Genetic dissection of IGF1-dependent and -independent effects of permanent GH excess on postnatal growth and organ pathology of mice

• Effects of GH and IGF1 can be dissected in GH transgenic Igf1 knockout mice in vivo.
• Permanent GH overabundance cannot reverse Igf1 deletion related dwarfism in mice.
• Kidney and liver alterations of GH transgenic mice can develop independently of IGF1.

To study insulin-like growth factor 1 (IGF1)-independent effects of permanent growth hormone (GH) excess on body and organ growth and pathology in vivo, hemizygous bovine GH transgenic mice with homozygous disruption of the Igf1 gene (Igf1−/−/GH) were generated, and examined in comparison to Igf1−/−, Igf1+/−, wild-type (WT), Igf1+/−/GH, and GH mice. GH mice and Igf1+/−/GH mice showed increased serum IGF1 levels and the well-known giant-phenotype of GH transgenic mice. In contrast, the typical dwarf-phenotype of Igf1−/− mice was only slightly ameliorated in Igf1−/−/GH mice. Similar to GH mice, Igf1−/−/GH mice displayed hepatocellular hypertrophy, glomerulosclerosis, and reduced volumes of acidophilic cells in the pituitary gland. However, GH excess associated skin lesions of male GH mice were not observed in Igf1−/−/GH mice. Therefore, development of GH excess induced liver-, kidney-, and pituitary gland-alterations in GH transgenic mice is independent of IGF1 whereas GH stimulated body growth depends on IGF1.