Liver-derived IGF-I contributes to GH-dependent increases in lean mass and bone mineral density in mice with comparable levels of circulating GH

Mol Endocrinol. 2011 Jul;25(7):1223-30. doi: 10.1210/me.2011-0047. Epub 2011 Apr 28.


The relative contributions of circulating and locally produced IGF-I in growth remain controversial. The majority of circulating IGF-I is produced by the liver, and numerous mouse models have been developed to study the endocrine actions of IGF-I. A common drawback to these models is that the elimination of circulating IGF-I disrupts a negative feedback pathway, resulting in unregulated GH secretion. We generated a mouse with near total abrogation of circulating IGF-I by disrupting the GH signaling mediator, Janus kinase (JAK)2, in hepatocytes. We then crossed these mice, termed JAK2L, to GH-deficient little mice (Lit). Compound mutant (Lit-JAK2L) and control (Lit-Con) mice were treated with equal amounts of GH such that the only difference between the two groups was hepatic GH signaling. Both groups gained weight in response to GH but there was a reduction in the final weight of GH-treated Lit-JAK2L vs. Lit-Con mice. Similarly, lean mass increased in both groups, but there was a reduction in the final lean mass of Lit-JAK2L vs. Lit-Con mice. There was an equivalent increase in skeletal length in response to GH in Lit-Con and Lit-JAK2L mice. There was an increase in bone mineral density (BMD) in both groups, but Lit-JAK2L had lower BMD than Lit-Con mice. In addition, GH-mediated increases in spleen and kidney mass were absent in Lit-JAK2L mice. Taken together, hepatic GH-dependent production of IGF-I had a significant and nonredundant role in GH-mediated acquisition of lean mass, BMD, spleen mass, and kidney mass; however, skeletal length was dependent upon or compensated for by locally produced IGF-I.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Bone Density
  • Female
  • Gene Expression
  • Growth Hormone / blood
  • Growth Hormone / pharmacology*
  • Growth Hormone / physiology
  • Insulin-Like Growth Factor Binding Proteins / genetics
  • Insulin-Like Growth Factor Binding Proteins / metabolism
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / metabolism
  • Kidney / anatomy & histology
  • Liver / metabolism
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Size
  • Receptors, Somatotropin / genetics
  • Receptors, Somatotropin / metabolism
  • Spleen / anatomy & histology
  • Weight Gain


  • Insulin-Like Growth Factor Binding Proteins
  • Receptors, Somatotropin
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Growth Hormone
  • Jak2 protein, mouse
  • Janus Kinase 2