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Nutrient-Gene Interactions

Reduced 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

Ying Wang, Satyanarayana Eleswarapu, William E. Beal, William S. Swecker, Jr.^*, R. Michael Akers and Honglin Jiang²

Departments of Animal and Poultry Sciences, ^* Large Animal Clinical Sciences and Dairy Science, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060

²To whom correspondence should be addressed. E-mail: hojiang{at}vt.edu.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Nutritional deprivation decreases blood insulin-like growth factor I (IGF-I) concentrations in a variety of species. In this study, we explored the underlying mechanism by determining the effects of food deprivation on the levels of total IGF-I mRNA and total growth hormone receptor (GHR) mRNA, as well as the levels of individual IGF-I mRNA variants and GHR mRNA variants in the liver of steers. Food deprivation for nearly 3 d decreased the levels of serum IGF-I by 63% (P < 0.01), and this decrease was associated with a 75% decrease (P < 0.01) in total IGF-I mRNA in the liver. The food deprivation–induced decrease in liver total IGF-I mRNA was associated with an equivalent decrease in the levels of both class 1 and class 2 IGF-I mRNA. In addition to IGF-I mRNA, food deprivation also decreased the levels of total GHR mRNA in the liver (P < 0.05), and this decrease was associated with a decrease in the liver expression of GHR mRNA variants 1C3 (P < 0.05) and 1A (P = 0.08). Food deprivation did not affect the levels of two other major GHR mRNA variants, 1B and 1C2, in the liver. These results demonstrate that the food deprivation–induced decrease in circulating IGF-I in steers is associated with a coordinate decrease in the expression of different IGF-I mRNA variants and a specific decrease in the expression of GHR mRNA variants 1C3 and 1A in the liver.

KEY WORDS: • cattle • liver • mRNA • insulin-like growth factor I • growth hormone receptor

Nutrition regulates animal growth through interactions with growth regulatory factors such as insulin-like growth factor I (IGF-I). In a variety of species, growth retardation caused by food deprivation or food restriction is accompanied by a decrease in blood IGF-I concentrations (1). The food deprivation–induced decrease in blood IGF-I is thought to be caused by impaired synthesis of IGF-I in the liver because the majority of blood IGF-I is secreted from the liver (2,3). In a variety of species, IGF-I mRNA is heterogeneous, with some containing exon 1 as the leader exon (class 1 IGF-I mRNA) and some containing exon 2 as the leader exon (class 2 IGF-I mRNA). Class 1 and class 2 IGF-I mRNA may differ in stability and translatability (4,5). In rats, it has been reported that food deprivation decreases the levels of both classes of IGF-I mRNA in the liver, with a greater decrease in class 2 IGF-I mRNA (6). The food deprivation–induced decrease in liver IGF-I mRNA is likely mediated at multiple levels, including reduced transcription of the IGF-I gene (7–9), decreased processing of IGF-I premRNA (10), and decreased stability of mature IGF-I mRNA (10).

Under normal conditions, IGF-I gene expression in the liver is regulated by pituitary growth hormone (GH) (2). Growth hormone binding to growth hormone receptor (GHR) in the liver activates a signaling pathway that culminates in IGF-I gene transcription (11). In most species, food deprivation increases blood GH concentrations, whereas it decreases IGF-I concentrations. Therefore, the food deprivation–induced decrease in blood IGF-I has been attributed to GH resistance in the liver (1). This GH resistance is associated with both decreases in the number of GHR (12–14) and defects in postreceptor signaling in the liver (15). The decrease in the GHR number in the liver is believed to be caused by a decrease in the levels of GHR mRNA (7,16,17). Like IGF-I mRNA, GHR mRNA in a variety of species is also expressed as variants that differ in the leader exon (18). For example, nine variants have been identified for bovine GHR mRNA (19,20). The expression of these GHR mRNA variants appears to be regulated differentially among different tissues, developmental stages and physiological status (19–21). It is not known whether the expression of these GHR mRNA variants is also affected differentially by food deprivation.

In this study, we sought to clarify the mechanism underlying the food deprivation–induced decrease in blood IGF-I by determining the effects of food deprivation on the levels of total IGF-I mRNA and GHR mRNA and the levels of individual IGF-I mRNA and GHR mRNA variants in the liver of steers.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Steers and experimental design.

Angus steers (n = 12) that were between 8 and 9 mo of age and weighed 274 ± 18 kg (mean ± SD) were maintained in a pasture at the Virginia Tech beef cattle farm (Blacksburg, VA). Each steer had free access to grass and water and also received 2.3 kg daily of a grain supplement containing 3.2 x 10⁴ kJ digestible energy and 17% crude protein. Steers were acclimated to periodic confinement and bleeding for 1 wk before the following experiments. All animal-related procedures were approved by the Virginia Tech Animal Care and Use Committee.

Steers were randomly assigned to two groups, with each group containing six steers. One group (fed group) continued to have free access to grass, water and the daily supplement; the other group (food-deprived group) had access to water only. Sixty-two hours after food deprivation was initiated, a liver biopsy sample of 200 mg was taken from each steer. The liver biopsy was performed according to a procedure described previously (22). Liver tissue samples were immediately frozen in liquid nitrogen and stored at -80°C. Sixty-six hours after food deprivation was initiated, serial blood samples were taken from each steer at intervals of 20 min for 6 h via jugular venipuncture. Blood samples were collected in tubes containing serum clot activator (Vacuette, greiner bio-one GmbH, Austria) and placed on ice immediately after collection. Serum from blood samples was harvested by centrifugation at 1000 x g for 15 min within 2 h of collection and stored at -20°C.

Radioimmunoassay.

Serum concentrations of IGF-I were determined by RIA. The RIA was performed on duplicate aliquots of ethanol-extracted serum as described previously (23). The IGF-I used for standards and iodination was the recombinant human IGF-I (GroPep, Adelaide, Australia). The first antibody for the RIA was the mouse anti-human IGF-I antibody, a gift of Dr. Bernard Laarveld (University of Saskatchewan, Saskatoon, Canada). The second antibody was the goat anti-mouse antiserum (Sigma Chemical, St. Louis, MO). The sensitivity of the assay was 0.9 ng/tube. The intra-assay CV was 8.7%.

Probes for ribonuclease protection assays.

Ribonuclease protection assays (RPA) were used to determine the levels of total IGF-I mRNA, class 1 and class 2 IGF-I mRNA variants, total GHR mRNA, GHR mRNA variants 1A, 1B, and 1C and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA. The antisense probes for the RPA were synthesized by in vitro transcription of appropriate cDNA plasmids (described below) using [-³²P]CTP and the Riboprobe Combination Systems kit (Promega, Madison, WI), essentially according to the manufacturer’s instructions. After transcription, free [-³²P]CTP was removed from the probe by phenol-chloroform extraction and filtration through Quick Spin Sephadex G-50 columns (Roche Molecular Biochemicals, Indianapolis, IN). The specific activity of the purified probe was estimated by liquid scintillation counting and the integrity of the probe was verified by gel-electrophoresis. The specific activity of IGF-I and GHR probes was at least 1 x 10⁸ cpm/µg; the specific activity of GAPDH probe was 1 x 10⁷ cpm/µg.

cDNA plasmids.

The cDNA plasmid used to synthesize the antisense probe for analysis of total IGF-I mRNA was a pGEM-T Easy plasmid (Promega) containing a 200-bp cDNA insert that corresponded to 137 bp of exon 3 and 63 bp of exon 4 of the bovine IGF-I gene (21). This plasmid was a gift of Dr. Matthew C. Lucy (University of Missouri, Columbia, MO). The cDNA plasmid used to synthesize the antisense probe for analysis of class 1 IGF-I mRNA variants was a pGEM-T Easy plasmid containing a 433-bp cDNA insert that was composed of 297 bp of exon 1 and 136 bp of exon 3 of the bovine IGF-I gene. This cDNA plasmid was cloned using the procedure of rapid amplification of cDNA ends (RACE). The cDNA plasmid used to synthesize the antisense probe for analysis of class 2 IGF-I mRNA was a pGEM-T Easy plasmid containing a 203-bp cDNA insert corresponding to 67 bp of exon 2 and 136 bp of exon 3 of the bovine IGF-I gene. This plasmid was also cloned using the RACE procedure. The cDNA plasmid used to synthesize the antisense probe for analysis of total GHR mRNA was a pGEM-T Easy plasmid containing a 317-bp cDNA insert that was composed of 81 bp of exon 2, 66 bp of exon 3, 131 bp of exon 4 and 39 bp of exon 5 of the bovine GHR gene. This cDNA plasmid was cloned by using a standard RT-PCR. The cDNA plasmid used to synthesize the antisense probe for analysis of GHR 1A mRNA was a pGEM-T Easy plasmid containing a 312-bp cDNA insert that represented 191 bp of exon 1A, 81 bp of exon 2, and 40 bp of exon 3 of the bovine GHR gene (21). This plasmid was also a gift of Dr. Matthew C. Lucy. The cDNA plasmid used to synthesize the antisense probe for analysis of GHR 1B mRNA was a pCR2.1 plasmid (Invitrogen, Carlsbad, CA) containing a 96-bp cDNA insert that was composed of 44 bp of exon 1B and 52 bp of exon 2 of the bovine GHR gene (20). The cDNA plasmid used to synthesize the antisense probe for analysis of GHR 1C mRNA was a pCR2.1 plasmid containing a 585-bp cDNA insert that was composed of 533 bp of exon 1C and 52 bp of exon 2 of the bovine GHR gene (19). The cDNA plasmid used to synthesize the antisense probe for GAPDH mRNA was a pGEM-T Easy plasmid containing a 90-bp bovine GAPDH cDNA insert and was cloned by a standard RT-PCR. The relationships between the riboprobes synthesized from these GHR and IGF-I cDNA and their corresponding mRNA transcripts are illustrated in Figure 1.

View larger version (22K): [in this window] [in a new window]   FIGURE 1 Diagram of riboprobes and corresponding mRNA. The mRNA transcripts are represented by boxes, each box representing an exon (not drawn to scale). The antisense probes are represented by lines under their corresponding mRNA. The relative positions of the boxes and lines indicate where the probes match the mRNA.

Total RNA from liver tissue samples was isolated by using TRI Reagent (MRC, Cincinnati, OH), according to the manufacturer’s instructions. RNA concentrations were determined by measuring absorbance at 260 nm and RNA integrity was verified by electrophoresis on formaldehyde-agarose gels.

The RPA was carried out on 20 µg of total RNA, using the RPA II kit (Ambion, Austin, TX), according to the manufacturer’s instructions with modifications described previously (19). Each hybridization tube contained 5 x 10⁴ cpm of IGF-I or GHR probe and 5 x 10⁴ cpm of GAPDH probe. The ribonuclease-protected RNA fragments were resolved by electrophoresis on 6% acrylamide gels containing 7 mol/L urea. After gel electrophoresis, gels were dried and exposed to phosphor screens. Exposed phosphor screens were scanned on a Molecular Imager FX System (Bio-Rad Laboratories, Hercules, CA). Protected RNA bands on scanned images were identified on the basis of size. The densities of protected bands were quantified by using the Alpha Imager program (Alpha Innotech, San Leandro, CA) and were used to represent the abundance of the corresponding mRNA.

Statistical analyses.

All statistical analyses were performed using SAS (SAS Institute, Cary, NC). The serum IGF-I data were analyzed using the Mixed Procedure, in which the effects of feeding level, time, and the interaction of feeding level x time were tested. The densities of the protected GHR mRNA or IGF-I mRNA bands were adjusted to the densities of GAPDH mRNA in the same sample. The adjusted densities were analyzed using the General Linear Model Procedure, in which the effect of feeding level was tested. The error variances of total GHR mRNA and GHR 1A mRNA data were heterogeneous, and statistical analyses were also performed on the logarithmic transformations of these data. Differences were considered significant if P < 0.05.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Serum IGF-I levels.

During a period of 6 h, food-deprived steers had lower serum IGF-I levels than fed steers (P < 0.01) (Fig. 2). The serum IGF-I concentration in food-deprived steers was only 37% of that in fed steers (Fig. 2). During the same period of time, the serum IGF-I levels in food-deprived steers also appeared to fluctuate less than that in fed steers (Fig. 2).

View larger version (24K): [in this window] [in a new window]   FIGURE 2 Serum concentrations of insulin-like growth factor (IGF)-I in fed (n = 6) and food-deprived (n = 6) steers. Serum IGF-I concentrations were analyzed over a period of 6 h at 20-min intervals. Values are means ± pooled SEM. Serum IGF-I concentrations of food-deprived steers were significantly lower than those of fed steers (P < 0.01).

To determine whether the food deprivation–induced decrease in serum IGF-I was associated with a decrease in the synthesis of IGF-I in the liver, we first measured the levels of total liver IGF-I mRNA in food-deprived and fed steers using an RPA with an antisense probe able to hybridize with all IGF-I mRNA variants (Fig. 1). On the basis of this RPA (Fig. 3A), the level of total liver IGF-I mRNA of food-deprived steers was reduced by 75% (P < 0.01) compared with that in fed steers (Fig. 3B). This magnitude of reduction in liver IGF-I mRNA was comparable to the 63% reduction in serum IGF-I (Fig. 2).

View larger version (41K): [in this window] [in a new window]   FIGURE 3 Effect of food deprivation on the levels of insulin-like growth factor (IGF)-I mRNA in the liver of steers. (A) Phosphor images of ribonuclease protection assay (RPA) for total IGF-I mRNA and class 1 and class 2 IGF-I mRNA in the liver of six fed steers (Y12, Y17, Y20, Y35, Y40 and Y47) and six food-deprived steers (Y7, Y26, Y27, Y37, Y41 and Y52). The RPA protected bands are indicated with arrows and the mRNA they represent. Note that class 1 IGF-I mRNA contain transcripts initiated at six different start sites (1 to 6) within exon 1 and that class 2 IGF-I mRNA contain transcripts initiated at two different start sites within exon 2. "Nonclass 1 IGF-I" and "nonclass 2 IGF-I" represent the IGF-I mRNA except class 1 IGF-I mRNA and the IGF-I mRNA except class 2 IGF-I mRNA, respectively. Yeast tRNA (tRNA) was included in each RPA as a negative control. The # indicates a band from incomplete digestion of the probe. (B) Relative abundance of total IGF-I mRNA, total class 1 IGF-I (total C1) mRNA, total class 2 IGF-I (total C2) mRNA and class 1 or class 2 IGF-I mRNA variants with different start sites in fed and food-deprived steers. Each bar represents the mean ± SEM (n = 6). *Different from fed steers, P < 0.01.

When the levels of all IGF-I mRNA variants within one class were combined, the levels of total class 1 IGF-I mRNA and total class 2 IGF-I mRNA in food-deprived steers were 62 and 66% lower (P < 0.01), respectively, compared with those in fed steers (Fig. 3B). Based on the densities of the third band on the RPA of class 2 IGF-I mRNA and the seventh band on the RPA of class 1 IGF-I mRNA, the levels of nonclass 2 IGF-I mRNA and the levels of nonclass 1 IGF-I mRNA in food-deprived steers were 66 and 68% lower (P < 0.01), respectively, than those in fed steers. Food deprivation appeared to decrease equally the levels of IGF-I mRNA variants with different start sites within class 1 or class 2 (Fig. 3B). Food deprivation did not change the expression of GAPDH mRNA in the liver (P = 0.87).

Liver GHR mRNA levels.

To determine whether the food deprivation–induced decrease in IGF-I mRNA was associated with a decrease in the levels of GHR mRNA in the liver, we first compared the levels of total GHR mRNA between fed and food-deprived steers, using an RPA (Fig. 4A) with a probe recognizing all known GHR mRNA variants (Fig. 1). The levels of total GHR mRNA were lower in food-deprived steers than in fed steers (P < 0.05) (Fig. 4B). To determine whether food deprivation decreased equally the levels of different GHR mRNA variants, we next measured the levels of three major GHR mRNA variants, GHR 1A, 1B and 1C, using RPA (Fig. 4A) with specific probes (Fig. 1). The level of GHR 1A mRNA in food-deprived steers tended to be lower (35%) than that in fed steers (P = 0.08) (Fig. 4B). The level of GHR 1B mRNA did not differ between food-deprived and fed steers (P = 0.22) (Fig. 4B). The level of a long form of GHR 1C mRNA called GHR 1C3, which is transcribed from a upstream start site in exon 1C of the GHR gene (19), was 29% lower in food-deprived steers than in fed steers (P < 0.05) (Fig. 4B). The level of a short form of GHR 1C mRNA, GHR 1C2, did not differ between food-deprived steers and fed steers (P = 0.85) (Fig. 4B).

View larger version (30K): [in this window] [in a new window]   FIGURE 4 Effect of food deprivation on the levels of growth hormone receptor (GHR) mRNA in the liver of steers. (A) Phosphor images of ribonuclease protection assay (RPA) for total GHR mRNA and GHR mRNA variants 1A, 1B, 1C3 and 1C2 in the liver of six fed steers and six food-deprived steers. The RPA protected bands are indicated with arrows and the mRNA they represent. (B) Relative abundance of total GHR mRNA, GHR 1A, GHR 1B, GHR 1C3 and GHR 1C2 mRNA in fed and food-deprived steers. Each bar represents the mean ± SEM (n = 6). The abundance of GHR 1B mRNA was combined levels of the two protected bands on the RPA of GHR 1B mRNA; these two bands represent GHR 1B mRNA with two different start sites (20). *Different from fed steers, P < 0.01.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

In this study, we found that food deprivation for nearly 3 d caused a 75% decrease in liver total IGF-I mRNA in steers. Because it is unlikely that the translatability of IGF-I mRNA is increased during food deprivation (24), a 75% decrease in liver IGF-I mRNA suggests a similar level of reduction in liver production of IGF-I protein. Because the IGF-I secreted from the liver contributes to the majority of blood IGF-I (2,3), a 75% decrease in liver IGF-I mRNA levels would decrease the blood IGF-I concentration in food-deprived steers. We found that the blood IGF-I concentration in food-deprived steers was decreased by 63%. Together, these results suggest that the decrease in blood IGF-I during food deprivation is caused mainly by the decrease in liver IGF-I mRNA expression. In addition to decreased liver expression of IGF-I, increased clearance of serum IGF-I has been reported to be responsible for decreased serum IGF-I in protein-restricted rats (25). It remains to be determined whether increased clearance of serum IGF-I also contributes to decreased blood IGF-I in food-deprived steers. We also noticed that circulating IGF-I in food-deprived steers was not only reduced, but also appeared to depart less from baseline. Under normal feeding conditions, fluctuations in circulating IGF-I in animals reflect changes in the level of its major regulator, GH. It has been reported that nutritional deprivation does not attenuate peak height or pulse frequency of GH in cattle (26). Therefore, attenuated fluctuation in circulating IGF-I in food-deprived steers suggests that IGF-I is no longer under the control of GH during nutritional deprivation.

A food deprivation–induced decrease in liver IGF-I mRNA in rats was reported to be mediated at multiple levels, including reduced transcription of the IGF-I gene (7–9), decreased processing of IGF-I premRNA (10) and decreased stability of IGF-I mRNA (10). Little is known about how food deprivation decreases IGF-I gene transcription, the processing of IGF-I premRNA or the stability of IGF-I mRNA. It is difficult to address these questions due to the presence of multiple forms of IGF-I mRNA in the liver. In rats, food deprivation decreases both class 1 and class 2 IGF-I mRNA in the liver, with a much greater effect on class 2 IGF-I mRNA (6), suggesting that different mechanisms mediate the effect of food deprivation on class 1 and class 2 IGF-I mRNA in rats. This does not mean, however, that a similar mechanism explains effects of food deprivation on IGF-I in all species. Indeed, we found that food deprivation equally decreased class 1 and class 2 IGF-I mRNA in cattle and also equally decreased the IGF-I mRNA variants with different start sites within each class. These results suggest that, unlike rodents, a common mechanism may mediate the food deprivation–induced decreases in the levels of different IGF-I mRNA variants in cattle. We speculate that this common mechanism involves a decrease in the activity of a transcription factor that controls the transcription from both exon 1 and exon 2 of the IGF-I gene (hence the transcription from both exon 1 and exon 2 is decreased) and/or a decrease in the binding of a RNA binding protein to both class 1 and class 2 IGF-I premRNA (hence the processing of both classes of IGF-I premRNA is decreased) and/or a decrease in the binding of an RNA binding protein to all mature IGF-I transcripts (hence all IGF-I transcripts are destabilized). These possibilities should be tested in future studies.

It is clear that decreased IGF-I gene transcription in the liver during food deprivation is due at least in part to GH resistance because decreased blood IGF-I is often accompanied by increased blood GH and cannot be restored by administration of GH (1). One well-accepted explanation for this GH resistance is that food deprivation decreases the number of GHR in the liver and hence the diminished GH response because many studies have observed that food deprivation or food restriction decreases GH binding (12–14,27) or GHR mRNA levels (7,16,17) in the liver. In agreement with these observations, we found that the levels of total GHR mRNA were decreased in food-deprived steers, suggesting that the same mechanism may also mediate the food deprivation–induced decrease in liver IGF-I mRNA. Interestingly, like IGF-I mRNA, GHR mRNA in a variety of species is also expressed as variants that differ in the leader exon in the liver (18). In previous studies, we identified nine such GHR mRNA variants in cattle, among which the variants called GHR 1A, 1B and 1C constitute the majority of GHR mRNA in the liver of postnatal cattle under normal conditions (19,20). In this study, we found that food deprivation decreased the levels of GHR 1A and 1C3 mRNA but not those of GHR 1B and 1C2 mRNA in the liver of steers, suggesting that the food deprivation–induced decrease in total liver GHR mRNA in steers is due mainly to a decrease in the expression of GHR mRNA variants 1C3 and 1A and that the expression of GHR mRNA variants is differentially regulated by nutritional status. It appears that differential regulation of GHR mRNA variants by nutritional status also exists in bull calves because it was found that increasing nutrient intake increased the levels of liver GHR 1A mRNA but not that of GHR 1B mRNA in those animals (28). However, the same may be not true for lactating cows because food restriction did not affect their expression of either GHR 1A mRNA or GHR 1B mRNA (29). Alternatively, as also discussed in the latter report (29), the effect of nutritional restriction on GHR mRNA expression may depend on the severity of the negative energy balance caused by food deprivation or food restriction in animals.

In summary, the results of this study suggest that the food deprivation–induced decrease in circulating IGF-I in steers is caused primarily by a coordinate decrease in the levels of all IGF-I mRNA transcripts in the liver and that this decrease in IGF-I mRNA expression is associated with a decrease in the levels of GHR mRNA variants 1C3 and 1A in the liver. Given that GH is the major regulator of IGF-I gene expression in the liver, it is tempting to hypothesize that decreased expression of GHR mRNA variants 1C3 and 1A is responsible in part for decreased IGF-I gene expression in the liver under conditions of food deprivation. This hypothesis remains to be tested in future studies.

	ACKNOWLEDGMENTS

 
The authors thank Matthew Lucy for providing cDNA plasmids, Bernard Laarveld for providing the IGF-I antibody and Sara Price for technical assistance. The authors also thank Eric Wong for critical reading of the manuscript and helpful comments.

	FOOTNOTES

 
¹ Supported in part by National Research Initiative Competitive Grant U.S. Department of Agriculture CSREES 2001–35205-11732 (to H.J.).

³ Abbreviations used: GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GH, growth hormone; GHR, growth hormone receptor; IGF-I, insulin-like growth factor I; RACE, rapid amplification of cDNA ends; RPA, ribonuclease protection assay.

Manuscript received 7 February 2003. Initial review completed 6 April 2003. Revision accepted 7 May 2003.

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