Essential Branched-chain Amino Acids Research Articles

Association of leucine and other branched chain amino acids with clinical outcomes in malnourished inpatients: a secondary analysis of the randomized clinical trial EFFORT.

The essential branched-chain amino acids leucine, isoleucine and valine are considered anabolic and stimulate protein synthesis in the muscles as well in the liver. They also promote muscle recovery and contribute to glucose homeostasis. Recent studies in critically ill patients have demonstrated that depletion of plasma leucine is associated with increased mortality, but data in the non-critical care setting is lacking. This secondary analysis of the randomized controlled Effect of early nutritional support on Frailty, Functional Outcomes, and Recovery of malnourished medical inpatients Trial (EFFORT), investigated the impact of leucine, isoleucine, and valine metabolism on clinical outcomes. The primary endpoint was 180-day all-cause mortality. Among 238 polymorbid patients with available metabolite measurements, low serum leucin levels were associated with a doubled risk of 180-day all-cause mortality in a fully adjusted regression model (adjusted HR 2.20 [95% CI 1.46-3.30], p < 0.001). There was also an association with mortality for isoleucine (1.56 [95% CI 1.03-2.35], p = 0.035) and valine (1.69 [95% CI 1.13-2.53], p = 0.011). When comparing effects of nutritional support on mortality in patients with high and low levels of leucine, there was no evidence of significant differences in effectiveness of the intervention. The same was true for isoleucine and valine. Our data suggest that depletion of leucine, isoleucine, and valine among malnourished polymorbid patients is associated with increases in long-term mortality. However, patients with low metabolite levels did not show a pronounced benefit from nutritional support. Further research should focus on the clinical effects of nutritional support in patients with depleted stores of essential branched-chain amino acids. clinicaltrials.gov as NCT02517476 (registered 7 August 2015).

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

Abstract 14967: Branching Out: Disrupted Branched Chain Amino Acid Metabolism Exacerbates Pulmonary Arterial Hypertension

Introduction: Valine, leucine, and isoleucine are essential branched chain amino acids (BCAA), and recent epidemiological studies report elevated BCAAs predict worse outcomes in several cardiovascular diseases with metabolic origins such as diabetes, heart failure, and hypertension. However, the role of BCAA metabolism in pulmonary arterial hypertension pathophysiology is relatively unexplored. Hypothesis: BCAAs are elevated in human PAH and reduction of BCAAs via small molecule activation of BCAA catabolism and dietary interventions combats PAH severity in preclinical PAH. Methods: Literature search of human PAH metabolomics studies was conducted. For rodent studies, male Sprague Dawley rats were divided into three groups: control (saline injection), monocrotaline (MCT) vehicle (MCT-V), or MCT-BT2, a small molecule inducer of BCAA catabolism. BT2 was administered at 20mg/kg/day. A low BCAA dietary intervention was implemented, with male Sprague Dawley rats divided into two groups: MCT-standard chow diet and MCT-low BCAA diet. To assess exercise capacity, rodents underwent a maximal exercise testing protocol before echocardiographic and hemodynamic assessments of PAH. Proteomic analysis of lung mitochondrial extracts was performed to define the molecular effects of BT2. Results: Of 11 studies evaluating human PAH metabolomics, 7 studies reported elevated BCAAs or BCAA metabolites in PAH. BT2 treatment improved exercise performance, reduced PA pressures, and augmented RV function. Moreover, the MCT-BT2 group possessed a distinct lung proteomic signature with changes in inflammatory and metabolic pathways. Finally, the low BCAA diet intervention modestly combatted PAH severity. Conclusions: BCAA metabolism is disrupted in human PAH and interventions that reduce circulating BCAAs display therapeutic potential in rodent PAH.

Can Leucine Supplementation Improve Frailty Index Scores?

Sarcopenia and frailty are important conditions that become increasingly prevalent with age. There is partial overlap between the two conditions, especially in terms of the physical aspects of the frailty phenotype: low grip strength, gait speed, and muscle mass. This study examined whether administration of the essential branched-chain amino acid leucine, besides improving sarcopenia, may reduce frailty assessed by frailty index (FI) in older institutionalized people living in nursing homes. We conducted a secondary analysis of a placebo-controlled, randomized, double-blind design study (ClinicalTrials.gov NCT03831399). The study included fifty males and females aged 65 and over who were living in nursing homes and did not have dementia. The participants were randomized to a parallel group intervention of 13 weeks' duration, with a daily intake of leucine (6 g/day) or placebo (lactose, 6 g/day). The outcome of this study was to evaluate whether there was a change in the level of a 95 item FI compared to the baseline and to compare the effect of the leucine group versus the placebo group. A significant inverse correlation was found between FI and performance of the activities of daily life, cognitive function, gait and balance, muscle function parameters, and nutritional status (p < 0.001 in all cases). There were no statistically significant differences in FI levels at baseline (placebo group FI 0.27 ± 0.08 and leucine group FI 0.27 ± 0.10) and at the 13 week follow-up (placebo group FI 0.28 ± 0.10 and leucine group FI 0.28 ± 0.09). There were also no significant differences between the leucine and placebo groups in the mean FI difference between baseline and follow-up (p = 0.316, Cohen's d: 0.04). This pilot study showed that a nutritional supplementation with leucine did not significantly modify the frailty index in older nursing home residents.

A comparative metabolomics analysis of domestic yak (Bos grunniens) milk with human breast milk.

Yaks are tough animals living in Tibet's hypoxic stress environment. However, the metabolite composition of yak milk and its role in hypoxic stress tolerance remains largely unexplored. The similarities and differences between yak and human milk in hypoxic stress tolerance are also unclear. This study explored yak colostrum (YC) and yak mature milk (YMM) using GC-MS, and 354 metabolites were identified in yak milk. A comparative metabolomic analysis of yak and human milk metabolites showed that over 70% of metabolites were species-specific. Yak milk relies mainly on essential amino acids- arginine and essential branched-chain amino acids (BCAAs): L-isoleucine, L-leucine, and L-valine tolerate hypoxic stress. To slow hypoxic stress, human breast milk relies primarily on the neuroprotective effects of non-essential amino acids or derivates, such as citrulline, sarcosine, and creatine. In addition, metabolites related to hypoxic stress were significantly enriched in YC than in YMM. These results reveal the unique metabolite composition of yak and human milk and provide practical information for applying yak and human milk to hypoxic stress tolerance.

Aumento acentuado da leucina como fator de mau prognóstico na doença da urina de xarope de bordo - relato de caso

INTRODUCTION: Leucinosis or Maple Syrup Disease (MSD) is an innate metabolism error caused by a deficiency in the activity of the alpha-keto acid-dehydrogenase enzyme complex, which leads to the accumulation of essential branched-chain amino acids (leucine, valine, and isoleucine), leucine is particularly toxic to the central nervous system (CNS). OBJECTIVES: Report a case of maple syrup disease in a 10-day-old newborn (NB), born to consanguineous parents, with late diagnosis, with high levels of leucine, with an unfavorable prognosis. COMMENTS: MSD is a rare condition, of autosomal recessive origin, which occurs due to the accumulation of essential branched-chain amino acids in tissues(leucine, valine, and isoleucine). The accumulation of amino acids mainly affects the CNS. Studies have shown that the elevated leucine concentration decreases the serum sodium concentration and increases intracellular water, causing cerebral edema. Neurological damage will depend on the degree and time of tissue exposure to metabolites. Despite the unfavorable outcome of the case presented, the prognosis of MSD can be modified with strict diet control and early and aggressive management of metabolic crisis.

EFFECT OF L-VALINE TREATMENT ON SIRTUIN (SIRT1 AND SIRT2) ISOFORMS

Abstract L-valine is one of the essential branched-chain amino acids (BCAAs) required for synthesis of proteins in human body. It promotes muscle growth and tissue repair and is important for immune function. Recent data indicate that BCAAs can activate sirtuins expression and elevate mitochondrial biogenesis and fatty acid oxidation in both adipocytes and myotubes thereby increasing life span. Sirtuins are a conserved family of proteins, play a critical role in maintaining metabolic health by deacetylating many target proteins in numerous tissues, and regulate mitochondrial function and the aging process. Due to multiple effect of sirtuins on aging, we sought to determine whether the addition of valine might enhance sirtuin gene expression. We utilized the C2C12 skeletal muscle cell line grown on physiological normal glucose (100mg/dL) media. The cells were treated with two different concentrations of valine (0.5 and 1.0mM) for different time intervals (18 and 24). Gene expression of sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) isoforms were determined by RT-PCR. The results showed increased expression of the sirtuin gene isoforms after treatment with valine. Relative expression varies with in different isoforms of SIRT1 (v1 and v2) and SIRT2 (v1, v2 and v3). Among all, SIRT1 v1 and SIRT2 v1 showed maximum expression as compared to the other isoforms used in the study. Our study showed that adequate supplementation of L-valine enhanced sirtuin gene expression, which may promote healthy muscles and healthy aging.

BAY-069, a Novel (Trifluoromethyl)pyrimidinedione-Based BCAT1/2 Inhibitor and Chemical Probe.

The branched-chain amino acid transaminases (BCATs) are enzymes that catalyze the first reaction of catabolism of the essential branched-chain amino acids to branched-chain keto acids to form glutamate. They are known to play a key role in different cancer types. Here, we report a new structural class of BCAT1/2 inhibitors, (trifluoromethyl)pyrimidinediones, identified by a high-throughput screening campaign and subsequent optimization guided by a series of X-ray crystal structures. Our potent dual BCAT1/2 inhibitor BAY-069 displays high cellular activity and very good selectivity. Along with a negative control (BAY-771), BAY-069 was donated as a chemical probe to the Structural Genomics Consortium.

Augmenting oxidation of branched-chain amino acids (BCAAs) treats murine chronic Graft-Versus-Host Disease (cGVHD)

Abstract Aberrant immune responses, such as high Tfollicular helper (Tfh) and germinal center B cells (GCB) in cGVHD inducing antibody (Ab) secretion with tissue deposition and fibrosis, require distinct metabolic reprogramming to sustain pathogenesis. Leucine, isoleucine, and valine are essential BCAAs that signal via mTORC1 to support glycolysis and protein synthesis. Alternatively, BCAAs can be oxidized to metabolites that directly enter the tricarboxylic acid cycle or become substrates for gluconeogenesis and ketogenesis. Branched chain ketoacid dehydrogenase kinase (BDK) is a negative regulator of BCAA metabolism, decreasing downstream oxidation and increasing mTORC1 and glycolysis. We sought to determine whether increasing BCAA oxidation could be exploited to inhibit cGVHD. BDK is inhibitable by 3,6-Dichlorobenzo[β] thiophene-2-carboxylic acid (BT2), increasing BCAA oxidation and decreasing T effector (Teff) activation. In a multiorgan cGVHD model with bronchiolitis obliterans, mice that received BDK knockout vs wildtype donor T cells had improved survival and pulmonary function with decreased GCB frequencies (p-value 0.005) and a trend toward decreased Tfh/Tfollicular regulatory ratios. An in vitro assay measuring Tfh-mediated B cell Ab production showed that BT2 downregulates IgG class switching, which is key for cGVHD pathogenesis. BT2-treated T effectors but not T regulatory cells (Treg) exhibited increased oxidative phosphorylation (OXPHOS). Therefore, limiting BCAAs inhibits Teff switch from a highly glycolytic state to OXPHOS. In contrast, BCAAs are not required for Treg energy production or survival. These data suggest that augmenting BCAA oxidation could be a new therapeutic approach for treating cGVHD. Supported by NIH P01 AI056299

Influence of Dietary Molecules on Human Health: Whey Proteins

Whey protein is one of the major sources of essential proteins which is being used widely now days for maintaining a healthy life style and to meet the daily protein requirement. In order to maintain a healthy body weight, regular exercise accompanied with a healthy diet is very important, and whey protein is a perfect source of fulfilling the protein requirements of the body. Whey is obtained majorly from milk which is formed by the production of cheese. Milk is the major source of whey as it comprises 20% of the total constituent of milk. Whey protein is a high-quality protein with a rich amino acid profile. It contains the broad spectrum of amino acids that includes essential amino acids (EAAs) and branched-chain amino acids (BCAAs) which are important in the growth and repair of tissues. Leucine, Isoleucine and Valine are the amino acids that play a major role in BCAA in protein synthesis and has recently been identified as playing role in muscle building and increase in the hormonal growth. It is easy to digest as compared to other components of milk like casein and has no fat content in it which makes it possible to help in gaining lean muscle mass in the body. These are one of the many advantages of consuming whey for which its demand in the market is rising. .Despite numerous advantages it can show some side effects like kidney problems, indigestion, bloating, etc. So it is advisable to consume it after consulting with a physician or some health expert in a specific dosage for a period of time. This review article gives a brief explanation of the role of whey proteins present in milk.

Intakes of Total and Branched-Chain Essential Amino Acids are Positively Associated with Handgrip Strength in African American and White Urban Younger and Older Adults

Essential amino acids (EAAs) initiate amino acid-induced stimulation of muscle protein synthesis. Study objectives were to calculate intake of EAAs after creating an EAA database, to explore the association of EAAs and branched-chain amino acids (BCAAs) with handgrip strength (HS) in a younger (<50 y) and older (≥50 y) sample, and to identify major food groups contributing EAAs. The sample consisted of African American and White adults aged, 33–71 years from the Healthy Aging in Neighborhoods of Diversity across the Life Span study, 2009–2013. Intake of total EAAs and BCAAs/kg body weight were positively associated (p < 0.001) with HS per body mass index (HS/BMI) ratio. Being male, African American, a nonsmoker, physically active, euglycemic, and normotensive were associated with higher HS/BMI ratio. EAAs were mainly obtained from red meats/poultry and mixed dishes groups. Findings support the role of high-quality proteins and being active in promoting HS.

Amelioration of hepatic steatosis by dietary essential amino acid-induced ubiquitination

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with no approved drugs. High-protein dietary intervention is currently the most effective treatment. However, its underlying mechanism is unknown. Here, using Drosophila oenocytes, the specialized hepatocyte-like cells, we find that dietary essential amino acids ameliorate hepatic steatosis by inducing polyubiquitination of Plin2, a lipid droplet-stabilizing protein. Leucine and isoleucine, two branched-chain essential amino acids, strongly bind to and activate the E3 ubiquitin ligase Ubr1, targeting Plin2 for degradation. We further show that the amino acid-induced Ubr1 activity is necessary to prevent steatosis in mouse livers and cultured human hepatocytes, providing molecular insight into the anti-NAFLD effects of dietary protein/amino acids. Importantly, split-intein-mediated trans-splicing expression of constitutively active UBR2, an Ubr1 family member, significantly ameliorates obesity-induced and high fat diet-induced hepatic steatosis in mice. Together, our results highlight activation of Ubr1 family proteins as a promising strategy in NAFLD treatment.

An evaluation of elevated branched-chain amino acid inclusions on the performance of broiler chickens offered reduced-crude protein, wheat-based diets from 7 to 28 days post-hatch

The physiological functions of essential branched chain amino acids (BCAA) are important in broiler nutrition, but antagonistic BCAA interactions may become evident. Given the increased implementation of reduced-crude protein (CP) diets, this study aimed to investigate whether elevated leucine inclusions in reduced-CP diets would advantage broiler growth performance, provided concomitant elevations in isoleucine and valine were employed. A total of 378 off-sex male Ross 308 broilers were allocated to 9 dietary treatments, each with 7 replicate cages and 6 birds in each. All diets were wheat-based with 190 g/kg CP. The dietary treatments comprised 3 leucine inclusions (12.71, 15.02, 17.33 g/kg) and 3 isoleucine plus valine inclusions (17.21, 20.32, 23.45 g/kg) in a 3 × 3 factorial array. The assessed parameters included growth performance, relative abdominal fat-pad weights, nutrient utilisation, apparent jejunal and ileal digestibility coefficients and disappearance rates of starch, protein (N), amino acids and free amino acid concentrations in systemic plasma. Elevated BCAA inclusions did not enhance growth performance; indeed, elevating isoleucine plus valine from 17.21 to 20.32 g/kg in the 15.02 g/kg leucine diet significantly compromised weight gain by 6.82% (1325 versus 1422 g/bird). However, elevating isoleucine plus valine inclusions from 17.21 to 20.32 g/kg decreased relative fat-pad weights by 8.49% (9.05 versus 9.89 g/kg; P = 0.046). Elevating leucine levels significantly depressed energy utilisation, AME and AMEn, by 0.39 MJ in both instances. Dietary enrichment with leucine had diverse impacts on amino acid digestibility coefficients coupled with free amino acid plasma concentrations. Increasing dietary leucine concentrations improved ileal digestibility of leucine by 4.74% (0.906 versus 0.865) but also significantly increased ileal digestibility coefficients of another 10 amino acids by an average of 3.37% ranging from 1.60% (methionine) to 4.96% (threonine). Overall, elevations of BCAA in wheat-based, reduced-CP diets did not advantage broiler growth performance. The likelihood is that several factors are responsible for this lack of response and consideration is given to these possibilities in this paper.

Essential Branched-Chain Amino Acids and Ribonic Acid Are Associated with Cardiorenal Events in Type 1 Diabetes

Essential Branched-Chain Amino Acids and Ribonic Acid Are Associated with Cardiorenal Events in Type 1 Diabetes

L-valine production in Corynebacterium glutamicum based on systematic metabolic engineering: progress and prospects.

L-valine is an essential branched-chain amino acid that cannot be synthesized by the human body and has a wide range of applications in food, medicine and feed. Market demand has stimulated people's interest in the industrial production of L-valine. At present, the mutagenized or engineered Corynebacterium glutamicum is an effective microbial cell factory for producing L-valine. Because the biosynthetic pathway and metabolic network of L-valine are intricate and strictly regulated by a variety of key enzymes and genes, highly targeted metabolic engineering can no longer meet the demand for efficient biosynthesis of L-valine. In recent years, the development of omics technology has promoted the upgrading of traditional metabolic engineering to systematic metabolic engineering. This whole-cell-scale transformation strategy has become a productive method for developing L-valine producing strains. This review provides an overview of the biosynthesis and regulation mechanism of L-valine, and summarizes the current metabolic engineering techniques and strategies for constructing L-valine high-producing strains. Finally, the opinion of constructing a cell factory for efficiently biosynthesizing L-valine was proposed.

Amino acid and biogenic amine composition of Busha cattle milk

AbstractTo our knowledge, there is a lack of information on the nutrient composition of Busha cattle milk with special regard to its amino acid and biogenic amine contents. The Busha cattle breed is known to be highly resistant to various diseases and well-adapted to the extensive breeding conditions of the Balkan Peninsula. Busha cow milk contains an average of 13.47% dry matter, 4.34% fat, 3.72 % protein, and 4.32% lactose. Significant differences were detected (P &lt; 0.05) in the amino acid compositions of the milk of different Busha cattle strains of Kosovo. Glutamic acid, proline, leucine, aspartic acid, lysine, and valine represented 68% of the total amino acid content. Essential amino acids, branched-chain and sulphur-containing amino acids were found in substantial amounts in the milk samples. Among the biogenic amines, however, spermine (0.16 mg kg−1) and cadaverine (0.09 mg kg−1) were present in low concentrations. Due to these excellent qualities of the Busha cow milk, preservation of this cattle breed is of great importance. Developing sustainable and secured breeding and feeding programs for this endangered cattle breed of the Balkan Peninsula should also be a high priority.

Differential expression of the BCAT isoforms between breast cancer subtypes

BackgroundBiological characterisation of breast cancer subtypes is essential as it informs treatment regimens especially as different subtypes have distinct locoregional patterns. This is related to metabolic phenotype, where altered cellular metabolism is a fundamental adaptation of cancer cells during rapid proliferation. In this context, the metabolism of the essential branched-chain amino acids (BCAAs), catalysed by the human branched-chain aminotransferase proteins (hBCAT), offers multiple benefits for tumour growth. Upregulation of the cytosolic isoform of hBCAT (hBCATc), regulated by c-Myc, has been demonstrated to increase cell migration, tumour aggressiveness and proliferation in gliomas, ovarian and colorectal cancer but the importance of the mitochondrial isoform, hBCATm has not been fully investigated.MethodsUsing immunohistochemistry, the expression profile of metabolic proteins (hBCAT, IDH) was assessed between breast cancer subtypes, HER2 + , luminal A, luminal B and TNBC. Correlations between the percentage and the intensity of protein expression/co-expression with clinical parameters, such as hormone receptor status, tumour stage, lymph-node metastasis and survival, were determined.ResultsWe show that hBCATc expression was found to be significantly associated with the more aggressive HER2 + and luminal B subtypes, whilst hBCATm and IDH1 associated with luminal A subtype. This was concomitant with better prognosis indicating a differential metabolic reliance between these two subtypes, in which enhanced expression of IDH1 may replenish the α-ketoglutarate pool in cells with increased hBCATm expression.ConclusionThe cytosolic isoform of BCAT is associated with tumours that express HER2 receptors, whereas the mitochondrial isoform is highly expressed in tumours that are ER + , indicating that the BCAT proteins are regulated through different signalling pathways, which may lead to the identification of novel targets for therapeutic applications targeting dysregulated cancer metabolism.

The bovine colostrum and milk metabolome at the onset of lactation as determined by 1H-NMR

The purpose of this study was to characterise the metabolome of bovine colostrum and milk in the initial days of lactation. Colostrum and milk samples were collected from 18 cows representing an even spread of 1st, 2nd and 3rd lactation (n = 6) over the first 6 days of lactation. Samples were subsequently analysed using 1H-NMR. The metabolome of defatted colostrum and milk in the days immediately post parturition was demonstrated to be complex and changed significantly over time. The colostrum was rich in nutrients beneficial for growth and development of the new-born mammal with significantly higher levels of essential branched chain amino acids and choline and orotic acid that decreased in the subsequent days as milk composition evolved to that of regular milk. Multivariate analysis of metabolome profiles using PLS-DA was demonstrated to clearly distinguish between colostrum and subsequent milk samples.

Tissue-specific deletion of mouse basolateral uniporter LAT4 (Slc43a2) reveals its crucial role in small intestine and kidney amino acid transport.

Key points LAT4 is a broadly expressed uniporter selective for essential branched chain amino acids, methionine and phenylalanine, which are involved in epithelial transport.Its global deletion leads to an early malnutrition‐like phenotype and death within 10 days after birth.Here, we tested the impact of deleting LAT4 selectively in the mouse intestine. This affected slightly the absorption of amino acids (AAs) and delayed gastrointestinal motility; however, it had no major phenotypic effect, even when combined with aromatic AA uniporter TAT1 knockout (KO).Conversely, kidney tubule‐selective deletion of LAT4 led to a substantial aminoaciduria that strongly increased under a high protein diet. Combining a partial tubular LAT4 deletion with TAT1 KO implicated their synergistic action on AA reabsorption.These results show that LAT4 plays an important role for kidney AA reabsorption, but that its functional role in intestinal AA absorption is largely dispensable. Amino acid (AA) transporter LAT4 (Slc43a2) functions as facilitated diffusion uniporter for essential neutral AAs and is highly expressed at the basolateral membrane of small intestine (SI) and kidney tubule epithelia. Previously, we showed that LAT4 global knockout (KO) mice were born at the expected Mendelian ratio but died within 10 days. Their failure to gain weight and a severe malnutrition‐like phenotype contrasted with apparently normal feeding, suggesting a severe intestinal AA absorption defect. In the present study, using conditional global and tissue‐specific LAT4 KO mouse models, we nullified this hypothesis, demonstrating that the selective lack of intestinal LAT4 does not impair postnatal development, although it leads to an absorption defect accompanied by delayed gastrointestinal motility. Kidney tubule‐specific LAT4 KO led to a substantial aminoaciduria as a result of a reabsorption defect of AAs transported by LAT4 and of other AAs that are substrates of the antiporter LAT2, demonstrating, in vivo, the functional co‐operation of these two transporters. The major role played by basolateral uniporters in the kidney was further supported by the observation that, in mice lacking TAT1, another neutral AA uniporter, a partial LAT4 KO led to a synergistic increase of urinary AA loss. Surprisingly in the SI, the same combined KO induced no major effect, suggesting yet unknown compensatory mechanisms. Taken together, the lethal malnutrition‐like phenotype observed previously in LAT4 global KO pups is suggested to be the consequence of a combinatorial effect of LAT4 deletion in the SI, kidney and presumably other tissues.

Valine acts as a nutritional signal in brain to activate TORC1 and attenuate postprandial ammonia-N excretion in Chinese perch (Siniperca chuatsi).

An emerging concept is that the hypothalamic nutrient sensor can regulate peripheral energy metabolism via a brain-liver circuit. Valine is an essential branched-chain amino acid (BCAA) that drives intracellular signaling cascades by the activation of target of rapamycin complex 1 (TORC1) which is critical to protein metabolism in mammals. However, in teleost fish, it remains scarce in this area especially about how the intraventricular (ICV) injection of valine can mediate the protein metabolism in peripheral organs. This study would tentatively explore the effects of ICV injection of valine on protein metabolism in peripheral organs through evaluating the postprandial ammonia-N excretion rate in Chinese perch. The control group was injected with 5-μL PBS, and the Val group was injected with 20-μgL valine dissolved into 5-μL PBS. The ammonia-N excretion rate of Val group was lower than control group at 4-, 12-, and 24-h postinjection, while the concertation of plasma glucose was increased sharply at 0.5-, 4-, 12-, and 24-h postinjection. We further checked both mRNA level and the enzyme activity of glutamate dehydrogenase (GDH) in the liver and adenosine monophosphate deaminase (AMPD) in muscle, and we found that they were obviously decreased in Val group at 4-, 12-, and 24-h postinjection. The phosphorylation level of ribosomal protein S6, a downstream target protein of TORC1, was markedly enhanced in the liver of Val group at 4-, 12-, and 24-h postinjection. Collectively, these results illustrated that ICV injection of valine can attenuate protein degradation in peripheral organs by depressing the GDH and AMPD enzyme activity; on the other hand, the injected valine can trigger the activation of TORC1 in the liver via a brain-liver circuit and then interdict proteolysis.