Amino Acid Imbalance Definition

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This term was defined by Harper (1964) as a change in the pattern of amino acids in the diet precipitating depressions in food intake and growth, which are completely alleviated by supplementation with the first-limiting amino acid. The prerequisite for a limiting amino acid may be satisfied by the use of a suitably deficient protein such as gelatin, but more generally this condition may be fulfilled by the use of low-protein diets. The definition of imbalance was devised as a result of investigations with the rat but is now being widely applied to the nutrition of farm animals.

© CAB International 2003. Amino Acids in Animal Nutrition, 2nd edition (ed. J.P.F. D'Mello)

It is, therefore, instructive to recall some of the fundamental tenets embodied in this class of adverse effects. Two types of imbalance may be recognized (Table 7.1): that caused by the addition of a relatively small quantity of an indispensable amino acid to a low-protein diet, and that precipitated by an incomplete mixture of amino acids. In the former case, there is a specific requirement that the agent precipitating the imbalance should be the second-limiting amino acid (Winje et al., 1954). A more reliable procedure involves the addition of an amino acid mixture devoid of one indispensable amino acid to a low-protein diet limiting in the same amino acid (Pant et al., 1972). Other studies show that imbalances may also be created by employing mixtures of the dispensable amino acids (Tews et al., 1980). In such instances, the most reliable technique involves the use of amino acids, individually or in mixtures, which compete with the dietary limiting amino acid for transport into the brain.

From experiments employing incomplete amino acid mixtures, Fisher et al. (1960) concluded that the chick is as sensitive to an imbalance as the growing rat (Table 7.1). The primary manifestation of adverse effects was a depression in food intake which consequently also decreased intake of the limiting amino acid, leading to reduced growth.

Practical implications

The issue of amino acid imbalance assumed practical significance in poultry nutrition with the studies by Wethli et al. (1975) who invoked this phenomenon to explain the inferior utilization, by broiler chicks, of the first-limiting amino acid in low-quality protein sources. Wethli et al. (1975) designed a series of cereal-based diets containing increasing quantities of groundnut meal to provide crude protein (CP) levels ranging from 120 to 420 g kg 1 diet. These diets were formulated with or without supplementary methionine plus lysine. Growth responses were compared with those of chicks fed on a series of control diets containing graded quantities of herring meal such that final dietary CP concentrations ranged from 120 to 240 g kg-1. Thus the assumed minimal amino acid needs of the young chick were considered to be satisfied at the high inclusion rates of either protein source. As expected, with the unsupple-mented groundnut meal diets, growth rates improved as CP concentrations increased up to 360 g kg-1 diet, but failed to match those of chicks fed lower levels of CP derived from herring meal. However, supplementation of the groundnut meal diets with methionine plus lysine induced progressive and more efficient gains at all CP levels up to 270 g kg-1 diet. At this concentration of CP, the supplemented groundnut meal diet supported

Table 7.1. Effects of dietary amino acid imbalance on growth of rats and chicks fed low-protein diets.

Protein source; dietary protein level; and amino acid supplements

First-limiting amino acid

Method of precipitating imbalance

Diets

Growth response (proportion of control)

Reference

Rats

Egg albumen; 80 g

His

Addition of second-

Control

1.00

Winje et al.

kg-1 diet; Thr + Val

limiting amino acid

I m balanced

0.65

(1954)

(Lys)

Corrected

0.95

Casein; 80 g kg 1

Trp

Addition of amino

Control

1.00

Pant et al.

diet; Met

acid mixture devoid

I m balanced

0.71

(1972)

of Trp

Corrected

1.10

Chicks

Sesame protein;

Lys

Addition of Lys-free

Control

1.00

Fisher et al.

110 g kg"1 diet;

amino acid mixture

I m balanced

0.87

(1960)

Lys (suboptimal)

Corrected

1.69

growth approaching that observed with the best herring meal control diet containing 210 g CP kg In a further experiment, Wethli et al. (1975) observed that diets based on soybean meal and maize were somewhat inferior to similar diets fortified with methionine even though the unsupplemented diets, at the higher CP concentrations, satisfied the calculated requirements for the first-limiting amino acid. Of several hypotheses examined, Wethli et al. (1975) concluded that the amino acids supplied by low-quality oilseed protein sources were in such disproportion to the needs of the chick as to impair utilization of the first-limiting amino acid. It was suggested that amino acid imbalances can occur in diets based on conventional ingredients and that pure supplements of limiting amino acids may be used to rectify these imbalances.

Further impetus to the study of imbalances emerged with the introduction of the diet-dilution technique to determine amino acid requirements of poultry. This method, originally devised to determine the methionine requirement of laying pullets, was adapted to investigate the growth responses of broiler chicks to different concentrations of an indispensable amino acid (Morris et al., 1987; Abebe and Morris, 1990a,b). The procedure involved the sequential dilution of a high-protein 'summit' diet with an isoenergetic, protein-free mixture. The summit diet was formulated to contain a large excess, typically 185% of assumed requirements, of all indispensable amino acids except the one under test, which was set at around 145% of assumed requirements. On blending the summit diet with the protein-free mixture, the amino acid under test would be expected to be first-limiting at all levels of dilution. Although successive dilutions resulted in progressively lower CP concentrations, the dietary amino acid pattern remained constant throughout the diluted series. Interpretation of responses to the different dilutions were attributed specifically to intakes of the first-limiting amino acid. Thus, the diet-dilution technique involved the deliberate creation of an amino acid imbalance in the classical manner established by Harper (1964). Nevertheless, the diet-dilution technique was used to determine the responses of broiler chicks to lysine

(Morris et al., 1987) and to tryptophan (Abebe and Morris, 1990b). As will be discussed at length later (Chapter 14), substantial disparity emerged between the growth responses obtained with the serial dilution of the summit diet and those observed with the addition of pure amino acid supplements (D'Mello, 1988). This incompatibility of responses was attributed to the effects of amino acid imbalance in the summit and diluted diets (Abebe and Morris, 1990a), but data by D'Mello (1990) question the validity of this interpretation. Since these issues relate to amino acid utilization by growing poultry, further discussion is reserved until Chapter 14.

Several studies with pigs indicate that amino acid imbalances may occur at the tissue level even though the diet may appear to be in ideal balance. Such imbalances are readily demonstrated on supplementation of cereal-based diets with crystalline amino acids. It has long been recognized that free amino acid supplements are absorbed more rapidly than protein-bound amino acids resulting in an imbalanced supply at sites of protein synthesis (Leibholz et al., 1986; Leibholz, 1989). For example, Leibholz et al. (1986) observed that the concentration of free lysine in plasma of pigs increased 1-2 h after feeding a diet containing pure lysine, declining thereafter, whereas the circulating concentrations of other amino acids originating from the protein-bound fraction of the diet peaked at 2-6 h postprandial. In pigs fed once daily, this lack of synchrony in absorption would precipitate an amino acid imbalance at the cellular level. Under these circumstances growth and efficiency of dietary nitrogen (N) would be impaired, but the deleterious effects could be offset by more frequent feeding. This expectation was confirmed by Batterham (1974) who observed that the efficiency of utilization of free lysine supplements for growth of pigs fed once daily was only 0.43-0.67 of values recorded with pigs fed the same ration in six equal portions at 3-hourly intervals. In contrast, no such benefit occurred on feeding the unsupplemented control diet more frequently. Subsequent investigations by Partridge et al. (1985) extended the benefits of increased feeding frequency and lysine supplementation to improvements in N utilization.

With the commercial development of rumen protected amino acids (Chapter 16), the question of imbalances in cattle nutrition is relevant, particularly in view of the uncertainty associated with the duodenal delivery of feed and microbial amino acids. In studies with lactating dairy cows, Robinson et al. (2000) fed a basal diet co-limiting in intesti-nally absorbable supplies of methionine and lysine. On abomasal infusion with excess methionine, cows fed this diet ate less dry-matter and produced less milk and lactose than unsupplemented controls. Evaluation of results with two metabolic models suggested that the basal diet may have been limiting in intestinally absorbable lysine, isoleucine or his-tidine. Thus the addition of methionine would have created an imbalance in the classical manner.

Effects on food intake

Accounts of amino acid imbalances conventionally focus on the growth-depressing effects in animals (Harper, 1964; Tews et al., 1979). However, it has been consistently recorded that a predisposing factor is a rapid and marked reduction in food intake. Thus Harper and Rogers (1965) reported that rats fed an imbalanced diet reduced their food intake within 3-6 h. These results implied that the depression in food intake was the primary event responsible for the ensuing retardation of growth. A considerable body of evidence supports this premise. If food intake in animals consuming imbalanced diets is increased by force-feeding, by insulin injections, by adjusting dietary protein to energy ratios or by exposing animals to cold environmental temperatures, then commensurate improvements in growth also occur (see D'Mello, 1994).

The biochemical mechanisms underlying the anorectic effects of imbalanced diets have been described by Harper and Rogers (1965) following extensive studies with the rat. It was suggested that surplus amino acids arriving in the portal circulation after consumption of an imbalanced diet stimulate synthesis or suppress breakdown of protein in the liver leading to greater retention of the limiting amino acid relative to that in control groups (Table 7.2). The supply of the limiting amino acid for peripheral tissues such as muscle is thereby reduced, although protein synthesis in these tissues proceeds unimpeded. Eventually, however, the free amino acid patterns of both muscle and blood plasma become so deranged as to invoke the intervention of the appetite-regulating system to reduce food intake. Growth is reduced as a consequence of the depressed appetite and intake of nutrients. This hypothesis is still accepted as a satisfactory explanation for the effects of amino acid imbalance in the rat and is thought to have wider application to other animals including poultry (D'Mello, 1994).

Alterations in dietary preferences are another feature of amino acid imbalance, at least in the rat. Thus, when offered a choice, rats consume a balanced diet in preference to an imbalanced one, but more remarkably, select a protein-free diet incapable of supporting growth instead of an imbalanced diet

Table 7.2. Sequence of events during amino acid imbalance leading to depressed food intake. (Based on the hypothesis of Harper and Rogers, 1965.)

Site

Effects

Liver

Surplus amino acids stimulate synthesis or suppress breakdown of proteins;

efficient utilization of limiting amino acid

Muscle

Protein synthesis continues normally; greater retention of limiting amino acid;

deranged free amino acid pattern

Plasma

Deranged free amino acid pattern

Brain

Abnormal pattern in blood monitored by appetite-regulating regions

Whole animal

Depressed food intake

Reduced nutrient intake

Reduced growth

which would allow growth, albeit at a low level (Sanahuja and Harper, 1962; Leung and Rogers, 1987).

A central tenet in the hypothesis advanced by Harper and Rogers (1965) is the association between food intake depression and changes in tissue patterns of amino acids. In both blood plasma and muscle, concentrations of the limiting amino acid decline, whereas there is an accumulation of those amino acids added to precipitate the imbalance. Since these events occur within a few hours of ingestion of such diets, it has been suggested that changes in plasma amino acid pattern may provide the metabolic signal that ultimately results in anorexia and abnormal feeding behaviour. In subsequent attempts to validate this hypothesis, the role of the first-limiting amino acid has featured prominently. For example initial studies (Leung and Rogers, 1969) indicated that the depression in appetite may be prevented by the infusion of a small quantity of the first-limiting amino acid via the carotid artery whereas administration through the jugular vein was ineffective. Tobin and Boorman (1979) confirmed that the cockerel fed an imbalanced diet responded in a similar manner to the rat following infusion of the limiting amino acid.

The studies by Leung and Rogers (1969) provided the basis of the proposition that food intake and feeding behaviour may be associated with changes in brain uptake and metabolism of critical amino acids. It was soon established that the concentration of the first-limiting amino acid declined more rapidly in cerebral tissues than in plasma (Peng et al, 1972). This observation led to the proposal that the fall in brain concentrations of the limiting amino acid initiates the signal which causes the changes in food intake and dietary choice, although the precise mechanisms remain obscure (Leung and Rogers, 1987). However, the regions of the central nervous system sensitive to amino acid imbalance have been delineated in the rat. These include the anterior prepyriform cortex, the medial amygdala and certain sites of the hippocampus and septum. In particular, the sensitivity of the prepyriform cortex to amino acid imbalance has been extensively investigated by Gietzen et al. (1986) and Beverly et al. (1990a,b,

1991a). Thus the selection of a protein-free diet in preference to an imbalanced one was reversed if the limiting amino acid was injected directly into the prepyriform cortex. Beverly et al. (1991b) showed that injected dose levels were important, exerting separate effects on dietary selection and on intake of imbalanced diets. Gietzen et al. (1998) developed this concept further by demonstrating that different neural circuits mediated the initial recognition and secondary conditioned responses to imbalanced diets.

Amino acid imbalance may affect food intake and dietary selection by modulating the synthesis and metabolism of neurotransmitters in the brain (Figs 4.10 and 4.11). In one study, feeding imbalanced diets reduced production of noradrenaline in the anterior prepyriform cortex of rats (Leung et al., 1985). However, Harrison and D'Mello (1987) showed that an imbalance caused by the addition of mixture devoid of tyrosine and phenylalanine to a diet deficient in these amino acids reduced food intake in chicks without affecting noradrenaline or dopamine levels in brain homogenates. This discrepancy may have more to do with neurotransmitter synthesis and disposition at specific sites in the brain than with any genuine differences between species or type of imbalance used in the two studies.

Effects on nutrient utilization

The effect of amino acid imbalance on nutrient utilization has been the subject of some debate. An imbalance would be expected to impair overall efficiency of utilization of dietary protein. Experiments with rats (Kumta et al., 1958) confirm this expectation, with N retention efficiency declining from 0.60 to 0.44 on addition of an unbalancing amino acid mixture to a control diet. However, in rats pair-fed the control diet to match intakes of the imbalanced group, efficiency of N retention decreased to 0.33, indicating that the effects of imbalance are mediated via reductions in appetite. Despite these observations, the accepted consensus is that amino acid imbalances reduce the efficiency of protein utilization in farm animals. Thus, Moughan (1991) attributed the low efficiency of protein utilization in pigs partly to dietary amino acid imbalance. In addition, Partridge et al. (1985) demonstrated that imbalances at the tissue level, induced by differential absorption of amino acids from crystalline and protein-bound sources, can reduce overall efficiency of protein utilization in pigs fed once daily. Furthermore, Wang and Fuller (1989) showed that manipulation of the composition of a mixture of amino acids to simulate the pattern in casein enhanced N retention in pigs by reducing imbalances. However, Langer and Fuller (1994) demonstrated that the addition of an imbalancing mixture containing leucine, isoleucine and valine to a diet limiting in methionine increased N efficiency in growing pigs. This somewhat unusual effect was attributed to a reduction in degradation of methionine by competitive inhibition of enzymes involved, leading to increased availability of methionine for body protein synthesis (Langer et al., 2000). The concept of enhanced utilization of the limiting amino acid is not new; thus Harper and Rogers (1965) reported that rats fed a threonine-imbalanced diet reduced oxidation of 14C-labelled threonine. In subsequent studies, Yoshida et al. (1966) and Benevenga et al. (1968) demonstrated increased incorporation of the first-limiting amino acid into hepatic proteins of rats fed imbalanced diets. Thus, both whole-animal and biochemical studies with rats have demonstrated enhanced utilization and retention of the limiting amino acid following feeding of amino acid imbalanced diets. Despite this evidence, other investigators continue to invoke such imbalances to explain differences in utilization of limiting amino acids in chicks fed excess protein (Abebe and Morris, 1990a,b) or imbalanced diets (Yuan et al., 2000). This issue is of sufficient practical significance to merit detailed attention (Chapter 14).

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