Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency

Endocrinology. 2006 Aug;147(8):3877-88. doi: 10.1210/en.2005-1537. Epub 2006 May 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Bone and Bones / anatomy & histology
  • Female
  • Gene Expression / physiology
  • Glucose Tolerance Test
  • Growth Disorders / chemically induced
  • Growth Disorders / physiopathology*
  • Growth Disorders / prevention & control
  • Growth Hormone / blood
  • Growth Hormone / deficiency*
  • 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
  • Insulin-Like Growth Factor I / genetics*
  • Insulin-Like Growth Factor I / metabolism*
  • Liver / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Organ Specificity
  • Prealbumin / genetics
  • Pregnancy
  • RNA, Messenger / metabolism
  • Transcription, Genetic / physiology


  • Insulin-Like Growth Factor Binding Protein 3
  • Prealbumin
  • RNA, Messenger
  • Human Growth Hormone
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • pegvisomant