Functional Alteration of the Somatotrophic Axis in Transgenic Mice with Liver-Specific Expression of Human Insulin-like Growth Factor Binding Protein-1

摘要

In earlier work, postnatal growth restriction (more marked in males) was observed in a model of transgenic mice with liver-specific expression of human IGF binding protein-1. This was associated with diminished plasma IGF-I levels, the cause of which remained unexplained. Subsequently, abnormalities of CNS development were ascertained, justifying investigation of the somatotrophic axis. Pituitary gland weight in transgenic animals was reduced proportionally to body weight. Immunohistochemical examination of the pituitaries in 3- to 4-mo-old mice revealed somatotrophs of normal size in homozygotes, but density was decreased to approximately two thirds of that in wild-type siblings (p = 0.001). The same was true of lactotrophs. The GH content of the pituitary was significantly reduced in heterozygotes (p p in vitro the amounts of GH secreted under basal conditions and under GH-releasing hormone stimulation were similar in transgenic and wild-type mice. Ten days of treatment with human GH (100 μg/d) in 45-d-old transgenic and wild-type mice provoked significant weight gain (p = 0.02) in all animals, the means being 12.4% for homozygotes and 10.4% in heterozygotes, as opposed to 5.8% in wild-type mice. The increase in weight tended to correlate with an increase in plasma IGF-I. From these results, we conclude that the reduced plasma IGF-I in IGF binding protein-1 transgenic mice may result from insufficient GH production by the depressed number of somatotrophs, possibly associated with functional alteration of hypothalamic control.Abbreviations: IGFBP, IGF binding protein; hIGFBP, human IGF binding protein; GHRH, GH releasing hormone; ALS, acid-labile subunit; DAB, 3,3′-diaminobenzidine tetrahydrochloride dihydrate