scholarly journals Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

2011 ◽  
Vol 23 (5) ◽  
pp. 665 ◽  
Author(s):  
Ellen C. Jensen ◽  
Laura Bennet ◽  
Charles Wood ◽  
Mark Vickers ◽  
Bernhard Breier ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Late Gestation ◽  
Control Group ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Low Cortisol

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. The hypothesis examined was that alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg kg–1 day–1 cortisol (high cortisol) and five adrenalectomised ewes given 0.5–0.6 mg kg–1 day–1 cortisol (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations were higher in the low cortisol group compared with those in the control group (P < 0.05). Fetal liver IGF-II and IGFBP-3 mRNA were decreased in low cortisol animals compared with controls (P < 0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

1996 ◽  
Vol 271 (6) ◽  
pp. R1632-R1637 ◽  
Author(s):  
K. L. Kind ◽  
J. A. Owens ◽  
F. Lok ◽  
J. S. Robinson ◽  
K. J. Quinn ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Intravenous Infusion ◽  
Feedback Inhibition ◽  
Fetal Liver ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Igf I

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

Insulin-like growth factor I promotes growth selectively in fetal sheep in late gestation

1996 ◽  
Vol 270 (5) ◽  
pp. R1148-R1155 ◽  
Author(s):  
F. Lok ◽  
J. A. Owens ◽  
L. Mundy ◽  
J. S. Robinson ◽  
P. C. Owens
Keyword(s):  
Growth Factor ◽  
Fetal Growth ◽  
Late Gestation ◽  
Skeletal Maturation ◽  
Long Bones ◽  
Insulin Like Growth Factor ◽  
Fetal Sheep ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

Insulin-like growth factor I (IGF-I) is required for normal fetal growth and skeletal maturation in late gestation, because null mutations of the IGF-I gene in mice reduce fetal weight and retard ossification of bones. To determine if, conversely, increased abundance of IGF-I promotes fetal growth and skeletal maturation, fetal sheep were infused intravascularly with recombinant human IGF-I (n = 7) (26 +/- 3 micrograms. h-1.kg-1) from 120 to 130 days gestation and compared with controls (n = 15). IGF-I infusion increased plasma IGF-I concentrations by 140% (P = 0.002) and weights of fetal liver, lungs, heart, kidneys, spleen, pituitary, and adrenal glands by 16-50% (P < 0.05). Weights and/or lengths of the fetus, placenta, gastrointestinal tract, individual skeletal muscles, and long bones were unchanged by IGF-I. However, IGF-I increased the percentage of proximal epiphyses of long bones present (P < 0.05) and their cross-sectional areas by 15 to 38% (P < 0.05). These results show that IGF-I promotes growth of major fetal organs, endocrine glands, and skeletal maturation in vivo, consistent with IGF-I actively controlling and not merely facilitating fetal growth. The variable response of different tissues may partly reflect tissue specificity in growth requirements for additional factors.

ELEVATING MATERNAL INSULIN-LIKE GROWTH FACTOR-I IN MICE AND RATS ALTERS THE PATTERN OF FETAL GROWTH BY REMOVING MATERNAL CONSTRAINT

1992 ◽  
Vol 134 (1) ◽  
pp. R1-R3 ◽  
Author(s):  
P.D. Gluckman ◽  
P.C.H. Morel ◽  
G.R. Ambler ◽  
B.H. Breier ◽  
H.T. Blair ◽  
...  
Keyword(s):  
Body Weight ◽  
Growth Factor ◽  
Litter Size ◽  
Fetal Growth ◽  
Negative Relationship ◽  
Late Gestation ◽  
Fetal Weight ◽  
Insulin Like Growth Factor ◽  
Direct Role ◽  
Igf I

ABSTRACT Fetal growth is normally constrained by maternal factors. This constraint is demonstrated by the usual inverse linear relationship between litter size and mean fetal weight. Cross-breeding experiments between mice of lines selected for high or low plasma insulin-like growth factor (IGF-I) levels suggested that elevations in maternal IGF-I abolish (P <0.01) this constraining effect and reverse the usual positive relationship between fetal and placental size in late gestation. This was confirmed by treating mice and rats throughout pregnancy with IGF-I. In normal mice and in low IGF-I line mice treatment with IGF-I 10μg 8-hourly s.c. from day 1 to 19 of pregnancy) abolished maternal constraint whereas 0.9% (w/v) NaCl treatment did not. In Wistar rats osmotic pumps were implanted to deliver IGF-I (1μg/g body weight per day), bovine GH (bGH; 0.6μg/g body weight per day) or saline from day 1 to 19 of pregnancy. IGF-I therapy but not bGH or saline abolished (P < 0.01) maternal constraint and altered (P <0.01) the relationship between placental and fetal weight. When high or low IGF-I line mice embryos were transplanted into a normal line of mice, the expected negative relationship (P <0.05) between mean fetal weight and litter size was maintained. However the embryos of the high line were heavier (P <0.05) than those from the low line irrespective of fetal number, suggesting a direct role for IGF-I in the regulation of fetal growth. Thus both endogenous and exogenous elevations in maternal IGF-I indirectly promote fetal growth either by altering nutrient delivery to the placenta or by affecting placental function.

Effects of Maternal Diabetes on Fetal Expression of Insulin-Like Growth Factor and Insulin-Like Growth Factor Binding Protein MRNAs in the Rat

1995 ◽  
Vol 147 (2) ◽  
pp. R5-R8 ◽  
Author(s):  
Randal D. Streck ◽  
Veeraramani S. Rajaratnam ◽  
Renata B. Fishman ◽  
Peggy J. Webb
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Fetal Growth ◽  
Fetal Liver ◽  
Expression Patterns ◽  
Maternal Diabetes ◽  
Limb Bud ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Increased Risk

ABSTRACT Matemal diabetes is associated in humans and rats with an increased risk for fetal growth abnormalities and malformations. Therefore, the effect of maternal diabetes on expression of genes that regulate fetal growth and differentiation is of considerable interest. Developmental growth is regulated in part by the expression and availability of insulin-like growth factors (IGFs). Postnatal expression of a subset of the IGFs and IGF binding proteins (IGFBPs) has been demonstrated to be regulated in response to diabetes and other metabolic conditions. We used in situ hybridization to analyze the effect of maternal diabetes, induced by streptozotocin (STZ) prior to mating, upon prenatal rat IGF and IGFBP mRNA expression. At gestational day (GD) 14, the most striking effect of maternal diabetes on fetal IGF/IGFBP gene expression was a marked increase in the abundance of IGFBP-1 mRNA within the liver primordia of fetuses isolated from diabetic dams compared to age-matched controls. This upregulation cannot be entirely due to the approximately one-half-day delay in fetal development (based on limb bud staging) associated with maternal diabetes, as there was no gross difference in the level of IGFBP-1 mRNA between GD13 and GD14 control fetal livers. In contrast, the fetal mRNA expression patterns of IGF-I, IGF-II and IGFBP-2, -3, -4, -5 and -6 were not grossly altered by maternal diabetes. These data are consistent with the hypothesis that IGFBP-1 produced within the fetal liver and secreted into fetal circulation may play a role in regulating rat fetal growth.

Influence of insulin-like growth factor-binding protein-2 on plasma clearance and transfer of insulin-like growth factors-I and -II from plasma into mammary-derived lymph and milk of goats

1996 ◽  
Vol 150 (1) ◽  
pp. 121-127 ◽  
Author(s):  
C G Prosser ◽  
J Schwander
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Plasma Clearance ◽  
Binding Protein ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Factor Binding ◽  
Lactating Goats ◽  
Igf I ◽  
Insulin Like Growth Factors

Abstract Plasma clearance of insulin-like growth factors-I and -II (IGF-I and -II) and insulin-like growth factor-binding protein-2 (IGFBP-2) from lactating goats (n=4) was determined following a single intravenous injection of the corresponding 125I-labelled human protein. Transfer of these proteins out of the vascular space was monitored by their subsequent appearance in mammary-derived lymph and milk. Clearance of 125I-IGFBP-2 from circulation was 0·37 ± 0·06 ml/min/kg, which is markedly greater than that of 125I-IGF-I or -II (0·11 ± and 0·12 ± 0·01 ml/min/kg respectively). This was also reflected in longer elimination half-lives for IGF-I (353 ± 6 min) and -II (254 ± 8 min) compared with IGFBP-2 (110 ± 9 min). Three hours after injection of the 125I-labelled protein, the plasma:lymph ratio of trichloroacetic acid-precipitable radioactivity was 1·54 ±0·04, 3·3 ±0·6 and 4·1 ±0·4 for IGFBP-2, IGF-I and -II respectively. The form of 125I-IGFBP-2 in lymph was not different from that of plasma. Elevation of plasma concentrations of IGFBP-2 by its intravenous infusion significantly decreased plasma half-life of both IGF-I and -II (251 ± 8 and 198 ±7 min respectively). Although the amount and rate of transfer of IGF into mammary-derived lymph was decreased slightly by IGFBP-2, concentrations eventually obtained were not different from control. However, secretion of IGFs into milk was significantly reduced by IGFBP-2, particularly in the case of IGF-I. These results are consistent with the ability of all three compounds to cross the vascular endothelium intact and of IGFBP-2 to decrease the uptake of IGF by mammary epithelium and subsequent secretion into milk. IGFBP-2 may well have acted to target plasma IGF towards non-mammary tissues, thus explaining the more rapid plasma clearance of IGFs in the presence of elevated IGFBP-2. Journal of Endocrinology (1996) 150, 121–127

Effects of elevated blood insulin-like growth factor-I (IGF-I) concentration upon IGF-I in bovine mammary secretions during the colostrum phase

1993 ◽  
Vol 137 (2) ◽  
pp. 223-230 ◽  
Author(s):  
D. L. Hadsell ◽  
C. R. Baumrucker ◽  
R. S. Kensinger
Keyword(s):  
Growth Factor ◽  
Nutrient Restriction ◽  
Control Group ◽  
Insulin Like Growth Factor ◽  
Dry Period ◽  
Entire Treatment Period ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
Serum Gh

ABSTRACT The objectives of these studies were to determine if the concentration of insulin-like growth factor-I (IGF-I) in mammary colostrum secretions could be altered through manipulation of IGF-I concentrations in blood and to compare the temporal changes of IGF-I in mammary secretions to those occurring for IgG1. Milking of 15 pregnant Holstein cows was stopped at 8 weeks prepartum and they were randomly assigned to one of three treatments. A control (C) treatment consisted of feeding the animals 100% of NRC requirements for protein and energy. A second group of cows was fed as the control group and injected with 1·8 μmol bovine GH/day. The third group was fed at 70% of NRC requirements for protein and energy to cause a moderate nutrient restriction (NR). Body weight was measured weekly. Blood was collected by tail venepuncture at 4 h intervals for 24 h. Mammary secretions were collected and pooled among contralateral front and rear quarters (diagonal) for measurement of volume, IGF-I and IgG1 concentrations. Samples were collected at −7, −5, −2, 0 and 1 week postpartum. Cows on the NR treatment failed to gain weight during the dry period compared with C cows (P < 0·05). Blood GH and IGF-I concentrations (P > 0·1) were unaffected by NR treatment. Cows treated with GH had higher (P < 0·01) serum GH and IGF-I levels throughout the entire treatment period, and higher serum IgG1 at 5 and 2 weeks prepartum (P < 0·01). Total mass of IGF-I secreted per diagonal averaged 3·6-fold greater for GH-treated cows during the prepartum period than C and NR cows (P < 0·01). The concentration of IGF-I in mammary secretions was not affected by treatment during the prepartum period, but was 40% greater (P < 0·05) in GH-treated cows than C and NR cows at parturition. Analysis of a selective index comparing IGF-I secretion with that of IgG1 suggested that IGF-I does not enter mammary secretions by passive diffusion from blood. Journal of Endocrinology (1993) 137, 223–230

scholarly journals Insulin-like Growth Factor II Signaling in Neoplastic Proliferation Is Blocked by Transgenic Expression of the Metalloproteinase Inhibitor Timp-1

1999 ◽  
Vol 146 (4) ◽  
pp. 881-892 ◽  
Author(s):  
David C. Martin ◽  
John L. Fowlkes ◽  
Bojana Babic ◽  
Rama Khokha
Keyword(s):  
Growth Factor ◽  
T Antigen ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Early Event ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Igf Binding Proteins ◽  
Protein Levels ◽  
Igf I ◽  
Igfbp 3

Insulin-like growth factor (IGF) II is overexpressed in many human cancers and is reactivated by, and crucial for viral oncogene (SV40 T antigen, [TAg])–induced tumorigenesis in several tumor models. Using a double transgenic murine hepatic tumor model, we demonstrate that tissue inhibitor of metalloproteinase 1 (TIMP-1) blocks liver hyperplasia during tumor development, despite TAg-mediated reactivation of IGF-II. Because the activity of IGFs is controlled by IGF-binding proteins (IGFBPs), we investigated whether TIMP-1 overexpression altered the IGFBP status in the transgenic liver. Ligand blotting showed that IGFBP-3 protein levels were increased in TIMP-1–overexpressing double transgenic littermates, whereas IGFBP-3 mRNA levels were not different, suggesting that TIMP-1 affects IGFBP-3 at a posttranscriptional level. IGFBP-3 proteolysis assays demonstrated that IGFBP-3 degradation was lower in TIMP-1–overexpressing livers, and zymography showed that matrix metalloproteinases (MMPs) were present in the liver homogenates and were capable of degrading IGFBP-3. As a consequence of reduced IGFBP-3 proteolysis and elevated IGFBP-3 protein levels, dissociable IGF-II levels were significantly lower in TIMP-1–overexpressing animals. This decrease in bioavailable IGF-II ultimately resulted in diminished IGF-I receptor signaling in vivo as evidenced by diminished receptor kinase activity and decreased tyrosine phosphorylation of the IGF-I receptor downstream effectors, insulin receptor substrate 1 (IRS-1), extracellular signal regulatory kinase (Erk)-1, and Erk-2. Together, these results provide evidence that TIMP-1 inhibits liver hyperplasia, an early event in TAg-mediated tumorigenesis, by reducing the activity of the tumor-inducing mitogen, IGF-II. These data implicate the control of MMP-mediated degradation of IGFBPs as a novel therapy for controlling IGF bioavailability in cancer.

Activation of insulin-like growth factor gene expression during work-induced skeletal muscle growth

1990 ◽  
Vol 259 (1) ◽  
pp. E89-E95 ◽  
Author(s):  
D. L. DeVol ◽  
P. Rotwein ◽  
J. L. Sadow ◽  
J. Novakofski ◽  
P. J. Bechtel
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Growth Factor ◽  
Muscle Growth ◽  
Experimental Period ◽  
Mrna Levels ◽  
Insulin Like Growth Factor ◽  
Muscle Weight ◽  
Skeletal Muscle Growth ◽  
Igf I

We have investigated the hypothesis that there is local regulation of insulin-like growth factor (IGF) gene expression during skeletal muscle growth. Compensatory hypertrophy was induced in the soleus, a predominantly slow-twitch muscle, and plantaris, a fast-twitch muscle, in 11- to 12-wk-old female Wistar rats by unilateral cutting of the distal gastrocnemius tendon. Animals were killed 2, 4, or 8 days later, and muscles of the nonoperated leg served as controls. Muscle weight increased throughout the experimental period, reaching 127% (soleus) or 122% (plantaris) of control values by day 8. In both growing muscles, IGF-I mRNA, quantitated by a solution-hybridization nuclease-protection assay, rose by nearly threefold on day 2 and remained elevated throughout the experimental period. IGF-II mRNA levels also increased over controls. A more dramatic response was seen in hypophysectomized rats, where IGF-I mRNA levels rose by 8- to 13-fold, IGF-II values by 3- to 7-fold, and muscle mass increased on day 8 to 149% (soleus) or 133% (plantaris) of the control contralateral limb. These results indicate that signals propagated during muscle hypertrophy enhance the expression of both IGF genes, that modulation of IGF-I mRNA levels can occur in the absence of growth hormone, and that locally produced IGF-I and IGF-II may play a role in skeletal muscle growth.

Blood Plasma Concentrations of Insulin-like Growth Factor-I (IGF-I) in Resting Standardbred Horses

2002 ◽  
Vol 163 (1) ◽  
pp. 45-50 ◽  
Author(s):  
Z.J. Champion ◽  
B.H. Breier ◽  
W.E. Ewen ◽  
T.T. Tobin ◽  
P.J. Casey
Keyword(s):  
Growth Factor ◽  
Blood Plasma ◽  
Plasma Concentrations ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I
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