Relationship between branched-chain amino acids and metabolic disease

Given their role in muscle metabolism, BCAAs have received considerable attention from the scientific community in the treatment/prevention of sarcopenia, muscle hypertrophy, and physical recovery in the context of sports practice.

However, the increasing availability and consumption of foods high in protein and glycemic acid (AACR) far exceeding recommended values, in the context of a sedentary population with a high prevalence of metabolic disease, serves no useful purpose for the consumer and has the potential to contribute negatively to the pathophysiology of metabolic diseases.

A necessary discussion that is now taking place here at Pensar Nutrição.

Abbreviations

Introduction

Branched-chain amino acids (BCAAs) isoleucine, leucine, and valine play very important roles in human metabolism. These amino acids are not synthesized by metazoans and are therefore nutritionally essential, and their hydrophobic side chains play a key role in protein structure [1].

It follows that BCAAs must be obtained from the diet, although it is possible to synthesize them de novo in small quantities by the intestinal microbiota [2]. BCAAs represent 20 to 25% of most dietary proteins and constitute about 35% of nutritionally essential amino acids in mammals [3].

BCAAs and leucine in particular are especially known for their anabolic effect on protein synthesis, both by promoting muscle protein synthesis and by preventing its degradation, these processes being essentially dependent on the activation of the mTOR signaling pathway [4, 5].

Beyond the effects on energy metabolism, fatigue and muscle damage during exercise, BCAA supplementation may have beneficial effects on nutritional status and conditions that promote muscle mass loss such as renal and hepatic disease and cancer cachexia [6-8]. BCAAs act as signaling nutrients, metabolic regulators of glucose homeostasis, neurotransmission, immune response, intestinal development, mitochondrial biogenesis and milk production by mammary glands [9].

Although supplementation with BCAAs or a diet rich in these amino acids has been shown to improve metabolic health in many clinical situations, many studies highlight their potential role in the pathophysiology and progression of metabolic diseases such as obesity and diabetes, as well as other pathologies such as heart failure, cancer and neurodegenerative diseases [10].

Figure 1 – Representative diagram of the main intracellular metabolic and signaling pathways involving BCAAs. BCAAs – branched-chain amino acids. BCAAs – branched-chain α-keto acids. mTOR – mammalian target of rapamycin. BCAAs – branched-chain amino acid transaminases. Diagram adapted from: Gojda, J.; Cahova, M. Biomolecules, 11, 2021.

Catabolism of AACR

The first two steps of catabolism of all BCAAs are common. BCAAs are converted into their respective branched-chain α-keto acids (BCAAs), 2-ketoisocaproate, 2-keto-3-methylvalerate, 2-ketoisovalerate, from leucine, isoleucine, and valine, respectively. This reaction is catalyzed by branched-chain amino acid transaminases (BCAAs), of which there are two isoforms: the cytosolic (BCAA1) expressed in the brain and immune system cells (e.g., activated T lymphocytes and macrophages) and the mitochondrial (BCAA2) expressed in most tissues, but mainly in skeletal muscle, kidney, pancreas, stomach, and colon [11-13]. Unlike most amino acids, the initial catabolism of BCAAs occurs in skeletal muscle, not the liver, due to the low activity of hepatic BCAAs.

The main acceptor of the amino group of BCAAs is α-ketoglutarate, forming glutamate. The amino group of glutamate can then be transferred to pyruvate, forming alanine, or glutamate can accept a second amino group, forming glutamine. This is one of the mechanisms for controlling ammonia levels in the body. Alanine, glutamine, and BCAAs are then released from the muscles into the systemic circulation.

The second stage of BCAA catabolism is the irreversible oxidative decarboxylation of their α-keto acids, forming the respective acyl-CoA esters, CO2, and NADH. In this process, the carbon skeletons of 2-ketoisocaproate, 2-keto-3-methylvalerate, and 2-ketoisovalerate are converted into isovaleryl-CoA, 2-methylbutyryl-CoA, and isobutyryl-CoA, respectively. This reaction is catalyzed by branched-chain ketoacid dehydrogenase (BCKA). This multienzyme complex is located in the inner mitochondrial membrane and consists of 3 catalytic components: a thiamine-dependent tetrameric decarboxylase (α2β2) (E1), which catalyzes the oxidative decarboxylation of BCAAs; a dihydrolipoyl transacylase (E2), which transfers acyl groups to CoA; and a FAD-dependent dihydrolipoyl dehydrogenase (E3) that transfers the released electrons to NAD+ [12]. The activity of the DCACR complex is regulated through reversible phosphorylation of the E1 subunit. Phosphorylation is catalyzed by a specific kinase (DCACR kinase, CDCACR) that inactivates the enzyme, while dephosphorylation by a specific phosphatase (2Cm protein phosphatase, FP2Cm) activates the enzyme. This specific kinase, which is the main regulator of the activity of this complex, is allosterically inhibited by CACR, with 2-ketoisocaproate being the compound with the highest affinity [14]. The DCACR complex can also be efficiently inhibited when intracellular NADH/NAD+, acyl-CoA/CoA-SH, and ATP/ADP ratios increase. The DCACR complex exhibits the highest activity in the liver, intermediate activity in the kidneys and cardiac muscle, and relatively low activity in muscle, adipose tissue, and brain [3]. Therefore, BCAA catabolism occurs mainly in muscles and liver compared to other tissues.

The third stage of BCAA catabolism leads to ATP production through different pathways for each amino acid. The catabolism of 2-ketoisocaproate forms acetyl-CoA and acetoacetate, which is why leucine is considered a ketogenic amino acid. 2-ketoisocaproate is catabolized to succinyl-CoA, which is why valine is classified as a glycogenic amino acid. In turn, isoleucine is considered both glycogenic and ketogenic because the catabolism of 2-keto-3-methylvalerate results in succinyl-CoA and acetyl-CoA.

In the cytosol of hepatocytes, an alternative catabolic pathway for leucine has been described. This involves the oxidation of 2-ketoisocaproate to 3-hydroxy-3-methylbutyrate by the enzyme 2-ketoisocaproate dioxygenase [15].

Figure 2 – Representative scheme of BCAA catabolism. α-CG – alpha-ketoglutarate. BCAA – branched-chain α-keto acids. mTOR – mammalian target of rapamycin. BCAA – branched-chain amino acid transaminases. BCAA – branched-chain amino acids. BCAA – branched-chain α-keto acids. CDCACR – branched-chain ketoacid dehydrogenase kinase. DCACR – branched-chain ketoacid dehydrogenase. FP2Cm – 2Cm protein phosphatase. HMB – 3-hydroxy-3-methylbutyrate. LAT – Large neutral amino acid transporter. mTOR – mammalian target of rapamycin. TAACRc(m) – cytosolic (mitochondrial) branched-chain amino acid transaminases. Scheme adapted from: Zhang et al. Nutrients, 15, 2023 Fengna et al. Amino Acids .48, 2016.

Blood concentrations of BCAAs essentially reflect the balance between amino acid intake and their mobilization from the body's "reservoirs," i.e., proteins, with BCAAs playing a key role in the control systems of food intake and protein metabolism. In contrast to what happens with dietary carbohydrates and lipids, whose excess can be stored in the form of glycogen and triacylglycerols, there are no true storage structures for excess amino acids. Thus, amino acids are used in protein synthesis, and any excess protein in the diet is subject to catabolic processes that form intermediates that can be used as energy substrates, or stored in the form of glycogen or triacylglycerols [16-18].

Following the ingestion of a protein-containing meal, there is a marked elevation in blood levels of BCAAs that persists for several hours. This occurs because first-pass metabolism of BCAAs in the liver is limited, and approximately 50% of absorbed BCAAs enter the systemic circulation [19]. Most of the remaining amino acids undergo extensive hepatic uptake and metabolism. Thus, postprandial blood levels of BCAAs are a better indicator of the amount of protein ingested than other amino acids. This aspect is relevant to the involvement of BCAAs in the activation of physiological processes that depend on the quantity and quality of protein ingested, for example: protein synthesis, insulin secretion, and appetite regulation. Of all BCAAs, leucine appears to be the most influential in regulating these processes [16]

Branched-chain amino acids and the mTOR pathway

The main role of leucine in the postprandial period is to promote muscle protein synthesis by activating the mammalian target of rapamycin (mTOR) protein. mTOR has two main protein complexes: mTORC1, a protein kinase that influences multiple cellular functions including protein synthesis and autophagy; and mTORC2, a protein complex that influences some insulin and IGF-1 receptor and cytoskeletal activities. Leucine and insulin, along with many other growth factors and metabolites influenced by energy status and substrate availability, activate the mTOR pathway, leading to muscle protein synthesis. Activation of the mTOR pathway also inhibits proteolysis and autophagy, preventing the degradation of muscle protein, including that being synthesized. Protein synthesis can occur if all the amino acids necessary for the process are available in adequate amounts [18, 20]. AACR supplements alone do not increase protein synthesis unless all other amino acids are available [21]. The source of amino acids, whether from food or in the form of supplements, also influences muscle protein synthesis due to its effect on concentration/time curves [22].

Branched-chain amino acids and insulin

Leucine stimulates insulin secretion by pancreatic islet beta cells [23-25] and acts synergistically with glucose in regulating insulin secretion as a function of dietary carbohydrate and protein intake. Depending on protein intake, leucine can also act synergistically with insulin to regulate protein synthesis via mTOR. Although leucine and isoleucine are insulinotropic, primarily in the postprandial period, during fasting valine and isoleucine are gluconeogenic, contributing modestly to endogenous glucose synthesis. However, it should be noted that prolonged exposure to high blood levels of leucine can indirectly trigger insulin resistance through downstream mTOR effects on insulin receptor-1 (IRS-1) substrate [20].

Branched-chain amino acids and the regulation of food intake

Dietary intake is influenced by dietary protein and imbalances in amino acid availability. “Protein leverage” is the process by which strong regulation of protein intake leverages the intake of other dietary components. High-protein diets tend to reduce dietary intake regardless of carbohydrate and lipid content, while low-protein diets tend to increase dietary intake [26, 27]. Assessing the effect of each amino acid on appetite is complex, varying depending on each amino acid and the imbalances in availability between them. The existence of rejection of diets deficient or poor in protein, as well as in at least one essential amino acid, has been described [28]. BCAAs influence the intestinal and hypothalamic release of appetite-regulating hormones. The relationship between dietary intake and BCAAs, particularly leucine, may take the form of a U-shaped curve, where low and high levels have an appetite-suppressing effect, while moderate elevation increases dietary intake [29-31]. One mechanism responding to the imbalance between BCAAs and other amino acids, particularly tryptophan, is the LAT1 transporter in the blood-brain barrier. The uptake of BCAAs and other large, neutral amino acids is competitive. When circulating concentrations of BCAAs are high, there is a reduction in cerebral uptake of tryptophan, the precursor of serotonin, which reduces appetite [29]. When present in very high concentrations in the brain, leucine acts directly on the hypothalamic mTOR pathway, suppressing appetite [32]. On the other hand, diets low in BCAAs, protein, and other amino acids activate pathways involving general non-repressible control kinase 2 (GCN2) and fibroblast growth factor 21 (FGF-21), which in turn inhibit the mTOR pathway [33]. The effects of BCAAs on appetite will depend on the individual context of nutritional intake. Thus, increased intake of BCAAs in the context of a high-protein diet leads to a reduction in food intake through protein leverage. Conversely, a higher intake of BCAAs in the form of supplements, without altering the intake of other amino acids, may increase food intake as a consequence of amino acid imbalance [29].

In addition to these important roles as a signaling molecule for leucine, BCAAs have several other functions. For example, as precursors of neurotransmitters, modifiers of mitochondrial function and immune response. The valine metabolite 3-hydroxyisobutyrate (3-HIB) is the only BCAA metabolite that can exit the mitochondria because it is not bound to coenzyme A. Elevated blood concentration of 3-HIB increases the transport of fatty acids from the circulation to the muscle [16, 18].

Branched-chain amino acids in the post-absorptive period and during fasting

While dietary protein intake influences postprandial blood BCAA levels by stimulating muscle protein synthesis, fasting blood BCAA levels are primarily regulated by protein catabolism, mobilizing amino acids for energy production. In humans, the association between fasting blood BCAA levels and protein intake is weak [34]. Conversely, in laboratory animals, which can be exposed to a wider range of protein intake, the association between dietary intake and blood BCAA levels is stronger [29, 34]. Any association between fasting blood BCAA levels and dietary intake is secondary to their indirect effects on BCAA catabolic pathways, and not a direct consequence of BCAA intake. There are more than forty mitochondrial enzymes involved in the catabolism of BCAAs during fasting, of which the two most relevant types are: branched-chain amino acid transaminases (TAACR2, a ubiquitous mitochondrial enzyme; and TAACR1, a cytoplasmic brain enzyme) and the branched-chain ketoacid dehydrogenase complex (BCAADC). Transamination by TAACR2 constitutes the first step in the degradation of BCAAs, occurring mainly in muscle, in contrast to what happens with other amino acids whose metabolism is mainly hepatic. This results in branched-chain ketoacids that are released into the circulation (2-ketoisocaproate, 2-keto-3-methylvalerate, and 2-ketoisovalerate). In this step, glutamine and alanine are also formed, which can be indicators of increased BCAA catabolism [9, 16, 35].

The next step involves the oxidative decarboxylation of CACR by the DCACR complex located in the mitochondria of muscle, liver, and adipose tissue. This catabolic process eventually results in gluconeogenic and ketogenic substrates (leucine is ketogenic, valine is gluconeogenic, and isoleucine is both glycogenic and ketogenic). In the case of succinyl-CoA, the formation of this intermediate can function as an anaplerotic reaction, contributing to the stability of the concentrations of tricarboxylic acid cycle intermediates. Glycogenic and ketogenic substrates that are not used as energy substrates can be stored as glycogen or triacylglycerols [16, 35]. As previously described, DCACR activity is strongly regulated. The DCACR complex is inhibited by phosphorylation and low levels of AACR, and activated by dephosphorylation and high levels of AACR. The DCACR complex is the rate-limiting step in BCAA catabolism, and its activity is the main determinant of fasting blood BCAA concentrations [16, 18, 36]. During fasting, whether short or long duration, there is an increase in blood concentrations of BCAA and CACR, as protein catabolism occurs to obtain energy [37], until the eventual depletion of muscle protein reserves, which will lead to a reduction in blood BCAA concentration.

One of the acute effects of insulin is the reduction of plasma concentrations of BCAAs; however, in the context of insulin resistance, type II diabetes mellitus, and obesity, an increase in fasting blood concentrations of BCAAs and BCAAs is observed. In addition to insulin, several anabolic (growth hormone, IGF-1) and catabolic (catecholamines, inflammatory cytokines, TNF-α, cortisol) factors regulate protein and BCAA catabolism through the activation or inhibition of the DCACR complex [9, 16, 38].

Branched-chain amino acids, body composition, and obesity

Many studies that have analyzed the relationship between AACR and body composition have reached one of two seemingly contradictory conclusions: one is that they are associated with greater adiposity and obesity; the other is that they are associated with increased muscle mass and/or lean mass.

Many studies have already attempted to characterize the “metabolic signature” of obesity. In 1969, Felig and his colleagues were the first to describe that obese individuals had higher plasma concentrations of BCAAs and that these were associated with resistance to insulin action [39]. More recently, large-scale metabolomics studies indicate that obesity is associated with elevated circulating BCAAs, and alterations in the blood concentration of several other amino acids have also been observed [40-42].

On the other hand, in population studies, including some that evaluate elderly individuals, the conclusions point to a positive relationship between higher concentrations of BCAAs and greater lean mass [34, 43-46]. However, when the databases of these studies are accessible, it is possible to observe that in some of them there is also a positive association between circulating BCAAs and body mass index and body fat mass.
A meta-analysis of cross-sectional studies on the relationship between BCAAs and body composition concluded that dietary BCAAs were associated with a lower risk of obesity (OR=0.62, 95% 0.47-0.82) when comparing the highest consumption quintile with the lowest quintile. These authors also describe a minimal correlation between BCAA intake and its fasting plasma levels [47].

A systematic review with meta-analysis on the use of leucine supplements in the elderly showed that leucine increased the rate of fractional protein synthesis, but no effects were observed on lean body mass and lean mass of the lower limbs [48]

Branched-chain amino acids, insulin resistance, and cardiometabolic diseases

Several mechanisms support the relationship between BCAAs and insulin: leucine and isoleucine are insulinotropic; valine and isoleucine are gluconeogenic; leucine can negatively influence the insulin receptor by overstimulating mTORC1; and insulin regulates the DCACR complex. Thus, BCAAs can have both positive and negative effects on insulin-dependent pathways, and resistance to insulin action can increase plasma BCAA concentrations. Given the above, it is difficult to determine a causal relationship when interpreting results from studies between BCAAs and metabolic pathology [17].

Despite the extensive research published in this area, there is still some uncertainty about whether elevated BCAAs constitute a biomarker of altered insulin function, whether they contribute to insulin resistance, and what role BCAAs play in these associations [17, 49].
Even so, most studies state that elevated circulating BCAAs are most likely secondary to insulin resistance states, due to inhibition of the DCACR complex by insulin [10]. However, given that elevated circulating BCAAs can be observed many years before insulin resistance is observed, it has also been proposed that this elevation of BCAAs may be a cause of insulin resistance. Elevated circulating BCAAs may be secondary to alterations in the microbiome or to inflammatory processes that reduce hepatic and/or adipocyte metabolism of these amino acids [16, 17, 50]. Existing data support the possibility that elevated circulating BCAAs lead to alterations in insulin-regulated metabolic pathways, even before insulin resistance is detectable, while hyperinsulinemia elevates BCAA concentrations in more advanced stages of the disease. The associations between blood BCAA levels, type II diabetes mellitus, and other cardiometabolic pathologies and risk factors have been the subject of in-depth investigation and review [10, 16, 17, 35, 36, 49-51].

A meta-analysis of eight longitudinal metabolomics studies with over 8000 participants showed a 1.39-fold increase (95% CI: 1.24-1.48) in the relative risk of developing type II diabetes mellitus in individuals with elevated circulating BCAAs. The aromatic amino acids phenylalanine and tyrosine were also associated with a higher risk of developing type II diabetes mellitus, while glutamine and glycine levels showed an inverse relationship with this pathology [52]. However, in animal models (mouses) with a high-fat diet, BCAAs were not identified as the main metabolites associated with insulin resistance [53].

Considering dietary intake of BCAAs, most studies conclude that higher intake corresponds to an increased risk of type II diabetes and other cardiometabolic pathologies. In a review of eleven observational studies with 2 to 32 years of follow-up, all concluded that there is a positive relationship between dietary BCAAs and cardiovascular disease [54]. A meta-analysis of four studies calculated that between the lowest and highest quintiles of dietary BCAA consumption, there is a 32% increase in the risk of type II diabetes mellitus [47]. In other studies, higher BCAA intake was associated with a higher incidence of hypertension [55] or cardiovascular mortality [51].

Several clinical trials have been conducted with BCAA supplements and multiple cardiometabolic factors. Ingestion of BCAA or leucine supplements for short periods of time resulted in little or no effect on insulin and glucose metabolism [54, 56, 57].

In animal models (mice), long-term BCAA supplementation was associated with increased food intake, increased fat mass, hepatic steatosis, and increased fasting insulinemia [29]. BCAA supplementation in mice simultaneously with a high-fat diet induced insulin resistance and alterations in glucose tolerance [40]. On the other hand, BCAA restriction in mice on a Western-type diet improved insulin resistance and glucose tolerance [58]. A two-thirds reduction in dietary BCAA intake in mice improved glucose and pyruvate tolerance and reduced insulin production by pancreatic islet cells [59].

The association of blood concentrations of BCAAs with insulin resistance and increased risk of type II diabetes mellitus appears to have robust support in the literature [60-63]. A systematic review of 23 metabolomics studies, with 20,000 participants aged 18 to 59 years, showed that elevated circulating BCAAs are a biomarker for insulin resistance and risk of developing type II diabetes mellitus. This relationship is affected by gender, ethnicity, and diet [64]. In older men, elevated levels of circulating BCAAs are associated with several cardiometabolic risk factors such as higher glycemia, insulinemia, HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), triacylglycerols, and reduced HDL cholesterol levels. However, frail elderly men had higher mortality and severe cardiovascular outcomes when BCAAs were at their lowest level. These results support the idea that at older ages, AACRs are robust biomarkers for common cardiometabolic risk factors, with frailty still being the main risk factor for mortality and severe cardiovascular outcomes [61].

Chronic diseases whose etiology is associated with inadequate diet constitute a serious public health problem in our country. In 2015, cardiovascular diseases caused 29.75% of all deaths, diabetes affected about 10% of the Portuguese population, and the prevalence of hypertension reached 36%. Obesity as a chronic disease and risk factor for other pathologies affects over 20% of the adult Portuguese population, while overweight affects more than 50% of the population [65]. In this context, it seems reasonable to evaluate all dietary factors that may affect the pathologies with the highest incidence and prevalence in our country, even those that are not particularly valued in daily practice, such as the high intake of protein and BCAAs.

Branched-chain amino acids and neurodegenerative disease

The relationship between excessive circulating BCAA concentrations and neurodegenerative disease is a topic that requires further investigation, given the biological plausibility of the mechanisms potentially involved in this relationship. Excessive plasma BCAA concentrations may increase the transport of these amino acids across the blood-brain barrier mediated by LAT1 (Large Neutral Amino Acid Transporter), limiting the transport of amino acids such as tryptophan and tyrosine that compete for LAT1. This phenomenon may contribute to a central reduction in serotonin and dopamine, affecting pathways and functions dependent on adequate levels of these neurotransmitters. The imbalance between serotonin and dopamine in the central nervous system may dysregulate the production of neurotrophic factors, thus contributing to neurodegenerative phenomena. On the other hand, excess circulating AACR can stimulate the release of pro-inflammatory cytokines by peripheral blood mononuclear cells, causing disruption of the blood-brain barrier, activating microglia and potentiating inflammatory phenomena in the central nervous system with neurodegenerative potential [66].

Reference values ​​in the diet for AACR

In 2005, the Panel on Macronutrients of the Institute of Medicine of the United States of America published reference intake values ​​for proteins and amino acids. This document defines some concepts that are important to recall here:

• Estimated Average Requirement (EAR): the average daily intake of a nutrient estimated to meet the needs of half of healthy individuals at a given stage of life and gender.
• Recommended Dietary Allowance (RDA): the average daily intake of a nutrient that is sufficient to meet the nutrient needs of nearly all (97-98%) healthy individuals at a given stage of life and gender.
• Adequate Intake (AI): the average daily recommended intake of a nutrient based on approximations obtained experimentally and by observation of the intake of that nutrient by a group (or groups) of apparently healthy individuals, which is assumed to be adequate when it is not possible to determine an RDA value.
• Tolerable Upper Intake Level (UL): The highest average daily intake of a nutrient that is unlikely to pose a risk of adverse health effects for most individuals in the general population. As intake rises above this level, the potential risk of adverse effects increases.

The average daily requirements estimated by the Institute of Medicine of the United States of America for adult males over 19 years of age are: 34 mg/kg/day of leucine, 15 mg/kg/day of isoleucine, and 19 mg/kg/day of valine.

The recommended daily intake of AACR by the United States Institute of Medicine for adult men over 19 years of age is: 42 mg/kg/day of leucine, 19 mg/kg/day of isoleucine and 24 mg/kg/day of valine [67]. Thus, for an adult male weighing 70 kg, the recommended daily intake of leucine, isoleucine and valine is: 2940 mg, 1330 mg and 1680 mg respectively.

The European Food Safety Authority (EFSA) proposes the average requirements for essential amino acids as those presented by the WHO and FAO in 2007, and for BCAAs, 39 mg/kg/day for leucine, 20 mg/kg/day for isoleucine and 26 mg/kg/day for valine [68].

In a clinical trial conducted on healthy young adult individuals, a tolerable upper intake level for leucine of 500 mg/kg/day or ∼35 g/day was proposed. This value was proposed as a cautious estimate under acute intake conditions, since above this intake level participants developed elevated circulating ammonia levels above the upper limit of the normal concentration range, reflecting the body's inability to cope with these acute intake levels [69].

AACR Consumption

When comparing the estimated food consumption values ​​from the National Food and Physical Activity Survey (IAN-AF) of 2015-2016 with the recommendations of the Portuguese Food Wheel, it is possible to conclude that the consumption of foods that are good sources of AACR is above the recommended level, 12% above in the case of the consumption of “Meat, fish and eggs” and 6% above in the case of dairy products [65].

Table 1 shows that with a perfectly "normal" level of consumption, it is possible to reach leucine intake levels several times higher than recommended.

Table 1 – Amount of leucine ingested from protein-rich foods that may be part of a typical daily diet. https://www.myfooddata.com/articles/high-leucine-foods.php#intro – RDI – Recommended Daily Intake. RDI Leucine for a 70 kg man = 2940 mg

In recent years, the market for food products with high protein content has experienced marked growth, as has the availability of BCAA-rich dietary supplements or proteins rich in BCAAs (e.g., whey protein and casein).

Table 2 shows the amount of BCAAs in a single package of fermented milk with 30g of protein (50% casein / 50% whey protein). This table shows that consuming a single package of this product exceeds the recommended daily intake of BCAAs for a 70kg adult male.

Table 2 – Amount of BCAAs and percentage of the recommended daily intake of BCAAs per 330 ml package of fermented milk with 30 g of protein.

Recently, the manufacturer reduced the protein content of this product to 26g per 330ml package, which alters the available AACR values ​​per package according to those presented in Table 3:

Table 3 – Amount of BCAAs and percentage of the recommended daily intake of BCAAs per 330 ml package of a fermented milk with 26 g of protein. [70]

From the examples above, it is easy to conclude that with regular consumption of foods rich in protein and BCAAs, a 70 kg adult male can exceed the recommended daily intake of leucine by 5.4 times. And, if that same individual adds to his diet one package per day of a protein-rich fermented milk like the one in the example above, he could exceed that recommendation by 6.3 times.

Even if it is considered necessary to increase the values ​​presented in the daily intake recommendations for proteins and amino acids, the intake levels in large segments of the general population are already so high with habitual consumption that the idea of ​​supplementation does not seem to have support.

To answer the question of whether reducing BCAA intake can decrease blood BCAA concentrations, a pilot study was conducted involving 12 healthy individuals who were assigned either a BCAA-restricted diet or a control diet for 7 days. The diets had similar nitrogen and energy contents, differing only in BCAA content. The BCAA-restricted diet reduced circulating BCAA concentrations by approximately 50% from baseline, from 437±60 to 217±40 µmol/L (p < 0.005). Individually, both valine (from 245±33 to 105±23 µmol/L; p < 0.0001) and leucine (from 130±20 to 75±3 µmol/L; p < 0.05) decreased significantly in response to a diet restricted in BCAAs. This diet showed a trend towards a reduction in the homeostatic model of insulin resistance (HOMA-IR) value: from 1.5±0.2 to 1.0±0.1, p = 0.096. The reduction in circulating BCAAs was possible while maintaining an isoazoite and isocaloric diet, maintaining the recommended daily protein intake.

This pilot study establishes the basis for a potential dietary therapeutic intervention in obesity and diabetes [71].

Conclusions

Branched-chain amino acids—isoleucine, leucine, and valine—are nutritionally essential and, as signals of nutritional status, are crucial in metabolic homeostasis.
Elevated plasma concentrations of BCAAs in fasting blood are a biomarker of metabolic alterations, including obesity, insulin resistance, and type II diabetes mellitus.

The mechanisms underlying the association between elevated BCAAs, obesity, type II diabetes mellitus, and cardiovascular disease are still the subject of intense investigation. However, we know that these mechanisms include mTOR serine/threonine protein kinase, mitochondrial dysfunction, alterations in the utilization of metabolic substrates (metabolic inflexibility), and platelet activation.

Restricting or adjusting the intake of BCAAs in the diet may reduce the plasma concentration of these amino acids, with positive effects on metabolic pathology.

The increasing availability and consumption of foods high in protein and BCAAs, in the context of a population with a high prevalence of metabolic pathology, serves no useful purpose and has the potential to contribute negatively to the pathophysiology of metabolic diseases.

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