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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:1547S-1552S, June 2005

4th Amino Acid Assessment Workshop

Hormonal and Signaling Role of Branched-Chain Amino Acids1,2

K. Sreekumaran Nair3 and Kevin R. Short

Mayo Clinic College of Medicine, Rochester, MN

3To whom correspondence should be addressed. E-mail: nair.sree{at}mayo.edu.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Amino acids (AAs), especially BCAAs, play pivotal roles in hormonal secretion and action as well as in intracellular signaling. There is emerging data showing that BCAAs regulate gene transcription and translation. Signaling proteins such as the mammalian target of rapamycin act as sensors of BCAAs, especially leucine, to modulate anabolic action. AAs stimulate protein synthesis and inhibit protein breakdown in skeletal muscle and liver. The specific role of BCAAs in regulating synthesis and breakdown of individual protein or proteins with common function or functions remains to be defined. Future studies should also focus on potential adverse effects of BCAAs on insulin sensitivity, renal function, and tumor growth. It also remains to be determined whether potential adverse effects of BCAA supplementation is similar in people of different age groups.

KEY WORDS: • branched-chain amino acids • signaling • hormonal secretion • hormonal action • protein synthesis • protein breakdown

Amino acids (AAs)4 are probably best known for their role as the building blocks of proteins. However, growing evidence has shown that AAs also play pivotal regulatory roles in body metabolism at multiple levels. The free (nonprotein bound) AAs in humans are traditionally classified as essential and nonessential based on whether they are endogenously produced or required in the diet, respectively. Based on their structure, they are also classified as aromatic, branched chain, sulfur containing, and so on, and, based on functional properties, they can be referred to as glucogenic or nonglucogenic. There is increasing evidence that individual AAs, alone or in combination, have unique physiologic effects. With a better understanding of these roles, it may be possible to better use AA supplementation for therapeutic applications in several clinical conditions. In this review, important aspects of branched-chain amino acids (BCAAs) as regulators of hormone secretion and signaling molecules will be discussed.

BCAAs as hormone secretagogues

AAs are well known to stimulate secretion of insulin, glucagon, growth hormone, and insulin-like growth factor 1. However, the potency in stimulating the secretion of hormones varies substantially among the individual AAs. Rocha and colleagues (1) demonstrated in dogs that when individual AAs were infused intravenously, the magnitude of insulin secretion was greatest with tryptophan, leucine, and aspartate, whereas valine, alanine, and histidine had minimal effect on insulin (Fig. 1). These results provide an example of 2 AAs with similar structures (both leucine and valine are BCAAs) but with different physiological effects. In contrast, leucine, isoleucine, and valine were poor secretagogues of glucagon, whereas glycine, serine, alanine, aspartate all stimulate glucagon secretion with a minimal effect on insulin. Interestingly, the data suggest that leucine and isoleucine not only stimulate insulin secretion but also may inhibit glucagon secretion. A limitation of these experiments was that the same absolute amount of each AA, 1 mmol, was infused. Because the plasma and tissue concentration varies among the individual AAs, infusion of the same absolute amount of each AA resulted in differential magnitude of change in plasma concentration above baseline among the AA. Nevertheless, this study is the only one to date to carefully measure the hormonal responses to all of the individual amino acids.



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  		FIGURE 1 Insulin and glucagon release in response to individual AAs. Values represent the change in insulin and glucagon for 30 min after i.v. injection of 1 mmol/L of individual AAs in conscious dogs (n = 4–5 animals per measurement). This demonstrates the differing effect of each AA on these 2 hormones, suggesting their unique potential clinical usefulness. TRP, tryptophan; LEU, leucine; ASP, aspartate; ILE, isoleucine; GLU, glutamate; PHE, phenylalanine; THR, threonine; MET, methionine; GLN, glutamine; GLY, glycine; CYS, cystine; PRO, proline; LYS, lysine; ORN, ornithine; SER, serine; ARG, arginine; ASN, asparagine; VAL, valine; ALA, alanine; HIS, histidine. Adapted from (1).

 
Using a somewhat similar approach Floyd and colleagues (2) were the first to compare the effect of the essential AAs, alone and in combination, on the changes in plasma insulin in humans. Of the single AAs tested, arginine, lysine, phenylalanine, and leucine resulted in the highest increments in plasma insulin in the hour after infusion. The insulin increment evoked by arginine was similar to that of a mixture of 10 essential AAs. Subsequently, arginine infusion has been used for many years as an insulin secretegogue. Other groups have examined the ability of AA mixtures to modulate the effect of carbohydrate ingestion on hormone secretion. Recently, for example, van Loon and colleagues (3) reported that adding a mixture of free AAs from wheat protein hydrolysate plus supplemental leucine and phenylalanine to a glucose drink resulted in a similar large increase in the area under the insulin curve for 2 h after the drink in patients with type 2 diabetes compared with matched controls. From the study design, however, it was not possible to determine if the increased insulin concentration affected glucose production and disposal, although glucose concentrations were similar between trials. As noted below, coingestion of AAs, especially of BCAAs and glucose, may have effects on glucose metabolism.

The physiologic role of individual AAs may vary with different conditions. For example, maturation and aging may affect the potency of AAs to elicit hormone secretion. It has been demonstrated that leucine, while a good secretagogue of insulin in children, has less potency in adults (4). Similarly, growth hormone secretion is stimulated by an AA mixture, but, the specific role of individual AAs on growth hormone in humans remains to be tested. Because the circulating concentrations of growth hormone and its main effector, insulin-like growth factor 1, decline with age, it is quite possible that the stimulatory effect of AAs on these hormones is also reduced with age.

Dietary manipulations may also modulate the ability of AAs to elicit hormone secretion and metabolism. When a diet high in carbohydrate (65% of total energy intake vs. 45% in a control diet) was consumed, the rise in circulating growth hormone in response to arginine infusion was blunted (5). It is not known how changes in the dietary BCAA intake affect patterns of hormone secretion. It has been shown, however, that during a 3-d period of fasting, there is wide variability in the change in plasma concentrations of individual AAs (6). Paradoxically, leucine, a strong insulin secretegogue under basal conditions, increases with fasting and yet insulin concentration declines (Fig. 2). At the same time, plasma arginine and alanine, which stimulate glucagon release under basal conditions, both decrease but glucagon concentration increases with fasting. In this same study, it was also shown that despite the increase in glucagon, the endogenous glucose production rate decreased with 3 d of fasting (Fig. 2). Fasting also resulted in increased leucine appearance rate, an index of whole-body protein breakdown (Fig. 2). The increase in leucine appearance is consistent with the decline in insulin, because insulin normally suppresses protein breakdown, whereas increased glucagon has a catabolic effect on BCAAs, e.g., leucine (7–9). However, the precise mechanism underlying the altered relations among AA levels, hormones, and glucose production during fasting are not yet well understood and require further studies.



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  		FIGURE 2 Metabolic effects of overnight vs. 3-d fasting. Six healthy men were studied. Fasting resulted in increased circulating concentrations of BCAAs leucine and valine (A), which are normally insulin secretagogues, yet insulin concentration decreased (B). Similarly, despite the fall in glucagon secretagogues alanine and arginine (A) glucagon levels increased with a 3-d fast (B). Even though glucagon increased, there was an increase in protein breakdown as shown by leucine flux (C) and a decrease in endogenous glucose production with the extended fast. Adapted from (6).

 
BCAAs as regulators of protein metabolism

Among the individual AAs, the role of leucine as a regulator of protein metabolism is the most studied to date. Previous work from our laboratory (10,11) demonstrated that an i.v. infusion of leucine in humans results in decreased plasma concentration of most other AAs (Fig. 3). These changes could arise from either reduced protein breakdown, which would reduce the rate of AAs being released into the circulation, or by an increased rate of AA disposal for protein synthesis and metabolism. When leucine was infused, both the rate of appearance from protein breakdown (flux) and oxidation of valine were reduced (10,11). Furthermore, the results of femoral arteriovenous studies showed that, when leucine was infused, the leg balance (difference between uptake and release) of essential AAs such as valine, lysine, and phenylalanine became more positive (10). This was the result of a reduction in the rate of AA appearance from skeletal muscle, as demonstrated with valine and phenylalanine tracers (Fig. 3), indicating a reduction in the rate of protein breakdown (Fig. 3). No increase in muscle protein synthesis was observed in this acute experiment. Therefore, reduced protein breakdown seems to be the main mechanism by which the essential AA levels were reduced by leucine.



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  		FIGURE 3 Effects of leucine (132 µmol · kg–1 · h–1) vs. saline infusion on protein metabolism in young healthy volunteers. Paired studies were performed on 6 men studied on 2 separate occasions. A) Leucine infusion resulted in a 320% increase in arterial leucine concentration (not shown) and a reduction of most other AAs. B) Leucine infusion reduced whole-body endogenous flux (protein breakdown) and oxidation of valine. C) Leucine increased the net balance across the leg of lysine, valine and phenylalanine. D) Leg net balance was increased with leucine infusion by slowing the rate of AA release, an index of protein breakdown. *Leucine effect differs from saline, P < 0.05. Adapted from (10).

 
Although leucine and other BCAAs play a role in the transcriptional and translational regulation of protein synthesis, during acute infusion of either leucine alone (10) or a mixture of BCAAs (12), there was a lack of stimulation of muscle protein synthesis rate in humans. This could be because of a decline in the availability of other essential AAs required for protein synthesis. In acute studies, it was shown that BCAAs have specific stimulatory effects on signaling pathways involving translation of mRNA that result in enhancement of protein synthesis (13–15). A question that has yet to be addressed, however, is whether this stimulation is transient or persists over a long period of time and how hypoaminoacidemia after leucine administration affects the protein synthesis rate. Another question is whether consuming a leucine supplement during meal ingestion would enhance the normal increase in muscle protein synthesis, because concentrations of other AAs should be abundant during this time. There is also a lack of data on the effects of chronic use of supplemental leucine.

There is increasing evidence that the regulation of AA metabolism varies among body regions and that AAs play key roles in the regulation of protein synthesis and breakdown in the splanchnic region and in skeletal muscle. Studies performed in the postabsorptive state suggest that there is an efflux of AAs from skeletal muscle to the systemic circulation (9). These AAs are taken up by the splanchnic bed where protein synthesis is maintained at a steady level, and the net uptake of AAs in the splanchnic bed remains positive even during the fasted state (9,16). After a meal, there is a substantial increase in the delivery of AAs from the gut to the liver and through the hepatic veins to the systemic circulation. When the systemic concentration of AAs increases, there is a large increase in AA uptake by skeletal muscles, presumably for synthesis of proteins (8). Therefore it appears that skeletal muscle rapidly takes up AAs after meal ingestion and then releases AAs in between meals (16). This process is critically important to maintain the supply of AAs for synthesis of essential proteins, such as clotting factors, albumin, and stress-response proteins, in liver.

Our recent work has examined the relative roles of insulin and AAs in the regulation of protein turnover in the splanchnic bed and skeletal muscle (8,9). As shown in Figure 4, in the postabsorptive state (saline infusion only) the protein synthesis rate remains slightly higher than the breakdown rate in the splanchnic bed, resulting in a positive net balance, whereas in the leg (predominately skeletal muscle) protein breakdown is higher than synthesis, leading to a net negative balance, and AAs release to the circulation. Whereas insulin reduced the difference between protein synthesis and protein breakdown in the leg, there was little effect of insulin in the splanchnic bed. These studies also showed that the stimulatory effect of AAs on protein balance is maintained, even at the basal level of insulin (8) (Fig. 4). A multivariate regression analysis of factors affecting regional protein dynamics demonstrated that a major effect of insulin in the leg is suppression of protein breakdown (8). Insulin also enhanced the stimulatory effect of AAs on leg-muscle protein synthesis. Thus, these data show that in leg muscle, insulin is a major regulator of protein breakdown, whereas AAs primarily affect protein synthesis. In contrast, in the splanchnic bed, insulin had no effect on protein metabolism, whereas AAs suppressed protein breakdown and enhanced protein synthesis (8). It should be noted that the effect of AA to enhance splanchnic protein synthesis was greater than the effect to suppress protein breakdown. The AA effect on splanchnic protein breakdown was evident in the multivariate analysis but did not reach statistical significance within individual study groups (Fig. 4). Infusion of AAs alone while maintaining basal insulin (SRIH + Hi AA) resulted in a net increase in protein synthesis in both leg and splanchnic beds. Infusion of AAs improved AAs net balance in both the leg and the splanchnic bed, although the effect was more pronounced in the splanchnic bed.



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  		FIGURE 4 Effects of insulin and AAs on protein metabolism across the leg and splanchnic regions. Healthy volunteers (n = 6 per group) were studied during infusion of either 1) saline, 2) insulin (0.5 mU · min–1 · kg–1), 3) insulin + AA infusion to maintain basal plasma AA concentrations (Lo AA), 4) insulin + AA infusion to raise AA concentrations 2- to 3-fold (Hi AA), 5) somatostatin, to inhibit pancreatic hormone secretion, with replacement of basal insulin, glucagon, and growth hormone (SRIH) + saline, or 6) SRIH + Hi AA. A) Compared with saline, insulin alone reduced the difference between protein breakdown (PB) and synthesis (PS) rates by reducing PB in leg. AA increased PS in the leg but did not affect PB. B) The leg net balance (PS-PB) is shown after the overnight fast (basal) and during each of the experimental infusions (clamp). In the leg insulin infusion made the net balance of phenylalanine across the leg less negative. C) AA stimulated PS in the splanchnic bed, whereas insulin had no significant effect on PS or PB. The effect of AA on PS was more pronounced in splanchnic vs. leg regions. D) Insulin reduced net positive balance across the splanchnic bed while AA made balance more positive. *Difference between PS and PB (A and C) or between basal and clamp (B and D) within group, P < 0.05. Adapted from (8).

 
What remains to be determined is whether the effects of AAs, particularly BCCAs, in skeletal muscle and the splanchnic bed affect only a specific set of proteins or if the effect is more global. Rapid effects of AAs and insulin on protein breakdown and synthesis was thought to be global, affecting the translation of most of the available transcripts. However, emerging evidence has demonstrated that transcription of specific genes and translation of specific proteins can be selectively enhanced in skeletal muscle by infusion of insulin and AAs (17,18). It is also now possible to perform detailed studies of the effects of elevated AA concentrations on the rate of synthesis of individual proteins (19,20). This is an area that requires substantial investigation and can be addressed with the use of rapidly emerging technology in protein purification and identification and measurement of the in vivo rate of incorporation of isotopically labeled AAs into specific proteins.

BCAA regulation of transcription and translation

The effect of AAs to stimulate muscle protein synthesis (8) appears to occur through the intracellular signaling pathway of PHAS-I and p70 S6-kinase, which are involved in the initiation of translation (21). Activation (phosphorylation) of these molecules occurred with feeding or AA infusion but did not occur with insulin infusion in male rats (21).

Recent work has begun to reveal the complex pathways through which intracellular protein metabolism is regulated by the complementary effects of BCAAs and insulin. There is increasing evidence that BCAAs act as signals at several regulatory points controlling transcription and translation (Fig. 5). Under specific conditions, such as AA deprivation, it has been demonstrated that changes in AA concentration can alter the expression of individual genes by acting through AA response elements (22). This is a relatively new area of research that will receive more attention in the near future.



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  		FIGURE 5 AA and insulin regulation of protein translation through the mammalian target of rapamycin (mTOR). Essential AAs, especially leucine, can stimulate protein synthesis through the mTOR-mediated phosphorylation of eukaryotic initiation factor 4E binding protein 1 (eIF4E BP1) and p70 S6 kinase 1 and 2 (S6K1/2). Enhancement of translation is not general but instead favors mRNA transcripts with highly structured 5' untranslated regions (UTRs) or contain terminal oligopyrimidine (TOP) tracts adjacent to the 5' cap structure. Insulin stimulates the same pathway via protein kinase B (PKB/Akt) and modulation of the inhibitory effect of tuberous sclerosis complexes 1 and 2 (TSC1/2). Control over which mRNA are translated in proteins can occur through phosphorylation of eIF2, via general control nonderepressing kinase-2 (GCN2). Signaling through this pathway can result in selective translation of mRNA transcripts with specific upstream open reading frames (uORFs) or an internal ribosome entry site (IRES).

 
Relatively more is known about the role of AAs in regulation of protein translation. It is now established that BCAAs, particularly leucine, stimulate protein synthesis through signal pathways that involve the mammalian target of rapamycin (mTOR) (23–25). The current understanding is that mTOR integrates information from AA sensing and the insulin-mediated signal cascade to regulate the process of translation initiation through downstream effectors such as p70 S6-kinase and the eukaryotic initiation factors (Fig. 5). Evidence suggests that regulation of mTOR is more sensitive to variation in the intracellular AA concentration than extracellular AA, supporting its proposed role as an energy sensor (25). It has also become evident within recent years that the effect of BCAAs on stimulation of protein synthesis through the mTOR pathway can preferentially affect specific genes. Discriminatory control of translation is achieved by recognition of specific structural domains present within individual gene transcripts, such as upstream open reading frames (uORFs), internal ribosome entry sites (IRES), terminal oligopyrimidine (TOP) tracts, and specific highly structured 5' untranslated regions (UTRs) (23,25). Thus, through cooperative signaling pathways with insulin, AAs can regulate the expression of specific genes at the levels of transcription or translation in response to the cellular metabolic environment.

Effect of BCAAs on glucose metabolism

Despite the fact that AAs can stimulate the release of insulin, it has been shown that AA infusion actually inhibits glucose utilization. This conclusion was reached in studies of healthy humans in which the amount of glucose needed to maintain euglycemia during insulin infusion was reduced when a mixed AA solution was also infused (26–28). One mechanism through which this could occur is preferential oxidation of AAs leading to glucose sparing. Interestingly, endogenous glucose production decreases during leucine infusion, although glucose metabolic clearance rate also falls, resulting in no change in plasma glucose (10). More recent work has begun to identify intracellular mechanisms through which AAs appear to control glucose metabolism. Elevation of AAs has been shown to inhibit the early steps in insulin-mediated glucose transport and gluconeogenesis in vitro (29,30). This inhibitory action is mediated through attenuated tyrosine phosphorylation of insulin receptor substrates 1 and 2, and subsequent interaction with the regulatory subunit of phosphoinositide 3-kinase (PI-3 kinase), leading to decreased activity of PI-3 kinase, protein kinase B (PKB/Akt), and mTOR (29–31). It remains to be determined how much the potency of this inhibitory effect of AAs on insulin-mediated glucose metabolism varies with specific AAs.

Potential concerns with BCAA supplementation

In situations where BCAA supplementation might be considered, it is important to also consider potentially undesirable side effects, such as the inhibition of insulin-mediated glucose uptake described above. Elevated AA levels have also been shown to alter renal function. Increased protein intake or AA infusion can increase renal plasma flow and glomerular filtration rate (32–34). This issue is of some concern for older people in whom creatinine clearance rate is reduced. Although AAs and protein supplementation have been recommended for the elderly, it remains to be determined whether AA administration has positive or negative impact on kidney function in this population.

A large dose of BCAAs may also have an impact on tumors, with modulation of anabolic signaling and potential impact on tumor growth. This is a new area of research, but, evidence has shown that signaling through PI 3-kinase and mTOR pathways is increased in some cancers (35). Thus, the role of AA supplementation on tumor growth requires further careful study.

What is the safe upper limit of BCAA intake? Administration of BCAAs, especially leucine inhibits protein breakdownand lower the levels of other essential AAs. The impact of this "hyperaminoacidemia" on protein balance needs careful evaluation. BCAAs may adversely affect insulin action on glucose metabolism, based on some clinical data and the effect on signaling proteins. Similarly, there is a potential impact on BCAA supplement on renal function, especially in elderly people. These areas need careful evaluation while assessing the beneficial effects of BCAAs.


   FOOTNOTES
 
1 Published in a supplement to The Journal of Nutrition. Presented at the conference "The Fourth Workshop on the Assessment of Adequate Intake of Dietary Amino Acids" held October 28–29, 2004, Kobe, Japan. The conference was sponsored by the International Council on Amino Acid Science. The Workshop Organizing Committee included Dennis M. Bier, Luc Cynober, David H. Baker, Yuzo Hayashi, Motoni Kadowaki, and Andrew G. Renwick. Guest editors for the supplement publication were David H. Baker, Dennis M. Bier, Luc Cynober, John D. Fernstrom, Yuzo Hayashi, Motoni Kadowaki, and Dwight E. Matthews. Back

2 Supported by U.S. Public Health Service Awards MO1-RR00585 to the Mayo Clinic General Clinical Research Center, and RO1-AG09531 and RO1-DK41973 to K.S.N. and by the Mayo Foundation and the Dole-Murdock Professorship to K.S.N. Back

4 Abbreviations used: AA, amino acid; IRES, internal ribosome entry site; mTOR, mammalian target of rapamycin; PI-3 kinase, phosphoinositide 3-kinase; PB, protein breakdown; PKB/Akt, protein kinase B; PS, protein synthesis; TOP, terminal oligopyrimidine tract; uORF, upstream open reading frame; UTR, 5' untranslated regions. Back


   LITERATURE CITED
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