Roles of Growth Hormone and Insulin-like Growth Factor 1 in Mouse Postnatal Growth (original) (raw)
Related papers
2000
To clarify the role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are characterized by serum GH levels in the range of 2 g/ml. Four genetic groups were obtained: animals carrying both transgenes (GB), the GH (G) or the IGFBP-2 transgene (B), and nontransgenic controls (C). Male offspring were analyzed for serum levels of IGF-I, for serum and tissue levels of IGFBP-2, and for body and organ growth. Serum IGF-I levels were 2-to 3-fold increased (P Ͻ 0.001) in the GH-overexpressing groups, with no difference between G and GB mice. Serum IGFBP-2 levels were 4-to 9-fold (P Ͻ 0.001) increased both in B and GB vs. C and G mice. Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice. IGFBP-2 levels were highest in pancreas, followed by skeletal muscle, heart, kidney, brain, skin, and spleen. No elevation of IGFBP-2 was found in the liver. Body weight gain of G and GB mice was significantly increased vs. C and B mice, resulting in almost 2-fold increased body weights at the age of 15 weeks. How
Pediatric Nephrology, 2000
Growth hormone (GH) and insulin-like growth factors (IGFs) are essential for normal growth and development during embryonic stages as well as postnatally. While GH has little effect on these processes prenatally, the IGFs are important during these stages. On the other hand the GH-IGF-I axis is important for pubertal growth. To determine whether postnatal growth and development are dependent on circulating or locally produced IGF-I, we deleted the IGF-I gene in the liver using the cre/LoxP system used for tissue-specific gene deletion. These animals demonstrated approximately 75%-80% reduction in circulating IGF-I and an approximate fourfold increase in circulating GH. Despite the marked reductions in circulating IGF-I, growth and development was apparently normal. Thus the original somatomedin hypothesis needs to be re-evaluated in the light of these new findings.
Endocrinology, 2001
To clarify the role of insulin-like growth factor (IGF)-binding protein-2 (IGFBP-2) in postnatal growth regulation, we crossed hemizygous CMV-IGFBP-2 transgenic mice with hemizygous PEPCK-bGH transgenic mice, which are characterized by serum GH levels in the range of 2 g/ml. Four genetic groups were obtained: animals carrying both transgenes (GB), the GH (G) or the IGFBP-2 transgene (B), and nontransgenic controls (C). Male offspring were analyzed for serum levels of IGF-I, for serum and tissue levels of IGFBP-2, and for body and organ growth. Serum IGF-I levels were 2-to 3-fold increased (P Ͻ 0.001) in the GH-overexpressing groups, with no difference between G and GB mice. Serum IGFBP-2 levels were 4-to 9-fold (P Ͻ 0.001) increased both in B and GB vs. C and G mice. Western immunoblot analysis did not reveal differences in tissue IGFBP-2 levels between B and GB mice. IGFBP-2 levels were highest in pancreas, followed by skeletal muscle, heart, kidney, brain, skin, and spleen. No elevation of IGFBP-2 was found in the liver. Body weight gain of G and GB mice was significantly increased vs. C and B mice, resulting in almost 2-fold increased body weights at the age of 15 weeks. How-
Cell, 1993
Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene 1 (Igf.1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf.2 null mutants (60% of normal blrthweight). Depending on genetic background, some of the Igf.l(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igflr gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasla in Igflr(-/-) embryos, including the muscles, and developmental delays In ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf.l(-/-)/Igflr(-/-) double mutants did not differ in phenotype from Igflr(-/-) single mutants, while in Igf.2(-)/Igflr(-/-) and Igf.l(-/-)/Igf.2(-) double mutants, which are phe-
Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production
Journal of Bone and Mineral Research, 2011
Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two-to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions.
Endocrinology, 1999
Organ weight was compared in adult mice with deletion of one (IRS-1 Ϫ/ϩ) or both (IRS-1 Ϫ/Ϫ) copies of the insulin receptor substrate-1 (IRS-1) gene and IRS-1 ϩ/ϩ littermates. IRS-1 Ϫ/ϩ mice showed modest reductions in weight of most organs in proportion to a decrease in body weight. IRS-1 Ϫ/Ϫ mice showed major reductions in weight of heart, liver, and spleen that were directly proportional to a decrease in body weight. In IRS-1 Ϫ/Ϫ mice, kidney and particularly small intestine and brain exhibited proportionately smaller weight reductions, and gastrocnemius muscle showed a proportionately greater weight reduction than the decrease in body weight. Growth deficits in IRS-1 Ϫ/Ϫ mice could reflect impaired actions of multiple hormones or cytokines that activate IRS-1. To assess the requirement for IRS-1 in insulinlike growth factor I (IGF-I)-dependent postnatal growth, IRS-1 Ϫ/ϩ mice were cross-bred with mice that widely overexpress a human IGF-I transgene (IGFϩ) to generate IGFϩ and wild-type mice on an IRS-1 ϩ/ϩ , IRS-1 Ϫ/ϩ , and IRS-1 Ϫ/Ϫ background. IGF-I overexpression increased body weight and weight of brain, small intestine, kidney, spleen, heart, and gastrocnemius muscle in IRS-1 ϩ/ϩ mice. IGF-I overexpression could not completely reverse the body growth retardation in IRS-1 Ϫ/Ϫ mice. Absolute or partial IRS-1 deficiency impaired IGF-I-induced body overgrowth more in females than in males. In males and females, IGF-I stimulated similar overgrowth of brain regardless of IRS-1 status, and intestine and spleen showed dose dependence on IRS-1 for IGF-I-induced growth. IGF-I-induced growth of gastrocnemius muscle had an absolute requirement for IRS-1. IGF-I-induced growth of kidney and heart was impaired by IRS-1 deficiency only in females. In vivo, therefore, most organs do not require IRS-1 for IGF-I-induced growth and can use alternate signaling molecules to mediate IGF-I action. Other organs, such as gastrocnemius muscle, require IRS-1 for IGF-I-induced growth in vivo.
Endocrinology, 2000
The actions of insulin-like growth factor-I (IGF-I) are modulated by IGF binding proteins (IGFBPs). The effects of IGFBP-1 in vivo are insufficiently known, with respect to inhibitory or stimulatory actions on IGF-induced growth of specific organs. Therefore, we studied the effects of IGFBP-1 on IGF-I-induced somatic and organ growth in pituitary-deficient Snell dwarf mice. Human GH, IGF-I, IGFBP-1, and a preequilibrated combination of equimolar amounts of IGF-I and IGFBP-1 were administered sc during 4 weeks. Treatment with IGF-I alone induced a significant increase in body length (108% of control) and weight (112%) as well as an increase in weight of the submandibular salivary glands (135%), kidneys (124%), femoral muscles (111%), testes (129%), and spleen (126%) compared with saline-treated controls. IGFBP-1 alone induced a significant increase in weight of the kidneys (152% of control). Coadministration of IGF-I with IGFBP-1 neutralized the stimulating effects of IGF-I on body length and weight as well as on the femoral muscles and testes.
The hormonal action of IGF1 in postnatal mouse growth
Proceedings of the …, 2008
The mammalian insulin-like growth factor 1 (IGF1), which is a member of a major growth-promoting signaling system, is produced by many tissues and functions throughout embryonic and postnatal development in an autocrine/paracrine fashion. In addition to this ...