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Articles

Temporal Response of Hepatic Threonine Dehydrogenase in Chickens to the Initial Consumption of a Threonine-Imbalanced Diet¹

Department of Animal Science, Cornell University, Ithaca, NY 14853

³To whom correspondence should be addressed at 248 Morrison Hall.

	ABSTRACT

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Amino acid imbalances contribute to higher requirements of amino acids than would occur if the dietary profile of amino acids perfectly matched the requirements. The mechanisms of imbalances have not been fully elucidated. Because threonine dehydrogenase (TDH) activity in liver mitochondria increases in chicks and rats subjected to threonine imbalance, the current study was carried out to determine whether the change in TDH activity occurs rapidly enough after the consumption of an imbalanced diet to be considered a possible primary metabolic response. In a series of experiments, Leghorn chicks were allowed free access to a semipurified basal diet marginally limited in threonine or the same diet containing a mixture of indispensable amino acids (IAA) lacking threonine to cause a threonine imbalance. In the first experiment, dietary supplements of 5.5 and 11.1% IAA were used to determine a level of supplement that would cause a robust response in the specific activity of TDH. Feed intake, body weight gains and efficiency of feed utilization were lower and specific activities of TDH were higher in chicks fed 11.1% IAA than in those fed 5.5% IAA. In subsequent experiments, hepatic TDH activities and plasma amino acid profiles of the control and experimental groups were determined at 1.5, 3, 6, 12 and 24 h after the first offering of the diet containing 11.1% IAA. The specific activities of TDH in chicks fed the IAA supplement were 40–150% higher (P < 0.05) and plasma threonine concentrations were 42–53% lower (P < 0.05) than in chicks fed the basal diet at all times except 1.5 h. These results indicate that changes in the capacity for threonine degradation via TDH may occur in the liver within a few hours after the consumption of a threonine-imbalanced diet and suggest the possibility that altered TDH activity may contribute to the increased threonine requirement associated with threonine imbalance.

KEY WORDS: • threonine dehydrogenase • chickens • threonine imbalance • temporal change • plasma amino acids

	INTRODUCTION

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Amino acid imbalances occur when diets limited by an essential amino acid are supplemented with one or more other amino acids. Food intake is rapidly and consistently reduced when animals are offered diets that are limited in an indispensable amino acid (IAA),⁴ such as those used in the imbalanced amino acid diet paradigm⁵ (Gietzen and Jhanwar 1993 , Harper et al. 1970 ). One of the biochemical responses of animals fed amino acid–imbalanced diets is a rapid decrease in the concentration of the limiting amino acid in the plasma (Leung et al. 1968 , Peng et al. 1972 ). We hypothesize that this decrease may be due in part to an increase in catabolism of the limiting amino acid (Davis and Austic 1982a and 1994 ).

The specific activity of threonine dehydrogenase (TDH) (EC 1.1.1.103) in isolated hepatic mitochondria was higher when diets marginally adequate in threonine were supplemented with a mixture of IAA lacking threonine (Davis and Austic 1994 ). The specific activity of TDH increased by 12 h in rats and by 24 h in chicks subjected to threonine imbalance, but earlier time periods were not investigated with either species. Rats adapted to the threonine-imbalanced diet, and after a period of 7 d, they had similar daily body weight gains as the rats fed the unsupplemented diet. At the end of this time period, the specific activity of TDH decreased to levels lower than those of the rats fed the basal diet. Chicks did not adapt; their TDH activities remained high and their growth rate remained low relative to chicks fed the basal diet after 7 d of the experiment. The correlation of the specific activity of TDH with growth suggested that TDH activity might be a factor in the growth depression that occurs in animals subjected to threonine imbalance. If changes in TDH contribute to the depression in plasma threonine concentration, feed intake and growth that occur rapidly after animals are fed threonine-imbalanced diets (Davis and Austic 1994 , Leung et al. 1968 , Sanahuja and Harper 1963 ), then the change in TDH activity must occur soon after the consumption of such diets. The current study was conducted to determine the temporal change in the specific activity of TDH and plasma concentrations of threonine and other amino acids within the first 24 h in chicks fed a threonine-imbalanced diet.

	MATERIALS AND METHODS

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Animals.

Day-old Single Comb White Leghorn chicks (ISA Babcock Breeders, Ithaca, NY) reared in battery brooder cages with raised-wire floors were fed a practical chick starter diet for 5–7 d. Chicks were sorted by weight in such a manner as to achieve equal weight distributions among all pens and then were fed the basal diet for 5 d. Feed was removed at 2200 h on d 5 (i.e., the day before the experiment), and experimental diets were provided from 0800 h on the next day until the end of the experiment. Six replicate pens of seven chicks per treatment were used in expt. 1, and four replicates of four chicks per treatment were used in expt. 2–5. Water was available continuously, and cages were lighted from 0800 to 2200 h. All animal procedures were approved by the Institutional Animal Care and Use Committee of Cornell University.

Diets.

The basal diet was identical to the basal diet used by Davis and Austic (1994) . It was a semipurified diet that contained 22.7% crude protein (N x 6.25), derived from isolated soybean meal and 17 crystalline amino acids. The diet contained all nutrients at levels sufficient to satisfy the nutrient requirements of Leghorn chicks according to the National Research Council (1994) , except for threonine, which was marginally adequate. A mixture (Table 1 ) of IAA was added to the basal diet at the expense of glucose to imbalance the diet with regard to threonine.

Experiments 2–4 were conducted to determine the temporal response of TDH in chicks after an initial feeding of a threonine-imbalanced diet. Feed was withheld overnight, and at 0800 h the next morning, chicks were allowed free access to the basal diet or the diet containing the 11.1% IAA mixture. In expt. 2, livers were sampled at 0, 12 and 24 h after provision of the experimental diets. Subsequent experiments followed the same protocol of expt. 2 except that the livers were sampled at 6 and 12 h in expt. 3 and at 1.5 and 3 h in expt. 4. It was necessary to conduct three experiments because it was not known how soon the change in TDH activity would be detected, and it was not technically feasible to study all possible time periods in a single experiment. Therefore, each experiment involved a shorter interval after feeding than the proceeding experiment and included an overlapping time point, except expt. 4. At the end of these experiments, chicks were killed by CO₂ asphyxiation followed by cervical dislocation to ensure death. Livers were sampled immediately for the determination of mitochondrial TDH activity, except in expt. 3, in which livers sampled at 1.5 h were kept on ice until after the 3-h sampling.

Experiment 5 was conducted to determine temporal changes in plasma amino acid concentrations. Whole blood was obtained through cardiac puncture from pools of two chicks per replicate pen at various times after the experimental diets were fed. The times corresponded to those of expt. 2–4.

Tissue preparation and analyses.

Plasma samples were prepared for amino acid analysis, and liver samples were prepared for measurement of TDH activity as previously described by Davis and Austic (1994) , except that modified time zero blanks⁶ were used in this study.

Statistical analysis.

In expt. 1, data were analyzed with one-way ANOVA followed by Fisher’s pairwise comparison procedure to detect differences among treatment means. Data from subsequent experiments were subjected to one-way ANOVA to detect differences due to diet within time. The effect of time was not tested. An arcsin percentage transformation of glycine (as a percentage of recovered products of TDH activity) was performed before statistical analysis. All statistical procedures were performed with Minitab statistical software (Version 11.12; Minitab, State College, PA). Differences were considered significant when P-values were <0.05.

	RESULTS

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Experiment 1.

Chicks fed the diets containing 5.5% IAA had lower (P < 0.05) weight gain and feed consumption than did chicks fed the basal diet (Table 2 ). Chicks fed the 11.1% IAA supplement had lower (P < 0.05) feed consumption, weight gain and efficiency of feed utilization than did the chicks fed the basal diet or the diet containing the 5.5% IAA supplement. The weight gain and feed consumption of the chicks fed the diet containing the 11.1% IAA supplement plus 1.4% threonine did not differ from those of chicks fed the basal diet. The efficiencies of feed utilization, however, were higher than those of chicks fed the basal diet. The specific activity of TDH was twice as high (P < 0.05) in the chicks fed 5.5% IAA and threefold to fourfold higher (P < 0.05) in chicks fed 11.1% IAA and 11.1% IAA plus 1.4% threonine than in chicks fed the basal diet. The specific activity of TDH in chicks fed the 11.1% IAA supplement plus 1.4% threonine did not differ from chicks fed the 11.1% IAA supplement alone. The percentage of product recovered as glycine⁷ did not differ among treatment groups, and the protein concentrations in the mitochondrial preparations used for the assays did not differ among treatments (P > 0.05).

In expt. 2, TDH activity was measured at 0, 12 and 24 h after the experimental diets were first fed. By 12 h, the specific activity of TDH in chicks fed the IAA-supplemented diet was more than twice (P < 0.05) that of chicks fed the basal diet (Table 3 ). The difference was somewhat less at 24 h. The percentage of product recovered as glycine was lower (P < 0.05) at 12 and 24 h in chicks fed the diet containing the IAA supplement than in chicks fed the basal diet. In expt. 3, specific activities were higher (P < 0.05) at 6 and 12 h in chicks fed the IAA-supplemented diet than in chicks fed the basal diet. The percentage of product recovered as glycine did not differ significantly (P > 0.05) between dietary treatment groups. In expt. 4, there were no differences (P > 0.05) in aminoacetone accumulation, glycine production or specific activity of TDH at 1.5 h between the chicks fed the basal diet and those fed the basal diet supplemented with IAA. At 3 h, the specific activity was 66% higher (P < 0.05) in chicks fed the IAA-supplemented diet than in chicks fed the basal diet. The percentage of product recovered as glycine did not differ between dietary treatment groups (P > 0.05). The protein concentrations in the mitochondrial preparations did not differ (P > 0.05) significantly among treatment groups with two exceptions: protein was 7% lower (P < 0.05) in the IAA group at 24 h in expt. 2 and 22% higher (P < 0.05) in the IAA group at 6 h in expt. 3.

The concentrations of several amino acids (lysine, arginine, valine, phenylalanine, tyrosine, isoleucine and tryptophan) in plasma were higher (P < 0.05) and alanine levels were lower (P < 0.05) by 1.5 h in the IAA-supplemented group than in chicks fed the basal diet (Fig. 1 ). By 3 h, several other amino acids (lysine, methionine, histidine and ornithine) were also present in higher (P < 0.05) concentrations in plasma of chicks fed the IAA-supplemented diet than in those fed the basal diet. The concentration of threonine was significantly lower (P < 0.05) in the IAA-supplemented group than in the basal group by 3 h. In addition, plasma concentrations of alanine, serine, glycine, proline and asparagine were lower (P < 0.05) at 3 h in the IAA-supplemented group than in the basal group. At 6 h, all of the above-mentioned amino acids and glutamate were lower (P < 0.05) in the chicks fed the IAA-supplemented diet than in chicks fed the basal diet. The pattern of plasma amino acid concentrations was similar from 6 to 24 h for all of the measured amino acids except methionine and isoleucine. The concentrations of methionine and isoleucine, which were higher (P < 0.05) in the IAA group at earlier times, were not significantly different (P > 0.05) from those of the basal group at 24 h. Cystine, hydroxyproline and 3-methylhistidine were not significantly affected by dietary treatment (P > 0.05). 1-Methylhistidine was lower in the IAA group than in the basal diet–fed chicks at 3, 12 and 24 h (means ± SEM 10 ± 2.2 versus 20 ± 1.3, 8 ± 1.3 versus 18 ± 3.4 and 8 ± 2.8 versus 22 ± 1.6 µmol/L, respectively). Tryptophan was significantly higher (P < 0.05) in the IAA group than in the basal group at 1.5 h; however, its concentration decreased and became lower (P < 0.05) than in the basal group by 24 h.

View larger version (24K): [in this window] [in a new window]   Figure 1. Concentrations of amino acids in blood plasma of chicks after they were fed the basal diet or basal diet supplemented with a 11.1% mixture of indispensable amino acids (IAA) for 1.5, 3, 6, 12 or 24 h (expt. 5). Each column represents the means ± SEM of four replicate determinations of pooled plasma from two chicks. O, ornithine; HPRO, hydroxyproline; 3MH, 3-methylhistidine; 1MH, 1-methylhistidine. Asterisk indicates significant difference from the basal group (P < 0.05).

	DISCUSSION

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TDH activity in liver mitochondria is affected by variations in dietary protein concentration in chickens (Aoyama and Motokawa 1981 , Davis and Austic 1997 ) and domestic cats (Hammer et al. 1996 ). The addition of amino acid mixtures, such as those used to cause threonine imbalance, increase TDH activities in chickens (Davis and Austic 1982a , 1994 and 1997 ) and in rats (Davis and Austic 1994 ). It is possible that the mechanisms by which dietary supplements of protein and mixtures of amino acids affect TDH activity are similar. In the current study, IAA supplementation of the diet with a mixture of IAA lacking threonine was used to cause a threonine imbalance. As expected, the IAA supplement resulted in depressions in feed intake and growth, and these depressions were prevented by the addition of threonine to the diet. The specific activity of hepatic TDH increased in response to IAA supplementation, and 11.1% IAA resulted in higher specific activity than 5.5% IAA. These results served as the basis for selection of the level of IAA supplementation in the following experiments. Because the 11.1% IAA treatment resulted in a large increase in specific activity of TDH, this level of IAA supplementation was used in subsequent experiments on the temporal response of TDH. The responses to 5% IAA were less than those reported by Davis and Austic (1994 and 1997) . The reason for this difference between the past and current results in regard to IAA supplementation might involve genetic variation, because the chicks used in the current study were from commercial crosses, whereas the studies of Davis and Austic (1994 and 1997) involved chickens of the Cornell-K strain.

In previous studies (Davis and Austic 1982a , 1994 and 1997 ), the activity of specific TDH was affected not by increased dietary threonine alone but rather by the total amount of protein or supplemental mixtures of all or selected IAA in the diet. TDH may be one of many enzymes that has increased activity in chicks under these nutritional conditions. Animals fed high-protein diets have been reported to have increased activities of many rate-limiting enzymes of amino acid catabolism compared with animals fed lower dietary levels of protein (Ashida and Harper 1961 , Bella et al. 1996 , Davis and Austic 1997 , Dixon and Harper 1984 , Featherston and Horn 1973 , Freedland and Avery 1964 , Gillim et al. 1983 , Pitot et al. 1961 , Sanahuja and Harper 1963 , Schimke 1962 , Torres et al. 1998 , Wergedel and Harper 1964 ).

The relative amounts of glycine and aminoacetone produced in the TDH assay might reflect the relative activities of TDH, of which the immediate product is 2-amino-3-oxobutyrate, and of 2-amino-3-oxobutyrate-CoA ligase, of which the products are glycine and acetyl-CoA. Aminoacetone is formed via nonenzymatic decarboxylation of 2-amino-3-oxobutyrate. In previous experiments (Davis and Austic 1994 ), the ratio of glycine to aminoacetone was higher in chicks that were fed a 5.3% IAA supplement for 7–9 d than in chicks fed the basal diet. In the current experiments, the proportions of glycine and aminoacetone were not affected at 3 d, but glycine tended to represent less of the product at 24 h when chicks were fed the diet containing the IAA mixture. This may indicate that the relative activities of the two enzymes or of other enzymes in related pathways change during a period of several days after exposure to the imbalancing mixture of amino acids. The glycine cleavage system, for example, was observed by Ewart et al. (1992) to increase within a few hours of the feeding of a high-protein diet to rats. More studies would be needed, however, to determine whether temporal changes in the activities of these enzymes can account for the altered ratios.

Temporal change in hepatic TDH activity.

In a rat model of threonine imbalance, the specific activity of TDH was significantly higher at 12 h in IAA-supplemented rats than in rats fed a basal diet; this difference was not detected at 24 h but reappeared at 72 h (Davis and Austic 1994 ). Activity was significantly higher at 24 h in a chick model. Earlier times were not investigated in either species. From the results of expt. 2–4, it is apparent that the specific activity of TDH in chicks fed an IAA-supplemented diet was higher than that in chicks fed the basal diet within 3 h after initial access to the IAA-supplemented diet and that this increase persisted for 24 h. The highest TDH activities in both basal and IAA groups occurred 1.5 h after the diets were fed. This may result from the circadian rhythms reported for various hepatic enzymes in both rats and chicks (Hopkins et al. 1973 , Rapoport et al. 1966 , Wurtman 1974 ). Davis and Austic (1982b) reported that the highest hepatic TDH activity in chicks was observed at the beginning of the light period of a 16:8-h light/dark cycle and that this activity was significantly greater than at other times of the day. The current result of the highest specific activity of TDH observed at 1.5 h after the diets were fed is consistent with the report of Davis and Austic (1982b) , because the light period began just 1.5 h before samples were taken.

In the current study and in previous studies (Davis and Austic 1994 and 1997 ), the crude mitochondrial preparations from 2-g samples of pooled minced liver per treatment were resuspended with 10 mL buffer. The actual volumes of sample, therefore, were 10 mL plus wet mitochondria in residual 0.25 mol/L sucrose; the volume was not known but was 1 mL. Because all samples were prepared similarly and only in two instances did the protein concentrations of the suspended preparations differ significantly, the differences in specific activity reflect differences in the total activities of recovered mitochondria.

Temporal change in plasma amino acid concentrations.

The anorectic response to supplementation of the diet with an imbalancing mixture of amino acids has been detected within 2 h after the initial feeding of the diet to rats (Gietzen et al. 1986 , Sanahuja and Harper 1963 ), and the concentration of threonine in the plasma of rats was observed to be lower within 3 h after an imbalanced diet was fed (Leung et al. 1968 ). In the current study, the chicks that were fed the IAA mixture had higher specific activity of hepatic TDH within 3 h of initial access to the diet. Furthermore, the increase in TDH activity at 3 h was associated with a lower plasma threonine concentration in animals fed the imbalanced diet, and this inverse response of TDH and plasma threonine persists through at least 24 h (Fig. 2 ). The reduction in the concentration of the limiting amino acid in plasma in rats and chicks correlates temporally with the well-characterized depression of the threonine concentration in the anterior prepyriform cortex within 2.5 h that is hypothesized by Gietzen et al. (1986 and 1998) to be involved in the anorectic response to threonine-imbalanced diets in rats. Therefore, it appears possible that the change in the concentration of threonine in the prepyriform cortex is, at least in part, secondary to changes in threonine concentration in blood.

View larger version (19K): [in this window] [in a new window]   Figure 2. Temporal responses of the specific activity of threonine dehydrogenase TDH) and plasma threonine (Thr) concentration. Values represent a composite of the results of expt. 2–5. TDH activities (expt. 2–4) are indicated by dashed (basal diet) and solid [basal + indispensable amino acids (IAA)] lines, and plasma Thr concentrations (expt. 5) are indicated by filled (basal diet) and striped (basal + IAA) columns.

Glycine metabolism.

Plasma glycine and serine concentrations were lower within 3 h in chicks fed the IAA-supplemented diet. This decrease in glycine occurred despite the higher specific activity of hepatic TDH, which could result in the formation of glycine from threonine. This suggests that either the flux from threonine to glycine via TDH activity was not increased significantly by IAA or the metabolism of glycine was increased when the diet was supplemented with IAA. The excess nitrogen that would arise from metabolism of the IAA supplement would be expected to increase uric acid synthesis. Glycine is a substrate for the synthesis of uric acid. Therefore, the rapid decrease in plasma concentrations of glycine and of serine, which can be converted to glycine via the activity of serine-glycine hydroxymethyltransferase (EC 2.1.2.1), could be due to an increased use of glycine in uric acid synthesis.

Glycine may also be depleted because of increased activity of the glycine cleavage system. This possibility has not been investigated in chicks. In rats, however, an increase in the activity of the glycine cleavage system occurred within 2 h from the initial consumption of a high-protein meal and involved a fourfold to sixfold enhancement of flux through this system as measured in isolated mitochondria (Ewart et al. 1992 ). If the stimulation of the hepatic glycine-cleavage system by protein in chicks were as rapid as in rats, this might account for the decreased plasma glycine and serine concentrations in the current study.

Approximately three fourths of the product of TDH activity in expt. 1–4 were recovered as glycine. The IAA treatment, averaged across expt. 2–4 for all times except 0 h, resulted in 68% of the product as glycine compared with 77% recovered as aminoacetone in mitochondria chicks fed the basal diet. This apparent difference between treatments is small, and although the difference was statistically significant at 12 and 24 h in expt. 2, it may not be real because the effect of IAA at 12 h in expt. 2 was not observed in expt. 3 (P = 0.07) and the difference between treatments was not observed after 3 d in expt. 1. If it is real, however, it suggests that a difference may exist in the relative temporal patterns of TDH and 2-amino-3-oxobutyrate CoA ligase activities or activities of other enzymes of glycine metabolism in the mitochondrion.

In conclusion, these results indicate that the addition of IAA to the diet to imbalance threonine produces an increase in specific activity to hepatic TDH within a few hours of the first feeding of such a diet to chickens. The adverse effects of imbalances on growth in rats have been attributed to changes in food intake that may result from the interactions of amino acids in a specific region of the anterior prepyriform cortex (Gietzen et al. 1998 ). Decreases in threonine concentration in this region and in plasma are evident by 3 h after the initial consumption of a threonine-imbalanced diet. This is approximately the same duration that is required for increased specific activity of mitochondrial TDH and for reduced plasma concentration of threonine in the chicken (see Fig. 2 , a composite of expt. 2–5). It is not known whether threonine flux via the hepatic TDH pathway is increased in vivo or whether such a change in threonine metabolism would contribute to the decreased concentration of threonine in plasma and other tissues that might trigger the anorectic response, but the rapid change in the specific activity of the enzyme after the initial consumption of an imbalanced diet suggests that these possibilities are worthy of further investigation.

	ACKNOWLEDGMENTS

 
The authors gratefully acknowledge the gift from BioKyowa (Chesterfield, MO) of amino acids that were used in this investigation and the advice and assistance of Barbara Smagner in preparation of the manuscript.

	FOOTNOTES

 
¹ Supported in part by Hatch Project 127444.

² Current address: Department of Poultry Science, University of Georgia, Poultry Science Building, Athens, GA 30602.

⁴ Abbreviations used: IAA, indispensable amino acids; TDH, threonine dehydrogenase.

⁵ In the imbalance paradigm using the laboratory rat, a mixture of IAA that lack the first-limiting amino acid is added to a low-protein diet that is first-limiting in one of the IAA. Threonine, isoleucine or histidine typically has been the first-limiting amino acid in this paradigm.

⁶ The modified time zero blanks contained mitochondria, all reagents except L-threonine, NAD and CoA. Trichloroacetic acid was added to terminate enzyme activity before the 15-min incubation. Studies in this laboratory indicate that modified time zero blanks and substrate blanks (mitochondria and all reagents except L-threonine incubated 15 min before termination with trichloroacetic acid) do not differ significantly (P > 0.05). Blanks were subtracted from the complete incubations in all experiments.

⁷ The product of TDH activity, 2-amino-3-oxobutyrate, is highly unstable and therefore cannot be measured directly. Two other products are recovered: aminoacetone, which forms nonenzymatically from 2-amino-3-oxobutyrate, and glycine, which is generated in the mitochondrion in a reaction catalyzed by 2-amino-3-oxobutyrate CoA ligase.

Manuscript received June 9, 2000. Initial review completed June 23, 2000. Revision accepted July 12, 2000.

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