The Experts below are selected from a list of 285 Experts worldwide ranked by ideXlab platform
Jose Donato - One of the best experts on this subject based on the ideXlab platform.
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reviewing the effects of l leucine supplementation in the regulation of food intake energy balance and glucose homeostasis
Nutrients, 2015Co-Authors: Joao A B Pedroso, Thais T Zampieri, Jose DonatoAbstract:Leucine is a well-known activator of the mammalian target of rapamycin (mTOR). Because mTOR signaling regulates several aspects of metabolism, the potential of leucine as a dietary supplement for treating obesity and diabetes mellitus has been investigated. The objective of the present review was to summarize and discuss the available evidence regarding the mechanisms and the effects of leucine supplementation on the regulation of food intake, energy balance, and glucose homeostasis. Based on the available evidence, we conclude that although central leucine injection decreases food intake, this effect is not well reproduced when leucine is provided as a dietary supplement. Consequently, no robust evidence indicates that oral leucine supplementation significantly affects food intake, although several studies have shown that leucine supplementation may help to decrease body adiposity in specific conditions. However, more studies are necessary to assess the effects of leucine supplementation in already-obese subjects. Finally, although several studies have found that leucine supplementation improves glucose homeostasis, the underlying mechanisms involved in these potential beneficial effects remain unknown and may be partially dependent on weight loss.
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oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus
PLOS ONE, 2013Co-Authors: Thais T Zampieri, Joao A B Pedroso, Isadora C Furigo, Julio Tirapegui, Jose DonatoAbstract:Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity.
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effects of leucine supplementation on the body composition and protein status of rats submitted to food restriction
Nutrition, 2006Co-Authors: Jose Donato, Rogerio Graca Pedrosa, Vinicius Fernandes Cruzat, Ivanir Santana De Oliveira Pires, Julio TirapeguiAbstract:Abstract Objective Acute administration of leucine has been shown to stimulate certain protein synthesis related anabolic processes. However, the effect of chronic leucine administration in a catabolic situation caused by food restriction (FR) has not been established. We therefore evaluated the effect of chronic leucine supplementation on the body composition and some indicators of protein nutritional status of rats submitted to FR. Methods Adult male Wistar rats were submitted to 50% FR for 6 weeks. The control group received the AIN-93M diet and the leucine group received the same diet supplemented with 5.91 g L-Leucine/kg ration. We then determined carcass chemical composition, serum leptin, albumin and total protein concentrations, and protein, DNA and RNA concentrations in gastrocnemius muscle and liver. Results No difference in final body weight was observed between groups. However, the leucine group presented a lower amount of body fat ( P P P = 0.08). Regarding protein nutritional status, liver protein concentration was higher in the leucine group ( P P P = 0.06) were observed in the leucine group. Conclusion The results indicate that low-dose leucine supplementation increases body fat loss and improves liver protein status and the capacity of muscle protein synthesis in rats submitted to FR.
Ilana Nissim - One of the best experts on this subject based on the ideXlab platform.
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astrocyte leucine metabolism significance of branched chain amino acid transamination
Journal of Neurochemistry, 2002Co-Authors: Marc Yudkoff, Yevgeny Daikhin, Lev Grunstein, Ilana Nissim, Janet Stern, David E PleasureAbstract:We studied astrocytic metabolism of leucine, which in brain is a major donor of nitrogen for the synthesis of glutamate and glutamine. The uptake of leucine into glia was rapid, with a Vmax of 53.6 +/- 3.2 nmol/mg of protein/min and a Km of 449.2 +/- 94.9 microM. Virtually all leucine transport was found to be Na+ independent. Astrocytic accumulation of leucine was much greater (3x) in the presence of alpha-aminooxyacetic acid (5 mM), an inhibitor of transamination reactions, suggesting that the glia rapidly transaminate leucine to alpha-ketoisocaproic acid (KIC), which they then release into the extracellular fluid. This inference was confirmed by the direct measurement of KIC release to the medium when astrocytes were incubated with leucine. Approximately 70% of the leucine that the glia cleared from the medium was released as the keto acid. The apparent Km for leucine conversion to extracellular KIC was a medium [leucine] of 58 microM with a Vmax of approximately 2.0 nmol/mg of protein/min. The transamination of leucine is bidirectional (leucine+alpha-ketoglutarate KIC+glutamate) in astrocytes, but flux from leucine-->glutamate is more active than that from glutamate-->leucine. These data underscore the significance of leucine handling to overall brain nitrogen metabolism. The release of KIC from glia to the extracellular fluid may afford a mechanism for the "buffering" of glutamate in neurons, which would consume this neurotransmitter in the course of reaminating KIC to leucine.
Julio Tirapegui - One of the best experts on this subject based on the ideXlab platform.
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oral leucine supplementation is sensed by the brain but neither reduces food intake nor induces an anorectic pattern of gene expression in the hypothalamus
PLOS ONE, 2013Co-Authors: Thais T Zampieri, Joao A B Pedroso, Isadora C Furigo, Julio Tirapegui, Jose DonatoAbstract:Leucine activates the intracellular mammalian target of the rapamycin (mTOR) pathway, and hypothalamic mTOR signaling regulates food intake. Although central infusion of leucine reduces food intake, it is still uncertain whether oral leucine supplementation is able to affect the hypothalamic circuits that control energy balance. We observed increased phosphorylation of p70s6k in the mouse hypothalamus after an acute oral gavage of leucine. We then assessed whether acute oral gavage of leucine induces the activation of neurons in several hypothalamic nuclei and in the brainstem. Leucine did not induce the expression of Fos in hypothalamic nuclei, but it increased the number of Fos-immunoreactive neurons in the area postrema. In addition, oral gavage of leucine acutely increased the 24 h food intake of mice. Nonetheless, chronic leucine supplementation in the drinking water did not change the food intake and the weight gain of ob/ob mice and of wild-type mice consuming a low- or a high-fat diet. We assessed the hypothalamic gene expression and observed that leucine supplementation increased the expression of enzymes (BCAT1, BCAT2 and BCKDK) that metabolize branched-chain amino acids. Despite these effects, leucine supplementation did not induce an anorectic pattern of gene expression in the hypothalamus. In conclusion, our data show that the brain is able to sense oral leucine intake. However, the food intake is not modified by chronic oral leucine supplementation. These results question the possible efficacy of leucine supplementation as an appetite suppressant to treat obesity.
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effects of leucine supplementation on the body composition and protein status of rats submitted to food restriction
Nutrition, 2006Co-Authors: Jose Donato, Rogerio Graca Pedrosa, Vinicius Fernandes Cruzat, Ivanir Santana De Oliveira Pires, Julio TirapeguiAbstract:Abstract Objective Acute administration of leucine has been shown to stimulate certain protein synthesis related anabolic processes. However, the effect of chronic leucine administration in a catabolic situation caused by food restriction (FR) has not been established. We therefore evaluated the effect of chronic leucine supplementation on the body composition and some indicators of protein nutritional status of rats submitted to FR. Methods Adult male Wistar rats were submitted to 50% FR for 6 weeks. The control group received the AIN-93M diet and the leucine group received the same diet supplemented with 5.91 g L-Leucine/kg ration. We then determined carcass chemical composition, serum leptin, albumin and total protein concentrations, and protein, DNA and RNA concentrations in gastrocnemius muscle and liver. Results No difference in final body weight was observed between groups. However, the leucine group presented a lower amount of body fat ( P P P = 0.08). Regarding protein nutritional status, liver protein concentration was higher in the leucine group ( P P P = 0.06) were observed in the leucine group. Conclusion The results indicate that low-dose leucine supplementation increases body fat loss and improves liver protein status and the capacity of muscle protein synthesis in rats submitted to FR.
Eva Blomstrand - One of the best experts on this subject based on the ideXlab platform.
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activation of mtorc1 by leucine is potentiated by branched chain amino acids and even more so by essential amino acids following resistance exercise
American Journal of Physiology-cell Physiology, 2016Co-Authors: Marcus Moberg, William Apro, Bjorn Ekblom, Gerrit Van Hall, Hanschrister Holmberg, Eva BlomstrandAbstract:Protein synthesis is stimulated by resistance exercise and intake of amino acids, in particular leucine. Moreover, activation of mammalian target of rapamycin complex 1 (mTORC1) signaling by leucin...
Michael Strupp - One of the best experts on this subject based on the ideXlab platform.
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acetylation of l leucine switches its carrier from the l amino acid transporter lat to organic anion transporters oat
bioRxiv, 2020Co-Authors: Grant C Churchill, Michael Strupp, Frances M Platt, Tatiana Bremovaertl, M Factor, Marc C Patterson, Antony GalioneAbstract:ABSTRACT N-acetyl-DL-Leucine is an analogue of the alpha amino acid leucine with a chiral stereocenter. The active L-enantiomer of the racemate is currently under development for rare neurological disorders. Here we present evidence that a selective recognition of N-acetyl-L-Leucine versus L-Leucine by different uptake transporters significantly contributes to the therapeutic effects of N-acetyl-L-Leucine. A previous study of the pharmacokinetics of racemic N-acetyl-DL-Leucine and N-acetyl-L-Leucine revealed D-L enantiomer competition and saturation kinetics, best explained by carrier-mediated uptake. The strategy we used was to first analyze the physicochemical properties associated with good oral bioavailable drugs and how these are alerted by N-acetylation by comparing N-acetyl-L-Leucine with L-Leucine. Using in silico computational chemistry we found that N-acetylation has a profound impact on certain physicochemical properties that can rationalize why N-acetyl-L-Leucine is drug-like compared to L-Leucine. Our calculations show that at physiological pH, L-Leucine is a zwitterion, whereas N-acetyl-L-Leucine is present as mainly an anion. Specifically, N-acetylation removes a charge from the nitrogen at physiological pH and N-acetyl-L-Leucine is an anion that is then a substrate for the organic anion transporters. We examined N-acetyl-L-Leucine uptake in human embryonic kidney cells overexpression candidate organic anion transporters (OAT) and pharmacological inhibitors. We found that N-acetyl-L-Leucine is a translocated substrate for OAT1 and OAT3 with low affinity (Km ~10 mM). In contrast, L-Leucine is known to be transported by the L-type Amino Acid Transporter (LAT) with high affinity (Km ~0.2 mM) and low capacity. The clinical consequence is that L-Leucine uptake becomes saturated at 50-fold lower concentration than N-acetyl-L-Leucine. These results demonstrate a mechanism of action that explains why N-acetyl-L-Leucine is effective as a drug and L-Leucine itself is not.
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unexpected differences in the pharmacokinetics of n acetyl dl leucine enantiomers after oral dosing and their clinical relevance
PLOS ONE, 2020Co-Authors: Grant C Churchill, Michael Strupp, Antony Galione, Frances M PlattAbstract:The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyL-Leucine after administration of the racemate (N-acetyl-DL-Leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-Leucine). The results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (ke and T1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-Leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-Leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyL-Leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the L-enantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-Leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of only N-acetyl-L-Leucine.
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unexpected differences in the pharmacokinetics of n acetyl dl leucine enantiomers after oral dosing and their clinical relevance
bioRxiv, 2019Co-Authors: Grant C Churchill, Michael Strupp, Antony Galione, Frances M PlattAbstract:These results suggest that during chronic administration of the racemate, the D-enantiomer would accumulate, which could have negative effects. The enantiomers of many chiral drugs not only exhibit different pharmacological effects in regard to targets that dictate therapeutic and toxic effects, but are also handled differently in the body due to pharmacokinetic effects. We investigated the pharmacokinetics of the enantiomers of N-acetyL-Leucine after administration of the racemate (N-acetyl-DL-Leucine) or purified, pharmacologically active L-enantiomer (N-acetyl-L-Leucine). Compounds were administered orally to mice. Plasma and tissue samples were collected at predetermined time points (0.25 to 8 h), quantified with liquid chromatography/mass spectrometry, and pharmacokinetic constants were calculated using a noncompartmental model. When administered as the racemate, both the maximum plasma concentration (Cmax) and the area under the plasma drug concentration over time curve (AUC) were much greater for the D-enantiomer relative to the L-enantiomer. When administered as the L-enantiomer, the dose proportionality was greater than unity compared to the racemate, suggesting saturable processes affecting uptake and/or metabolism. Elimination (ke and T1/2) was similar for both enantiomers. These results are most readily explained by inhibition of uptake at an intestinal carrier of the L-enantiomer by the D-enantiomer, and by first-pass metabolism of the L-, but not D-enantiomer, likely by deacetylation. In brain and muscle, N-acetyl-L-Leucine levels were lower than N-acetyl-D-leucine, consistent with rapid conversion into L-Leucine and utilization by normal leucine metabolism. In summary, the enantiomers of N-acetyL-Leucine exhibit large, unexpected differences in pharmacokinetics due to both unique handling and/or inhibition of uptake and metabolism of the L-enantiomer by the D-enantiomer. Taken together, these results have clinical implications supporting the use of N-acetyl-L-Leucine instead of the racemate or N-acetyl-D-leucine, and support the research and development of isolated N-acetyl-L-Leucine.
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n acetyl l leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus
PLOS ONE, 2015Co-Authors: Lisa Gunther, Roswitha Beck, Guoming Xiong, Heidrun Potschka, Klaus Jahn, Peter Bartenstein, Thomas Brandt, Mayank B Dutia, Marianne Dieterich, Michael StruppAbstract:An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-Leucine, N-acetyl-L-Leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-μPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-μPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-Leucine (p < 0.03) and the N-acetyl-L-Leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-Leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-Leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-Leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-Leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-Leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by activating the vestibulocerebellum and deactivating the posterolateral thalamus.
