Amino Acids as Metabolic Regulators

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Millward and Rivers (1988) proposed the 'anabolic drive' theory to account for the transient effect of protein intake on protein anabolism. They suggested that it would be an advantage to consume indispensable amino acids in excess of requirements to match identifiable needs. An overwhelming amount of research in the last 10 years appears to support that view. Exciting evidence has emerged demonstrating that amino acids are potent signals that either directly or indirectly regulate protein metabolism (Jefferson and Kimball, 2001). Amino acids therefore serve primary roles as precursors for protein synthesis, and they modulate the protein synthetic machinery within target cells. Further, amino acids are secretagogues of anabolic hormones and they also sensitize target tissues to hormonal actions.

Following consumption of a meal, amino acid availability and adequacy is detected at the cellular level where changes in expression of key genes involved in the initiation and elongation of polypeptide chains are regulated by a series of phosphorylation events to promote protein synthesis (Kimball et al., 2000). This 'nutrient sensing' mechanism involves specific amino acids. The branched-chain amino acids alone are capable of increasing net anabolism (net protein gain) in muscle, adipose tissue and in the liver, with leucine being the most potent (Garlick and Grant, 1988; Patti et al., 1998; Jefferson and

Kimball, 2001). The branched-chain amino acids sensitize tissues to the presence of insulin and insulin-like growth factor-1 (IGF-1). The role of the branched-chain amino acids as signals of nutritional adequacy or availability appears to be uniquely suited to these amino acids because in most animals species, except for fish, branched chain removal by the liver is low (Fig. 5.1). Catabolism of the branched chains occurs in two steps (Fig. 4.13). Removal of the amino group via branched chain aminotransferase occurs mainly in the muscle whereas irreversible oxidation of the keto-acid via branched chain keto-acid dehydrogenase occurs mainly in the liver. The supply of branched-chain amino acids to peripheral tissues, therefore, largely reflects that of the diet and provides the signal to peripheral tissues that additional nutrients are available for protein synthesis.

Non-essential amino acids also act as regulators of protein metabolism. Alanine, glycine, aspartate and glutamate, and gluta-mine, all of which are transported by Na+-dependent transporters, regulate cell swelling. This mechanism has been associated with regulation of protein, carbohydrate and fat metabolism (Haussinger et al., 1994). Glutamine is the most potent, and increased influx of this amino acid into the cell causes the cell to swell, stimulating protein synthesis via similar mechanisms as the branched-chain amino acids (Fig. 5.1). By contrast, during cell shrinkage, as occurs when intracellular levels of the amino acid become depleted (e.g. immune challenge), protein degradation is enhanced. Increased cell swelling also leads to an increase in amino acid oxidation and hepatic ureagenesis. Positive correlations between protein synthesis and amino acid catabolism have been established at the whole animal level (Benevenga et al., 1993). Taken together, there appears to be an obligatory loss of amino acids associated with protein anabolism. This does not always appear to be the case, however, because in pigs administered growth hormone (GH), there is an inverse relationship between muscle protein synthesis and lysine oxidation (Gahl et al., 1998). This issue will need to be resolved since it has important implications for current attempts to balance the amino acid supply from diets to attain optimal rates of protein gain and improved nitrogen efficiency.

Several amino acids are capable of stimulating hormone synthesis and secretion (Kuhara et ai, 1991). In general, leucine and arginine are the most potent stimulators of insulin (anabolic) secretion whereas alanine, glycine and serine are the most effective stimulators of both glucagon (catabolic) and insulin. Aspartate and arginine are most effective in stimulating GH secretion. In pigs, tryptophan stimulates insulin secretion and protein synthesis in the liver, muscle and skin (Ponter et ai, 1994). The stimulation of IGF-1 secretion by GH is dependent on level of protein intake. Specific amino acids appear to be important in the GH-IGF-1 axis, with single deletions of arginine, proline, threonine, tryptophan and valine each blocking GH stimulated IGF-1 mRNA expression (Brameld et ai, 1999). The GH-IGF-1 axis is re-established, however, at low physiological concentrations of valine or lysine, suggesting that under normal growing conditions, where intake is near maximal, the GH-IGF-1 axis is probably not limited by amino acid availability. At maintenance, low intakes and diseased states, however, these signals may become very important.

During gestation there is a window of time when the embryo and fetus are susceptible to maternal protein intake. Low protein intake by rat dams during the pre-implantation period reprogrammes the physiology and metabolism of the fetus resulting in reduced postnatal growth rate, compromised immune function and the development of impaired glucose tolerance and insulin resistance in later life (Metges, 2001). Dietary lysine sufficiency during gestation-lactation of first-litter sows affects maternal weight loss, sow lactation and piglet growth, and interestingly, the added lysine results in an additional (10.7 vs. 9.6) piglet born alive in the subsequent mating (Tritton et ai, 1996). By contrast, in adolescent pregnant sheep, where the drive towards maternal tissue growth is still considerable, higher intakes favour partition of nutrients towards maternal tissues, rather than towards the fetal-placental compartment (Wallace, 2000). In adult ewes, maternal protein restriction of 30% compromises the fetal-placental compartment, resulting in low birth weight lambs that grow poorly. Piglets born to sows fed a protein-restricted diet are 10% smaller, have a reduced muscle mass and plasma levels of IGF-1 are 30% lower (Schoknecht et ai, 1997), suggesting that maternal protein restriction reprogrammes IGF-1 activity. Remarkably, these pigs eventually recover the lost growth after weaning, but this may come too late since the most challenging periods in normal production units are the suckling and weaning phases. Reduced placental-fetal transport and metabolism of glucose, threonine, glycine, and methionine/cysteine appear to be hallmark metabolic features of gestational protein restriction.

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