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Biochemical and Molecular Actions of Nutrients

An Energy-Rich Diet Causes Rumen Papillae Proliferation Associated with More IGF Type 1 Receptors and Increased Plasma IGF-1 Concentrations in Young Goats^1,2

Zanming Shen^*,, Hans-M. Seyfert^*, Berthold Löhrke^*, Falk Schneider^*, Rudi Zitnan, Arthur Chudy^*, Siegfried Kuhla^*, Harald M. Hammon, Juerg W. Blum, Holger Martens^**, Hans Hagemeister^*,3 and Juergen Voigt^*

^* Research Institute for the Biology of Farm Animals (FBN), Dummerstorf, Germany; Nanjing Agricultural University, Nanjing, China; ^** Free University, Berlin, Germany; Research Institute of Animal Production, Nitra, Slovakia; and University of Berne, Berne, Switzerland

³To whom correspondence should be addressed. E-mail: hans.hagemeister{at}gast.uni-rostock.de.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
We tested the hypothesis that the dietary energy–dependent alterations of the rumen papillae size are accompanied by corresponding changes in systemic insulin-like growth factor (IGF)-1 concentration and in rumen papillary IGF type 1 receptors (IGF-1R). Young male goats (n = 24) were randomly allocated to two groups (n = 12) and fed a high level (HL) metabolizable energy [1200 kJ/(kg^0.75 · d)] or a low level (LL) [500 kJ/(kg^0.75 · d)] diet for 42 d. The concentration of ruminal total SCFA did not differ between the groups, but the molar proportion of butyric acid was enhanced by 70% in the HL group (P < 0.05). Both the length and width of the papillae were greater (P < 0.05) in the HL group, and the surface was 50–100% larger (P < 0.05) in the tissue sampled from the artrium ruminis, the ventral ruminal sac and the ventral blind sac. Transport of Na⁺ across the rumen epithelium, which is amiloride sensitive, was higher (P < 0.05) in the HL than in the LL group. Furthermore, the plasma IGF-1 concentration was about twofold higher in the HL group (P < 0.05), and the maximal rumen epithelial IGF-1R binding was also higher in the HL (P < 0.05) than in the LL group. IGF-1R mRNA and IGF-1 mRNA were detected in rumen papillae; however, they were unaffected by dietary treatments. DNA synthesis and cell proliferation of cultured rumen epithelial cells were higher (P < 0.05) after IGF-1 treatment (25 or 50 µg/L) compared with those in the medium without IGF-1. Thus dietary energy–dependent alterations of rumen morphology and function are accompanied by corresponding changes in systemic IGF-1 and ruminal IGF-1R.

KEY WORDS: • nutrition level • rumen papillae • Na⁺ transport • IGF-1 • IGF-1 receptor

The development and renewal of rumen papillae depend on adequate nutrient intake. The intake of protein- and energy-rich feed promotes the growth of rumen tissues (1–3). High concentrate rations markedly increased the number and size of ruminal papillae and enhanced the absorption of SCFA from the rumen of cows (2) and of Na⁺, Mg⁺⁺ (4) and Ca⁺⁺ in the rumen of sheep (5). Data concerning the dietary energy–dependent enhanced transport capacities of the rumen epithelium are supported by recent findings that the abundance of DNA and RNA of rumen epithelial cells increases with greater intake of metabolizable energy (ME)³ (3). However, the underlying mechanisms of the dietary energy–dependent physiologic, biochemical and histological alterations of the rumen epithelium are not known. Butyrate enhances the growth of rumen papillae in vivo (6,7), but not in vitro (8,9).

Insulin-like growth factor-1 (IGF-1) is produced in tissues throughout the body. However, the main source of circulating IGF-1 is the liver (10). Both energy (11) and protein (12) intake have marked effects on the plasma IGF-1 concentration and IGF-1 mRNA abundance in sheep (13,14), heifers (15), beef steers (12), bulls (16) and calves (17). The level of feed intake and nutritional status are considered to be the main factors affecting IGF-1 status in mammals (11,18).

IGF-1 is a growth promoter that regulates the proliferation of many cell types (19), including the epithelial cells of the intestine (20), and interacts with the type-1 IGF receptor (IGF-1R). Recent studies provided evidence that IGF-1 stimulates the growth of rumen epithelial cells in vitro (9). Nevertheless, an effect of IGF-1 on rumen papillae development in vivo has not yet been documented. Therefore, we tested the hypothesis that the level of feed intake and dietary energy–dependent alterations in the number and size of rumen papillae are accompanied by corresponding changes of IGF-1 concentration in plasma and in the number of IGF-1R in the rumen papillae of young goats.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Experimental design and goat management

Young male goats (n = 24) were used. Goats were housed and treated in accordance with the guidelines of the German Government in Mecklenburg-West Pommerania regarding animal welfare (LVL-MV 310–4/7221.3–2.1). Before the experiments, goats were acclimated to individual pens (120 x 100 cm) and consumed long and chopped hay ad libitum with progressively increasing amounts of concentrates for 4 wk. During the week immediately before initiating the experimental protocol, the energy consumed [750 kJ/(kg^0.75 · d)] was 1.5 x maintenance, and nitrogen intake [1500 mg/(kg^0.75 · d)] was 2.0 x maintenance, supporting growth rates of 100 g/d. The goats, aged 3 mo at the commencement of the experiment, were randomly allocated to two groups: a high nutrition level group (HL, n = 12) and a low nutrition level group (LL, n = 12). Each group was fed one of the two designed levels of diet containing concentrate and hay (Table 1). The HL group was fed 90 g concentrate/(kg^0.75 · d), and the LL group was fed 20 g concentrate/(kg^0.75 · d); both groups had free access to chopped hay. The intake of concentrate was recorded daily. During the course of the experiment, intakes of energy and nitrogen were 2.2 and 3.3 x maintenance, respectively [1200 kJ/(kg^0.75 · d) and 2750 mg/(kg^0.75 · d)] by the HL group and 1.1 x and 1.5 x maintenance, respectively [500 kJ/(kg^0.75 · d) and 1150 mg/(kg^0.75 · d)] by the LL group. The goats were fed once daily via an automatic feeder (produced by engineers of the institute for nutrition trials) that allowed individual and continuous feeding. Water was always available. The feeding period was 42 d.

    Sample collection. Feed ingredients were sampled and analyzed at the beginning and end of the experimental period to determine the nitrogen content and to calculate the energy value (Table 1).

Blood was sampled immediately before feeding. Blood samples were collected via jugular venipuncture into vacutainers containing heparin. The samples were immediately put on ice and centrifuged at 2500 x g at 4°C for 10 min to obtain the plasma. Plasma samples were stored at -80°C until analyzed for IGF-1. Samples were taken 1 d before commencement of treatments and weekly or biweekly throughout the experiment.

At the end of the feeding experiment, goats were slaughtered in a local slaughterhouse. After opening of the rumen, rumen liquid was strained through four layers of gauze and stored at -21°C until analysis. Rumen tissues from the atrium ruminis, ventral rumen sac and ventral blind sac were collected, transferred into liquid nitrogen and stored at -80°C until analyzed for IGF-1 mRNA, IGF-1R mRNA and IGF-1R binding capacity. The rumen epithelium was isolated, immediately rinsed, soaked in buffer solution and transferred to the laboratory.

Rumen tissue (1 cm²) from the atrium ruminis, ventral rumen sac and ventral blind sac was fixed in 4% formaldehyde solution for evaluation of rumen papillae morphology (21).

    Determination of rumen papillae morphology. After being rinsed in water, the samples of rumen tissue were dehydrated in a graded series of ethanol (30, 50, 70 and 90%), cleared in benzene, saturated with and embedded in paraffin, and sectioned. The length and width of papillae were determined by the computer-operated Image C picture analysis system (Intronic GmbH, Berlin, Germany) and the IMES analysis program, by using a color video camera (SONY 3 CCD) and a light microscope (Axiolab, Carl Zeiss Jena, Germany).

The number of papillae/cm² mucosa (papillae density) was estimated by video camera with a picture analysis system. The total surface of papillae/cm² mucosa was calculated as length x width x 2, multiplied by the number of papillae/cm².

    Sodium transport across the rumen epithelium. Preparation of isolated rumen epithelium. The goats were stunned with a commercial abattoir apparatus and killed by bleeding from the carotid arteries. Within 2–3 min after exsanguination, the reticulo-rumen was removed from the abdominal cavity, and two 150-cm² pieces of rumen wall were taken from the ventral sac. The pieces were first cleaned by immersion in buffer solution. The epithelium was stripped from the muscle layer. During preparation and transport, the buffer solution (38°C) was gassed with carbogen (95% O₂ + 5% CO₂; buffer composition for preparation and transport in mmol/L: NaCl 115, NaHCO₃ 25, NaH₂PO₄ 0.4, Na₂HPO₄ 2.4, KCl 5.0, glucose 5.0, CaCl₂ 1.2, MgCl₂ 1; osmolarity 285 mosmol/L; pH 7.4). Tissues were cut into squares (3 x 3 cm) and mounted between two halves of an incubation chamber with an exposed area of 3.14 cm². Rings of silicon rubber on both sides of the tissue were used to minimize edge damage. The mucosal and serosal surfaces were bathed in buffer solution. This standard electrolyte solution contained (mmol/L): NaCl, 115; CaCl₂, 1; MgCl₂, 1; NaHCO₃, 25; KCl, 5; NaH₂PO₄, 1; Na₂HPO₄, 2; Na-acetate, 25; Na-propionate, 10; Na-butyrate, 5; glucose 10. The temperature of the bathing buffers was kept at 37°C by a thermostat apparatus with a gas lift system of humidified carbogen (95% O₂ + 5% CO₂) during the measurement of the Na⁺ fluxes (Mußler Scientific Instruments, Aachen). The tissues were short-circuited after 20–30 min (equilibration).

    Calculation of Na⁺ flux rates. Unidirectional fluxes of Na⁺ were determined by ²²Na (Amersham, Braunschweig, Germany), which was added to the reservoirs, i.e., either to the serosal or to mucosal side, to give a radioactivity level of 80 kBq, and the tissues were incubated for 30 min for equilibration with the isotope. Fluxes were calculated from the rate of appearance of tracer in the other reservoir. From this, J_ms and J_sm fluxes were measured for the paired tissues; the difference between the paired estimates was the net flux (J_net). Paired determination of fluxes was accepted only if, between the start and the end of the experiment, electrical parameters of the tissue (conductance, PD and short circuit current) differed by <25%. Flux studies were performed under short-circuit conditions.

    Sampling procedure for ²²Na flux measurement. A 100-µL sample was taken from the "hot" (radioactive) side at the beginning and the end of each experiment as a control and to calculate the specific radioactivity of Na (Bq/µmol Na) from both samples. The mean of these two samples was taken for the calculation of Na transport rates. From the "cold" side (at which the tracer appeared from the radioactive side) a 2-mL sample was taken at the end of the equilibration time and then every 30 min for three flux periods. The sample volume was replaced by the corresponding buffer solution for the measurement of three flux periods; these probes were counted in a gamma counter (LKB Wallace-Perkin Elmer, Überlingen, Germany). The flux rates were calculated by standard equations. The method was described in detail by Martens et al. (22). To identify the underlying Na transport mechanism, amiloride (1 mmol/L), a blocker of Na⁺/H⁺-exchange, was added to the buffer solution on the mucosal side.

    Plasma IGF-1 concentration. Plasma IGF-1 concentration was measured by a competitive ¹²⁵I-RIA kit with an anti-IGF-1 raised in rabbits and an anti-rabbit precipitant (goat) (Nichols Institute Diagnostics, San Juan Capistrano, CA). IGF-1 standards were calibrated against a WHO IGF-1. IGF-1 was separated from binding proteins by acid/ethanol (12.5% of 2 mol/L HCl and 87.5% ethanol) precipitation. Each sample was analyzed in duplicate. Diluted plasma concentrations paralleled the standard curve, indicating that plasma IGF-1 and IGF-1 of standards were immunologically similar. The intra-assay (precision) and interassay CV (reproducibility) were 4 and 10%, respectively.

    Quantification of IGF-1 and IGF-1R mRNA. Total RNA was extracted using TRIZOL (Invitrogen, Karlsruhe, Germany) as described by Mao et al. (23). cDNA was prepared by priming 1 µg of total RNA with a mixture of three different reverse primers (25 pmol each). An oligo (dT) primer was combined with the gene-specific reverse primers IGF-1R(5'-CACTCATCCACGATTCCTGTCTG) for IGF-1 and R-IGF-1R (5'-GACCCATTCCCAGAGAGAGAG) for the IGF-1R. The mixture was heated to 93°C (2 min), kept for 5 min at 70°C and then chilled on ice. cDNA was generated with Superscript RT (Invitrogen) for 1 h at 42°C, as indicated by the manufacturer. Products were purified (HighPure PCR Purification Kit, ROCHE Diagnostics, Mannheim, Germany), and aliquots equivalent to an input of 12.5 ng total RNA were employed for the Real Time amplification used for all assays. A 184-bp segment of the cDNA from IGF-1 was amplified with the primers IGF-1f (5'-ACATCCTCCTCGCATCTCTTC) and cCHIGF-1R (5'-GGGGCGCTCTCCGACTGCT), whereas 211 bp of the IGF-1R were amplified with the primer R-IGF-1f (5'-CTGAGAATCCCAATGGATTGATC) combined with R-IGF-1. Copy numbers were determined from two independent cDNA preparations of any sample. Copy numbers were calculated relative to a dilution series of the respective reference plasmids, comprising 10⁶ to 10² copies. The reference plasmids contained the cloned RT-PCR products obtained with these primers. Authenticity of the isolates was verified by sequencing.

The IGF-1R sequence was derived by using oligo (dT)-primed cDNA from goat liver and amplifying this by RT-PCR with primers derived from the homologous bovine sequence (24). We found that two nucleotides were exchanged in our sequence of the goat amplification: an A vs. T residue at position 446, and an A vs. G at position 500 of the bovine reference file, respectively.

    Ligand binding. Rumen papillae were homogenized with an Ultra-Turrax homogenizer (T25, Janke & Kunkel, Staufen, Germany) at 8000 rpm for 50 s. The homogenate was centrifuged at 800 x g for 10 min; the supernatant was centrifuged at 10,000 x g for 10 min, and the supernatant thus obtained was centrifuged at 100,000 x g for 1 h. The remaining pellet was suspended in ice-cold buffer by a motor-driven Glass-Teflon homogenizer. The protein concentration of the suspended solution was determined by a kit (BCA Protein Assay Reagent, Pierce, Rockford, IL), and the membrane suspension was then adjusted with incubation buffer to a final concentration of 200 mg/L for IGF-1 binding studies. Binding of (¹²⁵I)-IGF-1 was measured as described by Hammon and Blum (25) and Georgiev et al. (26). IGF-1 for iodination and unlabeled IGF-1 were from Ciba Geigy, St. Aubin, Switzerland. For the determination of (¹²⁵I)-IGF-1 maximal binding, the radiolabeled ligand (0.35 ng) was incubated with increasing concentrations of the unlabeled ligand (24,25).

    Cell culture. Rumen papillae from the atrium ruminis were cut into small pieces and digested with 0.1% collagenase type 2 at 37°C for 10 min. This was repeated several times until the cells were completely dissociated. The first and second fractions were discarded, whereas the third and ensuing fractions were collected and then filtered through a cell strainer. Individual cells were obtained by centrifugation (80 x g, 10°C, 10 min) and were resuspended in culture medium (RPMI 1648, Sigma, Deisenhofen, Germany) to which 9% fetal calf serum (FCS), 2 mmol/L L-glutamine and antibiotics were added. The cells were seeded onto a 24-well plate (10¹⁰/L) and incubated at 37°C with 5% CO₂ for 24 h to allow attachment. The culture medium was then replaced by fresh medium without FCS supplement, and the cells were incubated for another 24 h to minimize influences of growth factors. LR₃-IGF-1 (Sigma) was administrated in amounts of 0 (control), 25 and 50 µg/L for 8 h.

    Cell cycle analysis by flow cytometry. Freshly prepared and cultured cells were fixed in ethanol (70%), washed and treated with RNAse solution (in PBS, 37°C, 30 min). The RNAse solution was heated (85°C, 60 min) to denature the contaminating DNAse. After incubation for 30 min with propidium iodide (70 µmol/L) in HBS (Hepes 5 mmol/L, pH 7.3, NaCl 150 mmol/L), flow cytometry was performed (Coulter-Elite, Krefeld, Germany) and the cell cycle was analyzed by a computer-aided Multicycle Program (Phoenix, San Diego, CA) to display the proportion of cells in S-phase (S-phase cell DNA concentration is greater than that of resting diploid cells) and the proportion of mitotic cells.

    Volatile fatty acid (VFA) determination. A mixture of 5 mL rumen fluid and 2 mL isocaproic acid (internal standard) was centrifuged at 3000 x g at 4°C for 20 min. The supernatant was then filtered to measure the SCFA concentration by GC (Shimadzu GC-14A, Kyoto, Japan) on an FFAP column (25 m x 0.25 mm i.d.).

    Statistical analyses. Data are expressed as means ± SEM. Data for Na⁺ transport and the electrophysiology of isolated rumen epithelium were analyzed by a two-way ANOVA. Nutrition level and amiloride treatment were the factors tested. The Least Significant Difference test was applied when the F-test was significant. Differences in ruminal SCFA concentrations, rumen papillae size and parameters of the IGF system in blood and tissue were analyzed by Student’s t test. The response of papillary cells from the LL and HL groups to IGF-1 was analyzed by a paired t test. Differences with P < 0.05 were considered to be significant.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
The total SCFA concentration in the rumen did not differ between the HL and LL groups (Table 2).

View larger version (12K): [in this window] [in a new window]   FIGURE 1 Effect of nutrition level on plasma insulin like-growth factor 1 (IGF-1) concentrations in young goats. Values are means ± SEM, n = 9. ***Different from LL at that time, P < 0.001. Low level (LL) intakes of energy and nitrogen were 1.1 x and 1.5 x maintenance levels, respectively. High level (HL) intakes of energy and nitrogen were 2.2 x and 3.3 x maintenance levels, respectively.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

Sodium transport rates across the rumen epithelium in vitro were associated with nutrition levels. The net flux of Na⁺ from the mucosal to the serosal side was higher in the epithelia of HL than of LL goats. This is in general agreement with other studies on ion transport across the rumen epithelium. All transport systems studied to date were enhanced by improved feed intake (2,4,5,30). Sehestedt et al. (30) concluded that this nutritional effect on ion transport cannot be explained by changes in epithelial surface area, structure or resistance, which agrees with the results of the present study (Table 4) because the tissue conductance, G_t, did not differ between the groups. Amiloride, an inhibitor of the Na⁺/H⁺-exchanger (NHE), partially reverses the stimulating effect of the nutrition level on Na⁺ transport, indicating that the increased activity of the NHE probably represents enhanced Na⁺ transport. In other tissues and epithelia, NHE activity appears to be regulated by IGF-1 (31–33). The data of this study indicate a similar link between IGF-1 and Na⁺ transport. However, it must be emphasized that this correlation has not been established. Despite the lack of evidence for a potential connection between the effects of the nutrition level on morphology and function of rumen epithelium and the IGF system, previous studies have shown nutritional effects on the IGF system at other intestinal sites (25,34,35), but not in the rumen. To our knowledge, this is the first report demonstrating the presence of IGF-1 mRNA, IGF-1R mRNA and IGF-1R protein in rumen papillae. Moreover, our data reveal that the numbers of rumen IGF-1R vary with nutritional intensity. IGF could mediate tropic actions of nutrients (36). Our study shows that an enhanced intake of energy and protein increases plasma IGF-1 concentration and IGF-1R number, and that this may contribute to the regulation of rumen papillae growth. The hyperplastic effect of systemic IGF-1 may have also resulted from decreased apoptosis (37). The actions and mechanisms of paracrine/autocrine IGF-1 on intestinal epithelium are not clear (38–40). Takenaka et al. (35) reported that the synthesis of the IGF-1R is regulated in a distinctive way in different tissues in response to protein intake. The response of the rumen IGF-1R mRNA to feeding level does not correspond to the pattern of IGF-1R protein synthesis. It was suggested previously that the regulation of IGF and IGF-1R by nutrition, regardless of the transcription rate, may also be under post-transcriptional control (26,41,42).

Other factors, such as SCFA, are also likely involved in the regulation of epithelial functions independently of the suggested cascade of nutrient intake plasma IGF-1 proliferation. Musch et al. (43) exposed the human colonic cell line C2/bbe to acetate, propionate and butyrate and found an increase in Na⁺/H⁺-exchange activity and protein expression in the apical membrane. Furthermore, rats fed pectin had higher colonic protein and mRNA involved in Na⁺/H⁺-exchange and as well as an increase in brush border activity (43). The above observation confirms results of previous in vivo and in vitro studies and supports the assumption of local (luminal) effects of SCFA. In the present study, the concentration of butyric acid increased significantly in the HL group (Table 2). Nosbush et al. (15) demonstrated that butyric acid does not influence plasma IGF-1 in heifers fed a high concentrate diet. Additionally, proliferation of the rumen epithelium can be explained in part by reduced rates of apoptosis in the presence of increased ruminal butyric acid concentrations (7). A direct action of butyrate cannot be determined from this experimental design; however, net proliferation of the rumen tissue may result from decreases in rumen epithelial turnover rate.

The dietary energy–dependent morphological and functional changes in the rumen epithelium are of basic physiologic importance. An enhanced absorption of SCFA (2) and Ca⁺⁺ (5) in intensively fed ruminants may help to prevent rumen acidosis (44) and milk fever, respectively. Unfortunately, the change in morphology and function of the rumen epithelium in cows requires 4–6 wk (2) and hence a special feeding regime during the final weeks of pregnancy. Because overconditioned cows are predisposed to a variety of metabolic disorders (45), any increase in energy intake before parturition must consider the amount of time required for adaptation of the rumen epithelium to dietary changes. A further complication arises because feed intake is usually reduced during the last 3 wk of pregnancy (46). If the IGF system is involved in the nutrition-dependent alterations of the rumen epithelium, this adaptation could be delayed by the decrease of IGF-1 concentration in plasma in early lactation (47,48).

In conclusion, the results of the present study are in agreement with established knowledge about dietary intake–dependent alterations in rumen morphology and functions. Furthermore, these changes are accompanied by variations in the plasma IGF-1 concentration and the number of IGF-1R in the rumen epithelium. However, the experimental design of this study does not allow a causal association to be made between the various parameters, although the results suggest a possible interaction.

	FOOTNOTES

 
¹ Presented at 2001 ASAS Meeting, Indianapolis, IN, July 24–28. Shen, Z.-M., Löhrke, B., Schneider, F., Franz, H., Chudy, A., Kuhla, S., Zitnan, R., Martens, H. & Hagemeister, H.

² Supported by Wilhelm Schauman Stiftung and the Chinese National Nature Science Foundation (39970552).

⁴ Abbreviations used: FCS, fetal calf serum; HL, high level diet; IGF-1, insulin like-growth factor 1; IGF-1R, IGF type 1 receptor; LL, low level diet; ME, metabolizable energy; NHE, Na⁺/H⁺-exchanger.

Manuscript received 28 July 2003. Initial review completed 3 September 2003. Revision accepted 6 October 2003.

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