1. Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency.
- Author
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Liao L, Dearth RK, Zhou S, Britton OL, Lee AV, and Xu J
- Subjects
- Animals, Body Weight, Bone and Bones anatomy & histology, Female, Gene Expression physiology, Glucose Tolerance Test, Growth Disorders chemically induced, Growth Disorders prevention & control, Growth Hormone blood, Human Growth Hormone analogs & derivatives, Human Growth Hormone pharmacology, Insulin-Like Growth Factor Binding Protein 3 blood, Insulin-Like Growth Factor Binding Protein 3 genetics, Mice, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Prealbumin genetics, Pregnancy, RNA, Messenger metabolism, Transcription, Genetic physiology, Growth Disorders physiopathology, Growth Hormone deficiency, Insulin-Like Growth Factor I genetics, Insulin-Like Growth Factor I metabolism, Liver physiology
- Abstract
The precise role of circulating IGF-I in somatic growth under normal and GH-deficient conditions remains unclear. To define the contribution of circulating IGF-I to the endocrine regulation of somatic growth and the GH/IGF-I axis, we constructed a transgene with the transthyretin (TTR) enhancer/promoter and the mouse IGF-I cDNA and generated TTR-IGF-I transgenic mice. The transgene was exclusively expressed in the liver, which resulted in a 50-60% increase in serum IGF-I, a decrease in serum GH, and an improved tolerance to glucose challenge. The body weight and lean mass of TTR-IGF-I mice were heavier compared with wild-type (WT) mice. The increase in lean mass was a result of increase in both number and thickness of skeletal muscle fibers. The femur, tibia, and body lengths of TTR-IGF-I mice also were longer. In WT mice, the GH antagonist pegvisomant (Peg) suppressed the transcription of endogenous IGF-I and acid-labile subunit (ALS) genes with no effect on IGF-binding protein 3 (IGFBP-3) mRNA. Consequently, Peg-induced GH deficiency in WT mice severely reduced ALS, IGF-I, and IGFBP-3 in the circulation and caused a severe growth deficit. In TTR-IGF-I mice, Peg reduced the mRNA of the endogenous IGF-I gene with no effect on the TTR-IGF-I transgene expression, leading to a blunted decrease in serum IGF-I levels. Interestingly, IGFBP-3 mRNA was elevated and circulating IGFBP-3 was less reduced in Peg-treated TTR-IGF-I mice. Peg-treated TTR-IGF-I mice also exhibited heavier body weight and longer body length than Peg-treated WT mice. Therefore, liver-expressed IGF-I can stimulate IGFBP-3 mRNA expression and stabilize IGFBP-3 under GH deficiency, leading to a better maintenance of IGF-I levels in the circulation. Higher circulating levels of IGF-I can stimulate somatic growth and lean mass and improve glucose tolerance.
- Published
- 2006
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