Effect of feeding level on serum IGF1 response to GH injection

in Journal of Endocrinology
(Correspondence should be addressed to H Jiang; Email: hojiang@vt.edu)

This study was conducted to further understand the mechanism by which nutrition modulates GH-induced changes in serum IGF1 concentration in cattle. Cows were fed hay only or corn-based concentrates in addition to hay for 8 weeks. At week 8, serum concentrations of IGF1, IGF-binding protein 3 (IGFBP3), and acid-labile subunit (ALS) as well as their mRNA levels in liver were determined immediately before and 7 days after an injection of GH formulated for sustained release. GH injection caused greater increases in both serum IGF1 concentration and liver IGF1 mRNA expression in the cows fed concentrates than in those fed hay. In the cows fed concentrates, the magnitude of the GH-induced increase in serum IGF1 concentration was, however, much greater than that in liver IGF1 mRNA expression. This difference was not due to GH-induced IGF1 mRNA being translated more efficiently. GH injection also induced greater increases in serum IGFBP3 and ALS concentrations in the cows fed concentrates than fed hay. The injection, however, did not induce a greater increase in IGFBP3 or ALS mRNA in the cows fed concentrates than fed hay. These data and the fact that the ternary complex of IGF1/IGFBP3/ALS stabilizes each of the components in the blood suggest that in cows, increased nutrition enhances serum IGF1 response to GH not only by increasing IGF1 mRNA response to GH in the liver, but also by elevating IGFBP3 and ALS concentrations in the blood.

Abstract

This study was conducted to further understand the mechanism by which nutrition modulates GH-induced changes in serum IGF1 concentration in cattle. Cows were fed hay only or corn-based concentrates in addition to hay for 8 weeks. At week 8, serum concentrations of IGF1, IGF-binding protein 3 (IGFBP3), and acid-labile subunit (ALS) as well as their mRNA levels in liver were determined immediately before and 7 days after an injection of GH formulated for sustained release. GH injection caused greater increases in both serum IGF1 concentration and liver IGF1 mRNA expression in the cows fed concentrates than in those fed hay. In the cows fed concentrates, the magnitude of the GH-induced increase in serum IGF1 concentration was, however, much greater than that in liver IGF1 mRNA expression. This difference was not due to GH-induced IGF1 mRNA being translated more efficiently. GH injection also induced greater increases in serum IGFBP3 and ALS concentrations in the cows fed concentrates than fed hay. The injection, however, did not induce a greater increase in IGFBP3 or ALS mRNA in the cows fed concentrates than fed hay. These data and the fact that the ternary complex of IGF1/IGFBP3/ALS stabilizes each of the components in the blood suggest that in cows, increased nutrition enhances serum IGF1 response to GH not only by increasing IGF1 mRNA response to GH in the liver, but also by elevating IGFBP3 and ALS concentrations in the blood.

Introduction

GH is a polypeptide hormone synthesized in the anterior pituitary gland, and is a major regulator of growth and metabolism in many animals. In farm animals, GH stimulates muscle growth and milk production, and inhibits fat deposition (Etherton & Bauman 1998). Based on these effects, injection of exogenous GH has been used in animal industry to increase milk and lean meat production (Etherton & Bauman 1998, Bauman 1999, Foster 1999).

A well-known cellular effect of GH is the enhanced biosynthesis of insulin-like growth factor 1 (IGF1) in the liver (Mathews et al. 1986, Daughaday 2000). Like GH, IGF1 is also an important polypeptide growth factor (Stewart & Rotwein 1996). Most of the circulating IGF1 is produced by the liver (Sjogren et al. 1999, Yakar et al. 1999). Therefore, liver IGF1 was traditionally thought to be the major mediator of the effect of GH on growth (Daughaday 2000). However, recent transgenic mouse studies designed to more definitively determine the role of liver IGF1 in growth have generated conflicting results, with some challenging (Sjogren et al. 1999, Yakar et al. 1999) but others supporting the importance of liver IGF1 in mediating the effect of GH on growth (Liao et al. 2006, Stratikopoulos et al. 2008). Although the role of liver or circulating IGF1 in large animals has not been studied with similar transgenic approaches, many studies have shown that serum IGF1 concentration and liver IGF1 mRNA expression are positively correlated with body gain, feed efficiency, and body protein synthesis rate in multiple domestic farm animals (Hannon et al. 1991, Hayden et al. 1993, Stick et al. 1998), suggesting that liver-derived IGF1 is also important for growth in these animals. Besides GH, a group of IGF-binding proteins, IGFBP1–6, and acid-labile subunit (ALS) serve to regulate circulating IGF1 concentration and action (Boisclair et al. 2001, Firth & Baxter 2002). Under usual physiological conditions, more than 80% of the circulating IGF1 is bound in a complex with IGFBP3 and ALS (Rajaram et al. 1997, Boisclair et al. 2001, Firth & Baxter 2002). This ternary complex is believed to hinder blood IGF1 from crossing the capillary walls to the extravascular tissue, and hence to retain IGF1 in the blood (Rajaram et al. 1997, Boisclair et al. 2001, Firth & Baxter 2002).

It has long been known that the effects of GH on serum IGF1 concentration, growth, or milk production depend on the nutritional status of the animals (McGuire et al. 1992b, Thissen et al. 1994, Etherton & Bauman 1998, Breier 1999). In cattle, increased feeding of either carbohydrate- or protein-based diet boosted blood IGF1, growth, or milk production response to GH administration compared with ad libitum or restricted feeding (Breier et al. 1988b, McGuire et al. 1992a). Given the apparent role of circulating IGF1 in the control of animal growth and metabolism, the nutrition-dependent IGF1 response to GH likely mediates the nutrition-dependent growth or milk production response to GH. However, the mechanism by which nutrition modulates blood IGF1 response to GH is not completely understood. In this study, we tried to further understand this mechanism in cattle. Specifically, we wanted to know whether the increased nutrition-enhanced serum IGF1 response to GH in cattle is due to increased IGF1 gene expression or increased IGF1 mRNA translation in the liver, or increased retention of IGF1 in the circulation as a result of increased IGFBP3 and ALS concentrations in the blood.

Materials and Methods

Animals, treatments, and sample collection

Twenty non-pregnant, non-lactating Angus crossbred cows were randomly assigned to two groups of 10, which were not different in age or body weight (4.4±0.4 vs 4.6±0.4 years old; 541.0±9.5 vs 538.7±9.5 kg). Both groups of cows were kept in outdoor pens under natural photoperiod and temperature throughout the study, and they had free access to water. The cows in one group, designated the ‘Hay’ group, had ad libitum access to tall fescue hay from the first day (day 0 or d0) to the last day of the experiment (d77). The cows in the other group, designated the ‘Hay+Corn’ group, had ad libitum access to hay from d0 to d7, had a 9.1-kg concentrate meal per cow per day in addition to ad libitum access to hay from d8 to d63, and had ad libitum access to hay from d64 to d77. The concentrate meal was composed of 91.2% corn, 8% soybean meal, and 0.8% urea. This experimental design is illustrated in Fig. 1.

Figure 1
Figure 1

Diagram of the animal experiment. Ten non-lactating, non-pregnant Angus crossbred cows were divided equally into two groups: the Hay group and the Hay+Corn group. Cows in the Hay group had ad libitum access to hay from d0 to d77. Cows in the Hay+Corn group had ad libitum access to hay from d0 to d7, 9.1 kg of corn-based concentrates per cow per day in addition to free access to hay from d8 to d63, and free access to hay from d64 to d77 respectively. On d0 and d56, each cow was injected with 500 mg of bovine GH formulated for sustained release. Blood samples were collected from each cow once a day during the week following GH administration and once a week between the two GH administrations. Blood samples and liver biopsies on d0 and d56 were collected immediately before GH administration.

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Body weight was recorded weekly at 0900 h (before the concentrate meal). On d0 and d56 of the experiment, each cow was injected s.c. with 500 mg of recombinant bovine GH formulated for slow release (Monsanto Company, St Louis, MO, USA). A blood sample was collected from each cow from the jugular vein via a puncture immediately before and every day after GH administration for seven consecutive days. In addition, weekly blood samples were collected from each cow between the two GH administrations. A liver biopsy (∼300 mg) was collected from each cow immediately before and the seventh day after each GH administration (i.e. on d0, d7, d56, and d63). The liver biopsy was performed as described previously (Eleswarapu & Jiang 2005). Blood samples were allowed to clot, and were centrifuged to separate the serum. Serum samples were stored at −20 °C. Liver samples were immediately frozen in liquid nitrogen and stored at −80 °C. Because the tissue sample from the same animal was not sufficient for all the assays, the samples from five randomly selected animals of a group were used for some assays, and the samples from the other five animals from the same group were used for other assays. Neither average age nor average body weight was different between the two groups of five cows.

All animal-related procedures were approved by the Virginia Tech Institutional Animal Care and Use Committee.

RIA

RIA was used to determine serum concentrations of total IGF1 and GH, and was done as described previously (Berry et al. 2003, Wu et al. 2008). An acid–ethanol cryoprecipitation extraction was performed using the serum samples for IGF1 RIA to remove the IGFBPs. The serum samples for GH RIA were not extracted. In the IGF1 RIA, 100 μl of each sample in duplicate were used; the IGF1 standard used was recombinant human IGF1 (GroPep, Adelaide, SA, Australia); the primary antibody used was a mouse anti-human IGF1 antibody previously validated for bovine IGF1 (Berry et al. 2003, Wu et al. 2008). In the GH RIA, 300 μl of each sample in duplicate were used; the GH standard used was a recombinant bovine GH; the primary antibody used was a rabbit anti-ovine GH antibody previously validated for bovine GH (Barnes et al. 1985). The IGF1 RIA had a sensitivity of 23 ng/ml, and an intra-assay coefficient of variation of 9.1%. The GH RIA had a sensitivity of 0.2 ng/ml, and an intra-assay coefficient of variation of 8.1%.

Ribonuclease protection assay

This assay was used to quantify IGF1, IGFBP3, and ALS mRNAs in the liver samples. Total RNA was extracted using TRI Reagent (MRC, Cincinnati, OH, USA), essentially according to the manufacturer's instructions. The quality of the extracted RNA was verified by electrophoresis on agarose gels containing formaldehyde. The probes for the ribonuclease protection assay (RPA) were synthesized from bovine IGF1, IGFBP3, ALS, and GAPDH cDNA plasmids in the presence of α-32P-CTP using the Riboprobe Combination Systems kit (Promega). These cDNA plasmids are described in detail in a previous paper (Wu et al. 2008). The RPA was carried out using the RPA II kit (Ambion, Austin, TX, USA) as described previously (Wu et al. 2008). Briefly, 20 μg of total RNA were hybridized with 1×105 dpm of the probe for IGF1, ALS, or IGFBP3 mRNA, and with 1×105 dpm of the probe for GAPDH mRNA at 42 °C overnight. The hybridization mixture was then digested with ribonuclease. The undigested probe fragments were resolved through gel electrophoresis, and were subsequently visualized by phosphoimaging. The density of the protected probe fragment representing IGF1, IGFBP3, or ALS mRNA was normalized to that representing GAPDH mRNA in the same RNA sample. The normalized density was compared between treatments.

Western blot analysis

This analysis was used to quantify ALS protein in the serum samples, and was carried out as described previously (Wu et al. 2008). Briefly, 0.5 μl of each serum sample was resolved by electrophoresis on a 10% SDS-PAGE. The protein was electro-transferred from the gel onto a nitrocellulose membrane. The primary antibody used was the anti-ALS 1082 antibody (a gift from Dr Yves Boisclair, Cornell University, Ithaca, NY, USA), a rabbit antiserum against a 28-amino acid carboxyl-terminal peptide of bovine ALS (Kim et al. 2006). The secondary antibody used was a HRP-conjugated donkey anti-rabbit IgG (Santa Cruz Biotechnology, Santa Cruz, CA, USA). The immunoblotting signals were detected using the SuperSignal West Pico Chemiluminescent Substrate kit (Pierce Biotechnology, Rockford, IL, USA). Equal protein loading and transfer was confirmed by staining the post-transfer gel with Coomassie blue.

Western ligand blot analysis

This analysis was used to detect IGFBP3 in the serum samples, and was done as described previously (Wu et al. 2008). Briefly, 4 μl of each serum sample was resolved by electrophoresis on a 12% SDS-PAGE. The protein was electro-transferred onto a nitrocellulose membrane. The membrane was incubated with 1.25×106 dpm/ml of 125I-IGF1 at 4 °C overnight. The membrane was washed to remove unbound 125I-IGF1, and was then exposed to an X-ray film. Equal protein loading and transfer was confirmed by staining the post-transfer gel with Coomassie blue.

Isolation of polysomal mRNA

Liver polysomes were isolated as described previously (Foyt et al. 1992), with minor modifications. Briefly, ∼0.3 g of frozen liver tissue was homogenized in 5 ml of sucrose buffer containing 0.25 M sucrose, 200 mM Tris (pH 8.5), 50 mM KCl, 40 mM MgCl2, 25 mM EGTA, 5 mM dithiothreitol, 0.5 U/μl porcine Optizyme RNase Inhibitor (Fisher Scientific, Fair Lawn, NJ, USA), and 2 μg/ml cycloheximide. Triton X-l00 was added to the homogenate to a concentration of 0.5%. The homogenate was then centrifuged at 1100 g for 10 min. The supernatant was collected, and Triton X-100 was added to a final concentration of 2.5%. The supernatant was incubated at 4 °C for 10 min, and was then centrifuged at 12 100 g for 15 min. The supernatant was collected and carefully layered on a gradient sucrose cushion with a lower layer of 4 ml of 1.9 M sucrose and an upper layer of 4 ml of 1.0 M sucrose, both in the buffer described above. The gradient was centrifuged at 184 000 g for 2 h to pellet the polysomes. The mRNA in the polysomes, i.e. polysomal mRNA, was isolated using Tri Reagent as described earlier.

Real-time reverse transcription-PCR

Reverse transcription (RT) coupled with real-time PCR was used to quantify the relative abundance of IGF1 and GAPDH mRNAs during liver polysomal mRNA isolation. RT was done using a TaqMan RT Reagents kit (Applied Biosystems, Foster City, CA, USA). The PCR was set up using a Power SYBR Green PCR Master Mix kit (Applied Biosystems). The forward and reverse primers for IGF1 cDNA were 5′-GTTGGTGGATGCTCTCCAGT-3′ and 5′-CTCCAGCCTCCTCAGATCAC-3′ respectively. The forward and reverse primers for GAPDH cDNA were 5′-GGGTCATCATCTCTGCACCT-3′ and 5′-GGTCATAAGTCCCTCCACGA-3′ respectively. The PCR was run on an Applied Biosystems 7300 Real-Time PCR System (Applied Biosystems) under the following conditions: 50 °C for 2 min, 95 °C for 10 min, and 40 cycles of 95 °C for 15 s and 60 °C for 1 min. The PCR data were analyzed using GAPDH mRNA as an internal control, the expression of which in bovine liver is not affected by nutritional level or GH treatment based on our previous studies (Wang et al. 2003, Eleswarapu & Jiang 2005).

Statistical analysis

Results are presented as mean±s.e.m. Multiple means were compared using the Tukey–Kramer Honestly Significant Difference method. Two means were compared using the t-test. Given the small number of animals (n=5) used in this study, a difference was considered as significant when the P value was <0.1 and not significant when the P value was >0.1.

Results

Body weight

The cows fed hay throughout the 77-d experiment showed no significant changes (P>0.1) in body weight during the experiment. The cows fed concentrates in addition to hay from d7 to d63 gained weight during this period, and lost weight from d63 to d77 when they were fed hay only (P<0.05). GH injection on d56 did not change the body weight of the cows fed hay on d63 (P>0.1), but it increased the body weight of the cows fed hay and concentrates on d63 (P<0.1). These data indicate that the effect of exogenous GH on growth in cows might depend on their feeding levels.

Serum IGF1 concentration

GH injection on d56 caused continuous increases in serum IGF1 concentration during the 7 days following the injection in both the cows fed hay and the cows fed hay and concentrates (P<0.05, Fig. 2A). The increases were greater in the cows fed hay and concentrates than in those fed hay only (P<0.05, Fig. 2A and B). Serum concentrations of IGF1 on d56 before GH injection were not different between the two groups of cows (P>0.1, Fig. 2A). GH injection also increased IGF1 concentrations from d0 to d7, but these increases were not different between the two groups of cows (data not shown). The IGF1 concentrations appeared to return to their pre-injection levels by the fourteenth day of the injection (i.e. d14 and d70 of the experiment). Overall, additional concentrate feeding enhanced GH-induced increases in serum IGF1 concentration, but it had no effect on basal serum IGF1 concentration.

Figure 2
Figure 2

Effects of feeding level and GH injection on serum concentration of IGF1. (A) Serum concentrations of IGF1 from d56 to d63. GH injection on d56 increased serum IGF1 concentration in both groups of cows (P<0.05, n=5), with the increase being greater in the Hay+Corn group than in the Hay group (P<0.05). *P<0.05 versus the other group on the same day. (B) GH-induced changes in serum IGF1 concentration between d56 and d63. *P<0.05 versus the other group.

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Serum GH concentration

Serum GH concentration was measured to determine whether the greater serum IGF1 response to GH injection in cows fed additional concentrates was due to a greater increase in serum GH concentration. As shown in Fig. 3A, GH injection on d56 increased serum GH concentration from 0.5–2 to 10–20 ng/ml during the 7 days following the injection in both groups of cows (P<0.05), but the increases were not different between the two groups (P>0.1). Pre-injection GH concentration on d56 and post-injection GH concentration on d63 (Fig. 3A) as well as the increases in GH concentration from d56 to d63 (Fig. 3B) were also not different (P>0.1) between the two groups of cows. The GH injection on d0 caused similar increases in serum concentration of GH in both groups of cows (data not shown). The GH concentration appeared to return to its pre-injection levels by the fourteenth day of the injection (i.e. d14 and d70), which was consistent with the fact that the injected GH was formulated for a two-week sustained release (Bauman 1999).

Figure 3
Figure 3

Effects of feeding level and GH injection on serum concentration of GH. (A) Serum GH concentrations from d56 to d63. GH injection on d56 increased serum GH concentrations in both groups of cows (P<0.05, n=5), but the increase was not different between the two groups (P>0.1). (B) Changes in serum GH concentration between d56 and d63. These changes were not different between the two groups (P>0.1).

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Liver IGF1 mRNA expression

Liver IGF1 mRNA expression was quantified to determine whether the GH-induced greater increase in serum IGF1 concentration in cows fed hay and concentrates might be due to a greater increase in IGF1 mRNA expression in the liver. As shown in Fig. 4A and B, GH injection increased liver IGF1 mRNA expression from d56 to d63 in both groups of cows (P<0.1). The GH-induced increase in liver IGF1 mRNA expression was greater in the cows fed additional concentrates than in those fed hay only (P<0.1, Fig. 4B). Liver expression of IGF1 mRNA on d56 or d63 was not different (P>0.1) between the two groups of cows (Fig. 4B).

Figure 4
Figure 4

Effects of feeding level and GH injection on liver IGF1 mRNA expression. Liver IGF1 mRNA was quantified by ribonuclease protection assay. The GAPDH mRNA was detected simultaneously as an internal control. (A) Representative images of the ribonuclease protection assays. (B) Relative abundance of liver IGF1 mRNA on d56 and d63 and GH-induced changes from d56 to d63. These data were obtained from densitometric analyses of the bands like those in panel A. The density of the IGF1 mRNA band was normalized to that of the GAPDH band from the same sample. The normalized IGF1 mRNA abundance was expressed with an arbitrary unit. Bars labeled with different letters were different (P<0.1, n=5). *P<0.05 versus the other group.

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Liver IGF1 mRNA translation

Liver polysomal IGF1 mRNA, the portion of IGF1 mRNA that is actively translated, was quantified to determine the possibility that increased translation of liver IGF1 mRNA contributed to the greater GH-induced increase in serum IGF1 concentration from d56 to d63 in the cows fed concentrates. GH injection increased liver expression of polysomal IGF1 mRNA in both groups of cows from day 56 to d63 (Fig. 5A, left panel, P<0.05), and this increase was greater in the cows fed concentrates and hay than in those fed hay only (Fig. 5A, right panel, P<0.05). However, the average percentage of IGF1 mRNA that was associated with the polysomes on d56 and d63 did not seem to be different between the two groups of cows (Fig. 5B, left panel). The percentage of IGF1 mRNA associated with the polysomes did not appear to change from d56 to d63 in either group of cows (Fig. 5B, right panel). These data indicate that the translational efficiency of IGF1 mRNA in liver was not affected by GH injection or feeding level.

Figure 5
Figure 5

Effects of feeding level and GH injection on liver expression of polysomal IGF1 mRNA. Liver polysomes were isolated by sucrose gradient centrifugation. The abundance of polysome-binding IGF1 mRNA was determined by real-time RT-PCR using GAPDH mRNA as an internal control. (A) Relative abundance of polysomal IGF1 mRNA. Bars labeled with different letters were different (P<0.05, n=5). *P<0.05 versus the other group. (B) Average percentages of total IGF1 mRNA associated with the polysomes. These percentages were obtained by dividing the values given in panel A of this figure by those given in panel B of Fig. 4.

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Serum IGFBP3 and ALS protein abundance

The GH-induced greater increase in serum IGF1 concentration in cows fed concentrates from d56 to d63 might be due to more IGF1 being retained in the blood as a result of increased presence of IGFBP3 and ALS protein in the blood. To determine this possibility, we measured the serum levels of IGFBP3 and ALS protein on d56 and d63. GH injection on d56 increased serum IGFBP3 abundance on d63 in the cows fed hay and concentrates (P<0.05, Fig. 6A and B), but not in the cows fed hay only (P>0.1, Fig. 6A and B). The increase in serum IGFBP3 abundance from d56 to d63 in the cows fed additional concentrates was greater than that in the cows fed hay only (P<0.05; Fig. 6B, right panel). GH injection on d56 increased serum ALS levels in both groups of cows (P<0.05, Fig. 6C and D). The increase in serum ALS from d56 to d63 was greater in the cows fed hay and concentrates than in those fed hay only (P<0.05; Fig. 6D, right panel).

Figure 6
Figure 6

Effects of feeding level and GH injection on serum levels of IGFBP3 and ALS protein. Serum IGFBP3 and ALS protein on d56 and d63 were determined by western ligand blot analysis and western blot analysis respectively. Equal protein loading and transfer was controlled by staining the post-transfer gel with Coomassie Blue. (A and C) Representative images of the western ligand blot and western blot analyses of serum IGFBP3 and ALS respectively. (B and D) Serum IGFBP3 and ALS abundance on d56 and d63 and GH-induced changes in them between d56 and d63. These data were obtained by densitometric analyses of the bands like those in panels A and D. Bars labeled with different letters are different (P<0.05, n=5). *P<0.05 versus the other group.

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Liver IGFBP3 and ALS mRNA expression

Like serum IGF1, most of serum IGFBP3 and ALS are produced by the liver (Scott et al. 1985, Donaghy et al. 1995, Boisclair et al. 2001). Therefore, it is possible that the greater GH-induced increase in serum IGFBP3 and ALS protein levels in the cows fed hay and concentrates was the result of a greater increase in IGFBP3 and ALS mRNA expression in the liver. To determine this possibility, we quantified liver IGFBP3 and ALS mRNA levels on d56 and d63. GH injection on d56 increased liver expression of IGFBP3 mRNA on d63 in the cows fed hay only (P<0.1, Fig. 7A), but it had no effect on liver expression of IGFBP3 mRNA in the cows fed hay and concentrates (P>0.1, Fig. 7B). The d56 to d63 change in liver IGFBP3 mRNA expression was not different between the two groups of cows (P>0.1; Fig. 7B, right panel). GH injection increased liver expression of ALS mRNA from d56 to d63 in both groups of cows (P<0.05, Fig. 7C and D), but this increase was not different between the two groups of cows (P>0.1; Fig. 7D, right panel).

Figure 7
Figure 7

Effects of feeding level and GH injection on liver expression of IGFBP3 and ALS mRNAs. Liver IGFBP3 and ALS mRNAs on d56 and d63 were quantified by ribonuclease protection assay. Equal RNA loading was controlled by simultaneous detection of GAPDH mRNA. (A and C) Representative images of the ribonuclease protection assays of IGFBP3 and ALS mRNAs respectively. (B and D) Liver IGFBP3 and ALS mRNA abundance on d56 and d63 and GH-induced changes between d56 and d63. These data were obtained by densitometric analysis of the bands like those in panels A and C. Bars labeled with different letters are different (P<0.1, n=5).

Citation: Journal of Endocrinology 206, 1; 10.1677/JOE-10-0015

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Discussion

This study focused on the mechanism by which feeding level modulates serum IGF1 response to GH. The majority of serum IGF1 is produced by the liver through IGF1 gene expression, which is controlled by GH through the JAK2–STAT5 signaling pathway from the GH receptor (Davey et al. 2001, Woelfle et al. 2003, Eleswarapu et al. 2008). Therefore, one obvious possible mechanism by which GH stimulates a greater increase in serum IGF1 concentration with improved feeding is that increased nutritional intake allows GH to stimulate a greater incremental increase in IGF1 gene expression in the liver. This possibility is supported by our finding that GH injection induced a greater net increase in liver IGF1 mRNA expression only in the cows fed hay and concentrates. However, this study also showed that the GH-stimulated increase in liver IGF1 mRNA expression in the cows fed hay and concentrates was smaller than the corresponding elevation in serum IGF1 concentration. This difference has not been reported before, and suggests that the greater liver IGF1 mRNA response is only partially responsible for the greater serum IGF1 concentration response to GH in cows with increased nutrition.

A second possibility for the greater serum IGF1 concentration response to GH under increased nutritional intake is that GH-induced IGF1 mRNA is more efficiently translated, and therefore, more IGF1 protein is synthesized. This possibility had not been assessed before. This study showed that although there was more IGF1 mRNA associated with the polysomes in the liver of the cows fed both hay and concentrates, the percentage of total IGF1 mRNA associated with the polysomes was not different between the cows fed two different levels of nutrition. These data indicate that increased nutrition enhanced the IGF1 mRNA expression response to GH, but not the translational efficiency of the GH-stimulated IGF1 mRNA. Thus, the data do not support the possibility that the greater serum IGF1 concentration response to GH under increased nutritional intake results from more efficient translation of the GH-induced IGF1 mRNA in the liver.

A third possibility for GH to cause a greater increase in serum IGF1 concentration under increased nutritional intake is that increased nutrition enhances the stability and/or retention of the GH-stimulated IGF1 in the blood. We indirectly determined this possibility by measuring the serum levels of IGFBP3 and ALS, two proteins that form a ternary complex with IGF1 that is believed to block IGF1 from crossing the blood vessels and from being degraded in the blood (Rajaram et al. 1997, Boisclair et al. 2001, Firth & Baxter 2002). Such roles of IGFBP3 and ALS are supported by many studies (Ueki et al. 2000, Boisclair et al. 2001, Modric et al. 2001, Haluzik et al. 2003, Hwa et al. 2006, Domene et al. 2007). Our study showed that GH injection caused a greater increase in both serum IGFBP3 and ALS protein levels in the cows fed additional concentrates than in the cows fed hay only, and that post-GH injection serum concentrations of both IGFBP3 and ALS were greater in the cows fed additional concentrates than in the cows fed hay only. These results support the possibility that under increased nutrition, GH causes a greater increase in serum IGFBP3 and ALS protein, and the increased IGFBP3 and ALS in turn increase the stability and/or retention of IGF1 in the blood. However, in theory, the ternary IGF1/IGFBP3/ALS complex could also function as a reservoir for IGFBP3 and ALS in the blood, which means an increase in serum concentration of IGF1 could increase that of IGFBP3 and ALS by increasing the retention and/or stability of the latter. This inter-relationship between serum IGF1 and serum IGFBP3 and ALS is indeed suggested by previous studies. For example, liver overexpression of IGF1 increased serum IGFBP3 concentration in addition to serum IGF1 concentration (Camacho-Hubner et al. 1991, Liao et al. 2006). Liver-specific inactivation of the IGF1 gene not only reduces serum IGF1 concentration, but also reduces serum IGFBP3 and ALS concentrations (Yakar et al. 2002, Haluzik et al. 2003). Therefore, it is possible that the greater increases in serum protein levels of IGFBP3 and ALS in response to GH under increased nutrition initially are a result rather than a cause of the greater increase in serum IGF1 concentration. The liver IGFBP3 and ALS mRNA data obtained from our study seem to support this alternative possibility. Like serum IGF1, most of the serum IGFBP3 and ALS are produced by the liver. In this study, GH did not stimulate a greater expression of IGFBP3 or ALS mRNA in the liver in the cows fed hay and concentrates than in the cows fed hay only. This means that the greater GH-induced increases in serum IGFBP3 and ALS protein under increased nutrition are not due to increased liver production. As discussed earlier, GH did induce greater expression of IGF1 mRNA in the liver in the cows fed hay and concentrates than in the cows fed hay only. Therefore, it is reasonable to suggest that the greater increases in serum concentrations of IGFBP3 and ALS associated with GH injection initially result from the increase in serum IGF1 concentration, and that the increases in serum IGFBP3 and ALS concentrations further increase serum IGF1 concentration by increasing its stability and/or retention in the blood.

GH is known to stimulate liver expression of IGF1 and ALS in various species (Stewart & Rotwein 1996, Boisclair et al. 2001), including cattle (Kim et al. 2006, Jiang et al. 2007). Consistent with this, this study showed that GH injection increased mRNA expression of IGF1 and ALS in both the cows fed concentrates and the cows fed hay. GH has been shown to stimulate liver expression of IGFBP3 mRNA in rats (Albiston & Herington 1992, Domene et al. 1993, Scharf et al. 1996), sheep (Bassett et al. 1998), and pigs (Dunaiski et al. 1999), but not in cattle (Hammon et al. 2003, Radcliff et al. 2004). This study showed that GH injection increased IGFBP3 mRNA expression in the liver of cows fed hay, but not in those fed concentrates. It seems like GH can stimulate liver IGFBP3 mRNA expression in cattle too, but this effect might depend on the feeding level of the cattle.

In this study, neither the pre-GH injection serum IGF1 concentration nor pre-GH injection liver IGF1 mRNA expression was different between the cows fed two different levels of nutrition, indicating that increased nutrition increases exogenous GH-induced changes in serum IGF1 concentration, but has no effect on basal serum IGF1 concentration. Similar results have been observed in previous studies with cattle (Breier et al. 1988a,b, MacRae et al. 1991, Houseknecht et al. 1992, McGuire et al. 1992a, Radcliff et al. 2004). Given that basal serum IGF1 concentration and basal liver IGF1 mRNA expression are also controlled by GH, it is not obvious why increased nutrition modulates exogenous GH regulation but not endogenous GH regulation of serum IGF1 concentration or liver IGF1 mRNA expression.

In summary, this study has shown that the overnutrition-enhanced GH stimulation of serum IGF1 concentration in cattle is accompanied by an enhanced GH stimulation of liver IGF1 mRNA, serum IGFBP3, and ALS protein, but not by an enhanced GH stimulation of liver IGFBP3 or ALS mRNA. Based on these results and the fact that the ternary complex of IGF1/IGFBP3/ALS can stabilize and retain each of them in the bloodstream, we propose the following positive feedback mechanism by which overnutrition enhances GH-induced increases in serum IGF1 concentration in cattle: under increased nutrition, GH first induces a greater increase in IGF1 mRNA expression in the liver; this increase directly contributes to the initial increase in serum IGF1 concentration; the resulting increase in serum IGF1 then enhances the retention and/or stability of serum IGFBP3 and ALS through an increased formation of the ternary complex of IGF1/IGFBP3/ALS; and the increased IGFBP3 and ALS help to further increase serum retention and/or stability of IGF1 through the ternary complex.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Acknowledgements

The authors wish to thank Dr Yves Boisclair for providing the ALS antibody, Dr Roberto Torres-Diaz for performing the liver biopsy, Dr Michael McGilliard for helping with the statistical analysis, and Gregory Bernard for helping handle the animals in this study.

References

  • AlbistonALHeringtonAC1992Tissue distribution and regulation of insulin-like growth factor (IGF)-binding protein-3 messenger ribonucleic acid (mRNA) in the rat: comparison with IGF-I mRNA expression. Endocrinology130497502.

  • BarnesMAKazmerGWAkersRMPearsonRE1985Influence of selection for milk yield on endogenous hormones and metabolites in Holstein heifers and cows. Journal of Animal Science60271284.

  • BassettNSCurrieMJBreierBHKlemptMMinSHMcCutcheonSNMacKenzieDDGluckmanPD1998The effects of ovine placental lactogen and bovine growth hormone on hepatic and mammary gene expression in lactating sheep. Growth Hormone and IGF Research8439446.

  • BaumanDE1999Bovine somatotropin and lactation: from basic science to commercial application. Domestic Animal Endocrinology17101116.

  • BerrySDHowardRDJobstPMJiangHAkersRM2003Interactions between the ovary and the local IGF-I axis modulate mammary development in prepubertal heifers. Journal of Endocrinology177295304.

  • BoisclairYRRhoadsRPUekiIWangJOoiGT2001The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. Journal of Endocrinology1706370.

  • BreierBH1999Regulation of protein and energy metabolism by the somatotropic axis. Domestic Animal Endocrinology17209218.

  • BreierBHGluckmanPDBassJJ1988aInfluence of nutritional status and oestradiol-17β on plasma growth hormone, insulin-like growth factors-I and -II and the response to exogenous growth hormone in young steers. Journal of Endocrinology118243250.

  • BreierBHGluckmanPDBassJJ1988bThe somatotrophic axis in young steers: influence of nutritional status and oestradiol-17β on hepatic high- and low-affinity somatotrophic binding sites. Journal of Endocrinology116169177.

  • Camacho-HubnerCClemmonsDRD'ErcoleAJ1991Regulation of insulin-like growth factor (IGF) binding proteins in transgenic mice with altered expression of growth hormone and IGF-I. Endocrinology12912011206.

  • DaughadayWH2000Growth hormone axis overview – somatomedin hypothesis. Pediatric Nephrology14537540.

  • DaveyHWXieTMcLachlanMJWilkinsRJWaxmanDJGrattanDR2001STAT5b is required for GH-induced liver IGF-I gene expression. Endocrinology14238363841.

  • DomeneHKrishnamurthiKEshetRGiladILaronZKochIStannardBCassorlaFRobertsCTJrLeRoithD1993Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats. Endocrinology133675682.

  • DomeneHMMartinezASFrystykJBengoleaSVRopelatoMGScagliaPAChenJWHeuckCWolthersODHeinrichJJ2007Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency. Hormone Research67243249.

  • DonaghyARossRGimsonAHughesSCHollyJWilliamsR1995Growth hormone, insulin like growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease. Hepatology21680688.

  • DunaiskiVDunsheaFRWaltonPEGoddardC1999Effect of growth hormone administration on IGF binding protein-3 mRNA levels in porcine tissues. Journal of Molecular Endocrinology22261272.

  • EleswarapuSJiangH2005Growth hormone regulates the expression of hepatocyte nuclear factor-3 gamma and other liver-enriched transcription factors in the bovine liver. Journal of Endocrinology18495105.

  • EleswarapuSGuZJiangH2008Growth hormone regulation of insulin-like growth factor-I gene expression may be mediated by multiple distal signal transducer and activator of transcription 5 binding sites. Endocrinology14922302240.

  • EthertonTDBaumanDE1998Biology of somatotropin in growth and lactation of domestic animals. Physiological Reviews78745761.

  • FirthSMBaxterRC2002Cellular actions of the insulin-like growth factor binding proteins. Endocrine Reviews23824854.

  • FosterTP1999Somatotropin delivery to farmed animals. Advanced Drug Delivery Reviews38151165.

  • FoytHLLanauFWoloschakMLeRoithDRobertsCTJr1992Effect of growth hormone on levels of differentially processed insulin-like growth factor I mRNAs in total and polysomal mRNA populations. Molecular Endocrinology618811888.

  • HaluzikMYakarSGavrilovaOSetserJBoisclairYLeRoithD2003Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes5224832489.

  • HammonHMZbindenYSauerweinHBreierBHBlumJWDonkinSS2003The response of the hepatic insulin-like growth factor system to growth hormone and dexamethasone in calves. Journal of Endocrinology179427435.

  • HannonKGronowskiATrenkleA1991Relationship of liver and skeletal muscle IGF-1 mRNA to plasma GH profile, production of IGF-1 by liver, plasma IGF-1 concentrations, and growth rates of cattle. Proceedings of the Society for Experimental Biology and Medicine196155163.

  • HaydenJMWilliamsJECollierRJ1993Plasma growth hormone, insulin-like growth factor, insulin, and thyroid hormone association with body protein and fat accretion in steers undergoing compensatory gain after dietary energy restriction. Journal of Animal Science7133273338.

  • HouseknechtKLBaumanDEFoxDGSmithDF1992Abomasal infusion of casein enhances nitrogen retention in somatotropin-treated steers. Journal of Nutrition12217171725.

  • HwaVHaeuslerGPrattKLLittleBMFrischHKollerDRosenfeldRG2006Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. Journal of Clinical Endocrinology and Metabolism9118261831.

  • JiangHWangYWuMGuZFrankSJTorres-DiazR2007Growth hormone stimulates hepatic expression of bovine growth hormone receptor messenger ribonucleic acid through signal transducer and activator of transcription 5 activation of a major growth hormone receptor gene promoter. Endocrinology14833073315.

  • KimJWRhoadsRPSegoaleNKristensenNBBaumanDEBoisclairYR2006Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation. Journal of Endocrinology189583593.

  • LiaoLDearthRKZhouSBrittonOLLeeAVXuJ2006Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency. Endocrinology14738773888.

  • MacRaeJCBruceLAHovellFDHartICInksterJWalkerAAtkinsonT1991Influence of protein nutrition on the response of growing lambs to exogenous bovine growth hormone. Journal of Endocrinology1305361.

  • MathewsLSNorstedtGPalmiterRD1986Regulation of insulin-like growth factor I gene expression by growth hormone. PNAS8393439347.

  • McGuireMABaumanDEMillerMAHartnellGF1992aResponse of somatomedins (IGF-I and IGF-II) in lactating cows to variations in dietary energy and protein and treatment with recombinant n-methionyl bovine somatotropin. Journal of Nutrition122128136.

  • McGuireMAViciniJLBaumanDEVeenhuizenJJ1992bInsulin-like growth factors and binding proteins in ruminants and their nutritional regulation. Journal of Animal Science7029012910.

  • ModricTSilhaJVShiZGuiYSuwanichkulADurhamSKPowellDRMurphyLJ2001Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology14219581967.

  • RadcliffRPVandeHaarMJKobayashiYSharmaBKTuckerHALucyMC2004Effect of dietary energy and somatotropin on components of the somatotropic axis in Holstein heifers. Journal of Dairy Science8712291235.

  • RajaramSBaylinkDJMohanS1997Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocrine Reviews18801831.

  • ScharfJRamadoriGBraulkeTHartmannH1996Synthesis of insulinlike growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: regulation by insulin, insulinlike growth factor, and growth hormone. Hepatology23818827.

  • ScottCDMartinJLBaxterRC1985Production of insulin-like growth factor I and its binding protein by adult rat hepatocytes in primary culture. Endocrinology11610941101.

  • SjogrenKLiuJLBladKSkrticSVidalOWalleniusVLeRoithDTornellJIsakssonOGJanssonJO1999Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. PNAS9670887092.

  • StewartCERotweinP1996Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiological Reviews7610051026.

  • StickDADavisMELoerchSCSimmenRC1998Relationship between blood serum insulin-like growth factor I concentration and postweaning feed efficiency of crossbred cattle at three levels of dietary intake. Journal of Animal Science76498505.

  • StratikopoulosESzabolcsMDragatsisIKlinakisAEfstratiadisA2008The hormonal action of IGF1 in postnatal mouse growth. PNAS1051937819383.

  • ThissenJPKetelslegersJMUnderwoodLE1994Nutritional regulation of the insulin-like growth factors. Endocrine Reviews1580101.

  • UekiIOoiGTTremblayMLHurstKRBachLABoisclairYR2000Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. PNAS9768686873.

  • WangYEleswarapuSBealWESweckerWSJrAkersRMJiangH2003Reduced serum insulin-like growth factor (IGF) I is associated with reduced liver IGF-I mRNA and liver growth hormone receptor mRNA in food-deprived cattle. Journal of Nutrition13325552560.

  • WoelfleJBilliardJRotweinP2003Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. Journal of Biological Chemistry2782269622702.

  • WuMWangABernardGCHallJBBealWEMichael AkersRBoisclairYRJiangH2008Increased degradation of insulin-like growth factor-I in serum from feed-deprived steers. Domestic Animal Endocrinology35343351.

  • YakarSLiuJLStannardBButlerAAcciliDSauerBLeRoithD1999Normal growth and development in the absence of hepatic insulin-like growth factor I. PNAS9673247329.

  • YakarSRosenCJBeamerWGAckert-BicknellCLWuYLiuJLOoiGTSetserJFrystykJBoisclairYR2002Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation110771781.

(M Wu is now at The Biology Department, Marshal University, Huntington, West Virginia, USA)

(J B Hall is now at Animal and Veterinary Science Department, University of Idaho, Moscow, Idaho, USA)

 

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Figures

  • Diagram of the animal experiment. Ten non-lactating, non-pregnant Angus crossbred cows were divided equally into two groups: the Hay group and the Hay+Corn group. Cows in the Hay group had ad libitum access to hay from d0 to d77. Cows in the Hay+Corn group had ad libitum access to hay from d0 to d7, 9.1 kg of corn-based concentrates per cow per day in addition to free access to hay from d8 to d63, and free access to hay from d64 to d77 respectively. On d0 and d56, each cow was injected with 500 mg of bovine GH formulated for sustained release. Blood samples were collected from each cow once a day during the week following GH administration and once a week between the two GH administrations. Blood samples and liver biopsies on d0 and d56 were collected immediately before GH administration.

    View in gallery
  • Effects of feeding level and GH injection on serum concentration of IGF1. (A) Serum concentrations of IGF1 from d56 to d63. GH injection on d56 increased serum IGF1 concentration in both groups of cows (P<0.05, n=5), with the increase being greater in the Hay+Corn group than in the Hay group (P<0.05). *P<0.05 versus the other group on the same day. (B) GH-induced changes in serum IGF1 concentration between d56 and d63. *P<0.05 versus the other group.

    View in gallery
  • Effects of feeding level and GH injection on serum concentration of GH. (A) Serum GH concentrations from d56 to d63. GH injection on d56 increased serum GH concentrations in both groups of cows (P<0.05, n=5), but the increase was not different between the two groups (P>0.1). (B) Changes in serum GH concentration between d56 and d63. These changes were not different between the two groups (P>0.1).

    View in gallery
  • Effects of feeding level and GH injection on liver IGF1 mRNA expression. Liver IGF1 mRNA was quantified by ribonuclease protection assay. The GAPDH mRNA was detected simultaneously as an internal control. (A) Representative images of the ribonuclease protection assays. (B) Relative abundance of liver IGF1 mRNA on d56 and d63 and GH-induced changes from d56 to d63. These data were obtained from densitometric analyses of the bands like those in panel A. The density of the IGF1 mRNA band was normalized to that of the GAPDH band from the same sample. The normalized IGF1 mRNA abundance was expressed with an arbitrary unit. Bars labeled with different letters were different (P<0.1, n=5). *P<0.05 versus the other group.

    View in gallery
  • Effects of feeding level and GH injection on liver expression of polysomal IGF1 mRNA. Liver polysomes were isolated by sucrose gradient centrifugation. The abundance of polysome-binding IGF1 mRNA was determined by real-time RT-PCR using GAPDH mRNA as an internal control. (A) Relative abundance of polysomal IGF1 mRNA. Bars labeled with different letters were different (P<0.05, n=5). *P<0.05 versus the other group. (B) Average percentages of total IGF1 mRNA associated with the polysomes. These percentages were obtained by dividing the values given in panel A of this figure by those given in panel B of Fig. 4.

    View in gallery
  • Effects of feeding level and GH injection on serum levels of IGFBP3 and ALS protein. Serum IGFBP3 and ALS protein on d56 and d63 were determined by western ligand blot analysis and western blot analysis respectively. Equal protein loading and transfer was controlled by staining the post-transfer gel with Coomassie Blue. (A and C) Representative images of the western ligand blot and western blot analyses of serum IGFBP3 and ALS respectively. (B and D) Serum IGFBP3 and ALS abundance on d56 and d63 and GH-induced changes in them between d56 and d63. These data were obtained by densitometric analyses of the bands like those in panels A and D. Bars labeled with different letters are different (P<0.05, n=5). *P<0.05 versus the other group.

    View in gallery
  • Effects of feeding level and GH injection on liver expression of IGFBP3 and ALS mRNAs. Liver IGFBP3 and ALS mRNAs on d56 and d63 were quantified by ribonuclease protection assay. Equal RNA loading was controlled by simultaneous detection of GAPDH mRNA. (A and C) Representative images of the ribonuclease protection assays of IGFBP3 and ALS mRNAs respectively. (B and D) Liver IGFBP3 and ALS mRNA abundance on d56 and d63 and GH-induced changes between d56 and d63. These data were obtained by densitometric analysis of the bands like those in panels A and C. Bars labeled with different letters are different (P<0.1, n=5).

    View in gallery

References

AlbistonALHeringtonAC1992Tissue distribution and regulation of insulin-like growth factor (IGF)-binding protein-3 messenger ribonucleic acid (mRNA) in the rat: comparison with IGF-I mRNA expression. Endocrinology130497502.

BarnesMAKazmerGWAkersRMPearsonRE1985Influence of selection for milk yield on endogenous hormones and metabolites in Holstein heifers and cows. Journal of Animal Science60271284.

BassettNSCurrieMJBreierBHKlemptMMinSHMcCutcheonSNMacKenzieDDGluckmanPD1998The effects of ovine placental lactogen and bovine growth hormone on hepatic and mammary gene expression in lactating sheep. Growth Hormone and IGF Research8439446.

BaumanDE1999Bovine somatotropin and lactation: from basic science to commercial application. Domestic Animal Endocrinology17101116.

BerrySDHowardRDJobstPMJiangHAkersRM2003Interactions between the ovary and the local IGF-I axis modulate mammary development in prepubertal heifers. Journal of Endocrinology177295304.

BoisclairYRRhoadsRPUekiIWangJOoiGT2001The acid-labile subunit (ALS) of the 150 kDa IGF-binding protein complex: an important but forgotten component of the circulating IGF system. Journal of Endocrinology1706370.

BreierBH1999Regulation of protein and energy metabolism by the somatotropic axis. Domestic Animal Endocrinology17209218.

BreierBHGluckmanPDBassJJ1988aInfluence of nutritional status and oestradiol-17β on plasma growth hormone, insulin-like growth factors-I and -II and the response to exogenous growth hormone in young steers. Journal of Endocrinology118243250.

BreierBHGluckmanPDBassJJ1988bThe somatotrophic axis in young steers: influence of nutritional status and oestradiol-17β on hepatic high- and low-affinity somatotrophic binding sites. Journal of Endocrinology116169177.

Camacho-HubnerCClemmonsDRD'ErcoleAJ1991Regulation of insulin-like growth factor (IGF) binding proteins in transgenic mice with altered expression of growth hormone and IGF-I. Endocrinology12912011206.

DaughadayWH2000Growth hormone axis overview – somatomedin hypothesis. Pediatric Nephrology14537540.

DaveyHWXieTMcLachlanMJWilkinsRJWaxmanDJGrattanDR2001STAT5b is required for GH-induced liver IGF-I gene expression. Endocrinology14238363841.

DomeneHKrishnamurthiKEshetRGiladILaronZKochIStannardBCassorlaFRobertsCTJrLeRoithD1993Growth hormone (GH) stimulates insulin-like growth factor-I (IGF-I) and IGF-I-binding protein-3, but not GH receptor gene expression in livers of juvenile rats. Endocrinology133675682.

DomeneHMMartinezASFrystykJBengoleaSVRopelatoMGScagliaPAChenJWHeuckCWolthersODHeinrichJJ2007Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency. Hormone Research67243249.

DonaghyARossRGimsonAHughesSCHollyJWilliamsR1995Growth hormone, insulin like growth factor-1, and insulinlike growth factor binding proteins 1 and 3 in chronic liver disease. Hepatology21680688.

DunaiskiVDunsheaFRWaltonPEGoddardC1999Effect of growth hormone administration on IGF binding protein-3 mRNA levels in porcine tissues. Journal of Molecular Endocrinology22261272.

EleswarapuSJiangH2005Growth hormone regulates the expression of hepatocyte nuclear factor-3 gamma and other liver-enriched transcription factors in the bovine liver. Journal of Endocrinology18495105.

EleswarapuSGuZJiangH2008Growth hormone regulation of insulin-like growth factor-I gene expression may be mediated by multiple distal signal transducer and activator of transcription 5 binding sites. Endocrinology14922302240.

EthertonTDBaumanDE1998Biology of somatotropin in growth and lactation of domestic animals. Physiological Reviews78745761.

FirthSMBaxterRC2002Cellular actions of the insulin-like growth factor binding proteins. Endocrine Reviews23824854.

FosterTP1999Somatotropin delivery to farmed animals. Advanced Drug Delivery Reviews38151165.

FoytHLLanauFWoloschakMLeRoithDRobertsCTJr1992Effect of growth hormone on levels of differentially processed insulin-like growth factor I mRNAs in total and polysomal mRNA populations. Molecular Endocrinology618811888.

HaluzikMYakarSGavrilovaOSetserJBoisclairYLeRoithD2003Insulin resistance in the liver-specific IGF-1 gene-deleted mouse is abrogated by deletion of the acid-labile subunit of the IGF-binding protein-3 complex: relative roles of growth hormone and IGF-1 in insulin resistance. Diabetes5224832489.

HammonHMZbindenYSauerweinHBreierBHBlumJWDonkinSS2003The response of the hepatic insulin-like growth factor system to growth hormone and dexamethasone in calves. Journal of Endocrinology179427435.

HannonKGronowskiATrenkleA1991Relationship of liver and skeletal muscle IGF-1 mRNA to plasma GH profile, production of IGF-1 by liver, plasma IGF-1 concentrations, and growth rates of cattle. Proceedings of the Society for Experimental Biology and Medicine196155163.

HaydenJMWilliamsJECollierRJ1993Plasma growth hormone, insulin-like growth factor, insulin, and thyroid hormone association with body protein and fat accretion in steers undergoing compensatory gain after dietary energy restriction. Journal of Animal Science7133273338.

HouseknechtKLBaumanDEFoxDGSmithDF1992Abomasal infusion of casein enhances nitrogen retention in somatotropin-treated steers. Journal of Nutrition12217171725.

HwaVHaeuslerGPrattKLLittleBMFrischHKollerDRosenfeldRG2006Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. Journal of Clinical Endocrinology and Metabolism9118261831.

JiangHWangYWuMGuZFrankSJTorres-DiazR2007Growth hormone stimulates hepatic expression of bovine growth hormone receptor messenger ribonucleic acid through signal transducer and activator of transcription 5 activation of a major growth hormone receptor gene promoter. Endocrinology14833073315.

KimJWRhoadsRPSegoaleNKristensenNBBaumanDEBoisclairYR2006Isolation of the cDNA encoding the acid labile subunit (ALS) of the 150 kDa IGF-binding protein complex in cattle and ALS regulation during the transition from pregnancy to lactation. Journal of Endocrinology189583593.

LiaoLDearthRKZhouSBrittonOLLeeAVXuJ2006Liver-specific overexpression of the insulin-like growth factor-I enhances somatic growth and partially prevents the effects of growth hormone deficiency. Endocrinology14738773888.

MacRaeJCBruceLAHovellFDHartICInksterJWalkerAAtkinsonT1991Influence of protein nutrition on the response of growing lambs to exogenous bovine growth hormone. Journal of Endocrinology1305361.

MathewsLSNorstedtGPalmiterRD1986Regulation of insulin-like growth factor I gene expression by growth hormone. PNAS8393439347.

McGuireMABaumanDEMillerMAHartnellGF1992aResponse of somatomedins (IGF-I and IGF-II) in lactating cows to variations in dietary energy and protein and treatment with recombinant n-methionyl bovine somatotropin. Journal of Nutrition122128136.

McGuireMAViciniJLBaumanDEVeenhuizenJJ1992bInsulin-like growth factors and binding proteins in ruminants and their nutritional regulation. Journal of Animal Science7029012910.

ModricTSilhaJVShiZGuiYSuwanichkulADurhamSKPowellDRMurphyLJ2001Phenotypic manifestations of insulin-like growth factor-binding protein-3 overexpression in transgenic mice. Endocrinology14219581967.

RadcliffRPVandeHaarMJKobayashiYSharmaBKTuckerHALucyMC2004Effect of dietary energy and somatotropin on components of the somatotropic axis in Holstein heifers. Journal of Dairy Science8712291235.

RajaramSBaylinkDJMohanS1997Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocrine Reviews18801831.

ScharfJRamadoriGBraulkeTHartmannH1996Synthesis of insulinlike growth factor binding proteins and of the acid-labile subunit in primary cultures of rat hepatocytes, of Kupffer cells, and in cocultures: regulation by insulin, insulinlike growth factor, and growth hormone. Hepatology23818827.

ScottCDMartinJLBaxterRC1985Production of insulin-like growth factor I and its binding protein by adult rat hepatocytes in primary culture. Endocrinology11610941101.

SjogrenKLiuJLBladKSkrticSVidalOWalleniusVLeRoithDTornellJIsakssonOGJanssonJO1999Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. PNAS9670887092.

StewartCERotweinP1996Growth, differentiation, and survival: multiple physiological functions for insulin-like growth factors. Physiological Reviews7610051026.

StickDADavisMELoerchSCSimmenRC1998Relationship between blood serum insulin-like growth factor I concentration and postweaning feed efficiency of crossbred cattle at three levels of dietary intake. Journal of Animal Science76498505.

StratikopoulosESzabolcsMDragatsisIKlinakisAEfstratiadisA2008The hormonal action of IGF1 in postnatal mouse growth. PNAS1051937819383.

ThissenJPKetelslegersJMUnderwoodLE1994Nutritional regulation of the insulin-like growth factors. Endocrine Reviews1580101.

UekiIOoiGTTremblayMLHurstKRBachLABoisclairYR2000Inactivation of the acid labile subunit gene in mice results in mild retardation of postnatal growth despite profound disruptions in the circulating insulin-like growth factor system. PNAS9768686873.

WangYEleswarapuSBealWESweckerWSJrAkersRMJiangH2003Reduced serum insulin-like growth factor (IGF) I is associated with reduced liver IGF-I mRNA and liver growth hormone receptor mRNA in food-deprived cattle. Journal of Nutrition13325552560.

WoelfleJBilliardJRotweinP2003Acute control of insulin-like growth factor-I gene transcription by growth hormone through Stat5b. Journal of Biological Chemistry2782269622702.

WuMWangABernardGCHallJBBealWEMichael AkersRBoisclairYRJiangH2008Increased degradation of insulin-like growth factor-I in serum from feed-deprived steers. Domestic Animal Endocrinology35343351.

YakarSLiuJLStannardBButlerAAcciliDSauerBLeRoithD1999Normal growth and development in the absence of hepatic insulin-like growth factor I. PNAS9673247329.

YakarSRosenCJBeamerWGAckert-BicknellCLWuYLiuJLOoiGTSetserJFrystykJBoisclairYR2002Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation110771781.

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