment have a differential effect on the relative abundance of liver IGF-I mRNA variants in adult rats. To further elucidate the time of appearance and the extent of GH control of liver GH receptor, IGF-I, and IGFBP-3 gene expression, we studied the effect of hypophysectomy and GH and IGF-I treatment in juvenile rats. Male Wistar rats were hypophysectomized (Hx) on postnatal day 26 and received twice daily sc injections of saline, recombinant human GH (2.5 U/kg. day), or recombinant human IGF-I (500 mug/kg.day) for 7 days. Sham-operated rats received the same treatment. Hx animals also received T4 (20 mug/kg.day). In Hx animals, there was a significant reduction in body weight (69.8 +/- 6.6 vs. 100.4 +/- 5.4 g; P < 0.001). GH, but not IGF-I, treatment increased body weight (79.6 +/- 9.6 g after GH vs. 69.8 +/-6.6 g before GH; P < 0.05). GH treatment partially maintained liver, kidney, and lung weights in Hx animals and increased them in intact animals, whereas IGF-I treatment did so only in the lungs of intact and Hx animals. Serum GH and IGF-I levels were markedly reduced in Hx animals compared with those in intact controls, and GH treatment maintained, albeit partially, circulating IGF-I levels compared with those in saline-treated Hx animals. IGF-I mRNA levels were markedly reduced in Hx liver (25.0 +/- 5.4%; P < 0.001 compared with intact controls). GH treatment for 7 days increased IGF-I mRNA levels by 4.8-fold over the levels in 9-day Hx animals and increased IGF-I mRNA levels by 2.2-fold in control rats. Hypophysectomy decreased exon 2-containing transcripts by 7.0-fold and exon 1-containing transcripts by 4.1-fold. GH treatment, however, affected both exon 1- and exon 2-containing transcripts similarly. Hepatic IGFBP-3 mRNA levels were reduced in Hx (53.2 +/- 1.8%; P < 0.01 compared with intact controls) and IGF-treated Hx animals, but were not decreased in Hx GH-treated animals (100.6 +/- 9.5). No changes in GH receptor or GH-binding protein mRNA levels were caused by Hx, GH, or IGF-I treatment. These findings suggest that in juvenile rats, the IGF-I, IGFBP-3, and GH receptor/GH-binding protein genes are differentially sensitive to GH. Whereas IGF-I gene expression is extremely sensitive to changes in circulating GH levels, IGFBP-3 mRNA appears to be less sensitive to GH, and GH receptor/GH-binding protein mRNA levels appear to be GH independent.