Last Updated: September 28 2022

Leucine is a branced-chain amino acid (BCAA) and potent nutrient- based signal to activate protein synthesis.

Leucine is most often used for.

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Sources and Structure



Leucine (also known as 2-Amino-4-methylpentanoic acid) is an essential amino acid of the branched chain amino acid class (alongside isoleucine and valine). Of the three amino acids, leucine stands out for being the most potent activator of a protein known as mTOR (its activation is able to positively influence muscle protein synthesis) and also being an exclusively ketogenic amino acid[8][9] (producing ketone bodies after catabolism) whereas valine is glucogenic (produced glucose) and isoleucine is both.

Leucine is one of the branched chain amino acids, sometimes referred to as the main BCAA. It is the most potent inducer of muscle protein synthesis on a molecular level, and is ketogenic (produced ketones when metabolized)



Leucine is reversibly metabolized in the body first by the branched-chain aminotransferase enzyme (BCAT) into the intermediate known as α-Ketoisocaproic acid (KIC). KIC can be metabolized into a few intermediates, either β-hydroxyisovalerate (via the mitochondrial KIC dioxygenase enzyme[10]), into isovaleryl-CoA (via branched-chain α-keto acid dehydrogenase (BCKDH)[11]) or into HMB (via the cytosolic KIC dioxygenase enzyme[10]); the last route of metabolism into HMB is approximately 5% of ingested leucine[12] and the only source of HMB in the body.[12]

The first route that converts α-Ketoisocaproic acid (KIC) into β-hydroxyisovalerate can also convert KIC into the metabolite known as α-hydroxycaproic acid (Leucic acid or HICA).

Leucine is metabolized into one of several metabolites which may contribute to the effects of leucine. Of these, two of them are standalone supplements (HMB and HICA)




Mechanism of action

The primary mechanism of action from leucine is activation of Target of Rapamycin (TOR) which is referred to as mTOR in mammals (specifically, leucine activates mTORc1 which is one of two subsets of the complex[13]).

The first complex (mTORc1) is a complexation of a few proteins; TOR itself alongside the regulatory associated protein of TOR (Raptor), G-protien β-subunit like protein (GβL), and proline-rich PKB/Akt substrate of 40kDa (PRAS40).[14][15] This complex is activated by leucine supplementation, whereas the other complex (containing another regulatory protein of TOR known as Rictor and its own regulatory protein known as Proctor, GβL again, and a protein known as mSin1) is not activated by leucine.

TOR, or mammalian TOR (mTOR) is a protein complex that serves a pivotal role in regulating cellular signalling. Leucine is able to activate one of the two complexes it makes up, known as mTORc1 (c1 standing for 'complex one'). When mTOR is mentioned in this article, it is shorthand for mTORc1 unless otherwise specified

Although signalling via the insulin receptor is able to stimulate mTOR (via class 1 PI3K and Akt/PKB, which activate Rheb and mTOR[15]) mTOR from leucine appears to due to a protein officially known as human vacuolar protein sorting 34 (hVPS34)[16] but sometimes colloquiolly referred to as PI3K class 3[17]

hVPS34 depletion is known to blunt leucine-induced mTOR activation[16] while not hindering insulin-induced Akt activation.[16] Incubation of a cell with leucine actiates mTOR without activating Akt[18][19] and this effect is very similar to a general increase in intracellular calcium;[20][21] interestingly, leucine seems to induce mTOR activity via increasing intracellular calcium, as the increase in calcium and the binding of calmodulin (a protein involved in calcium homeostasis) to hVPS34 are vital to leucine-induced mTOR activation.[22][23]

There is a protein known as SHP-2 (a tyrosine phosphatase) which is critical to muscle protein synthesis[24] and is known to limit muscle growth under periods of nutrient deprivation,[25] and it appears to signal to S6K1 via mobilizing intracellular calcium at a point upstream of upstream of phospholipase C β4 and seems to work via Rheb protein stimulation of mTOR,[23] Rheb proteins are known to be positive modulators of mTOR function inherently.[26]

Leucine and/or its metabolites appear to increase intracellular calcium, similar to muscle contractions, and the increase in calcium will activate proteins such as mTOR which then induce muscle protein synthesis. Unlike muscle contraction, however, leucine likely does this in all cells rather than localized to skeletal muscle

In other words: SHP-2 (currently the furthest far back in the chain) -> calcium mobilization -> hVPS34 binding to calmodulin -> mTORc1 activation (possibly via Rheb) -> S6K1 activation -> muscle protein synthesis



Hyper(aminoacid)emia is a term used to refer to an excess (hyper-) of amino acids in the blood (-emia), and similar to that hyperleucinemia refers to an excess of leucine in particular.

In older men, leucine has been found to increase muscle protein synthesis independent of hyperaminoacidemia suggesting it itself is an independent predictor of muscle protein synthesis.[27]





Sirtuin proteins (SIRT being an acronym for Silent Information Regulator Transcript) are NAD+ dependent enzymes that are sensitive to a cellular NAD+/NADH ratio and thus energy status of a cell.[28] Of these, SIRT1 is a histone deacetylase that can modify signalling of the nuclear proteins p53, NF-κB and FOXO[29][30] and can induce the mitochondrial biogenesis factor PGC-1α.[31] Activation of SIRT1 (the molecule most commonly said to do this is resveratrol) is thought to be a pro-longevity mechanism.

Leucine is thought to underlie the health benefits of dairy proteins on lifespan[32][33] which have independently been shown to promote health and reduce the risk of premature death in rats.[34] Serum taken from patients consuming a dairy-rich diet has been shown in vitro to stimulte SIRT1 activity by 13% (adipose) and 43% (muscle tissue), suggesting biological plausibility.[32]

Both leucine metabolites (α-Ketoisocaproic acid and HMB) are activators of SIRT1 in the range of 30-100%, which is a comparable potency to resveratrol (2-10μM) but requires a higher concentration (0.5mM).[32] Mitochondrial biogenesis has been noted with leucine incubation in both fat and muscle cells, and abolishing SIRT1 attenuates (but does not eliminate) leucine-induced mitochondrial biogenesis.[35]

Leucine metabolites are able to stimulate SIRT1 activity, which is a mechanism thought to underlie mitochondrial biogenesis. It is actually moderately potent at doing so


Interactions with Glucose Metabolism


Glucose Uptake

Leucine has potential to promote insulin-induced activation of Akt, but it requires PI3K to be inhibited or suppressed first (and then leucine preserves insulin-induced Akt activation).[36] Due to leucine also stimulating insulin secretion from the pancreas (insulin then activates PI3K) this is likely not practically relevant.

Otherwise, in conditions where insulin is not present 2mM leucine and (to a lesser degree) its metabolite α-ketoisocaproate appear to promote glucose uptake via PI3K/aPKC (atypical PKC[37]) and indepedent of mTOR (blocking mTOR does not alter the effects).[38] This study noted stimulation only at 2-2.5mM for 15-45 minutes (resistance developed at 60 minutes) and was comparable in potency to physiological concentrations of basal insulin but underperformed (50% as potent) as 100nM insulin.[38] This mechanism of action is similar to isoleucine and appears to be of somewhat similar potency.

However, leucine is also able to hinder cellular glucose uptake[39][40][41] which is thought to either be related to activation of mTOR signalling which naturally suppresses AMPK signalling[42] (AMPK signalling being one that mediates glucose uptake during periods of low cellular energy and exercise[43][44]) in combination with mTOR signalling acting on S6K; signalling via mTOR/S6K will cause degradation of IRS-1[45] (the first protein that carries the 'signal' of insulin-induced effects) via activating proteasomal degradation of IRS-1 or simply directly binding to IRS-1,[46] this forms a negative feedback control loop of insulin signalling.[47] Inhibiting the negative effects on IRS-1 promotes leucine-induced glucose uptake[48] and this negative feedback explains why glucose is taken up for 45-60 minutes and then suddenly inhibited.[38] Since isoleucine is less potent at activating mTOR and thus this negative feedback pathway, isoleucine but not leucine leads to appreciable glucose uptake in muscle cells.

Leucine appears to initially promote glucose uptake into muscle cells for about 45 minutes, and then cuts itself off which reduces overall effects somewhat. The 'cut off' is a negative feedback that normally occurs after mTOR activation. Isoleucine is better than leucine at promoting glucose uptake due to less activation of mTOR


Insulin Secretion

Leucine, via its metabolite KIC, is able to induce insulin secretion from the pancreas and this insulin release is suppressed by both other BCAAs and two similar branched amino acids (norvaline and norleucine).[49] The potency at 10mM is approximately 73% that of glucose.[49]

In general, leucine is either additive or synergistic with glucose in inducing insulin secretion (for example, a 170% and 240% increase seen with leucine and glucose respectively is increased to 450% with the combination[50]). Despite leucine and yohimbine being of comparable potencies, they are not additive due to having overlapping mechanisms.[50]

Leucine is known to stimulate insulin secretion from the pancreas, and appears to be the most potent BCAA at doing this. On a equimolar basis (same concentration of the molecule within a cell), leucine is approximately as potent as yohimbine but about two-thirds as potent as glucose itself

Leucine is a positive allosteric regulator of glutamate dehydrogenase (GDH),[51][52] an enzyme that can convert some amino acids into α-ketoglutarate. This conversion increases cellular ATP concentrations (relative to ADP), and the increase in ATP levels causes an increase in insulin secretion by mechanisms that are independent of mTOR activation.[53][54]

The metabolite KIC is able to both inhibit KATP channels[55] and trigger calcium oscillations[56][57] in pancreatic β-cells. The calcium release can further act upon mTOR (standard target of leucine)[22] and activation of mTOR can suppress the expression of α2A receptors.[50] Since α2A receptors are suppressors of insulin release when activated[58] and overexpression induced diabetes,[59] less expression of these receptors causes a relative increase in insulin secretion. This pathway is likely the more important one from a practical standpoint, since the mTOR antagonist rapamycin is able to abolish leucine-induced insulin secretion[50] and suppress insulin secretion by itself.[60][61]

Leucine works via two pathways to stimulate insulin secretion from pancreatic beta-cells, but the major pathway appears to be due to reducing the influence of a negative regulator (α2A receptors). Reducing a negative regulator's influence causes a refractory increase in activity


Skeletal Muscle and Physical Performance


Protein Synthesis

Is leucine the only amino acid that turns on protein synthesis?

It depends. Leucine is by far the most 'anabolic' (protein-synthesis activating) amino acid, but as with most science, the results can be nuanced.

Leucine and protein synthesis in cultured cells

Scientists first published back in 1986 that amino acids were needed to turn on protein synthesis in rat skeletal muscle.[62]

Subsequent work tested which amino acids or mixtures of them were capable of stimulating protein synthesis (mTOR activity) in cultured cells.[63] One particularly informative study examined the ability of amino acid mixtures lacking certain amino acids to activate mTOR signaling, as measured by p70 S6 kinase activation.

Both leucine and arginine were found to be essential for mTOR activation in the cultured cells, but protein synthesis was suppressed overall when cells were lacking the other remaining 18 amino acids.

Lack of leucine had the most potent effect, decreasing protein synthesis by 90%, compared to an 81% decrease when the amino acid mixture lacked arginine.

The study also revealed that neither leucine nor arginine alone were able to stimulate maximal protein synthesis, with arginine or leucine alone stimulating protein synthesis by only 7.1% or 10.8%, respectively, compared to the full complement of amino acids. Leucine and arginine in combination fared a little better, but not my much. Leucine and arginine in combination only stimulated protein synthesis to 28% of maximal levels obtained all 20 amino acids.

Both leucine and arginine alone are capable of activating protein synthesis in cultured cells, but leucine is more potent than arginine. Neither leucine alone, arginine alone, nor leucine and arginine in combination were sufficient for full-activation of protein synthesis in the absence of other amino acids.

Later research examining the effects of individual essential amino acids found that although each of the essential amino acids (EAAs; valine, leucine, isoleucine, phenylalanine, tryptophan, lysine, histidine, methionine, and threonine) is capable of stimulating protein synthesis in cultured cells to a certain extent, leucine was the most potent.[63][64]

Further studies in cultured cells revealed that the ability of different amino acids to turn on protein synthesis is somewhat dependent on the type of cell used, however, as leucine is the only amino acid capable turning on the protein synthesis machinery in amino acid-depleted adipocytes (fat cells).[65] Similar results were found in experiments of cultured muscle cells, with leucine alone, but not the EAA histidine alone capable of restoring protein synthesis to basal levels in amino acid-depleted cells.[66]

Although studies in cultured cells have consistently identified leucine as the most protein-synthesis stimulating amino acid, the extent to which this occurs is dependent on the cell type.

Effects of leucine on protein synthesis in animal models

Similar to cell culture studies, animal studies on leucine suggest that it is the most anabolic amino acid. Decreased protein synthesis after food deprivation in rats can be restored by leucine alone to the same extent as a complete meal.[67] Further research confirmed this result, revealing that leucine, but not the other BCAAs isoleucine or valine were capable of restoring protein synthesis in food-deprived rats.[68]

Comparing results in cultured cells and animal models leucine stands out as the most anabolic amino acid. The models differ in that leucine alone failed to rescue protein synthesis in amino acid-depleted cultured cells, but succeeded in animal models. How do we make sense of this?

The differences can be explained by the nature of protein synthesis, and differences in the experimental models. First, cellular proteins often contain most or all of the 20 total amino acids. Irrespective of the individual amino acid, if some or many from the full complement are lacking inside a cell during protein synthesis, protein synthesis will be limited. (If you want to build a bridge, you'll need all of the required bricks.) This explains why leucine alone failed to restore protein synthesis in the most of the cultured cells; in the absence of the full complement of amino acids in the growth media, the cells didn't have enough amino acids to make new proteins through synthesis.

In contrast, food or protein deprivation causes body proteins to be broken down in living animals, increasing amino acid levels in the blood. With more amino acids available, protein synthesis is activated to a greater extent in response to leucine in vivo.

Leucine, but not isoleucine or valine was capable of restoring protein synthesis to fed levels in food-deprived rats


Protein Synthesis- signaling

Leucine's primary mechanism of action is stimulating the activity of mTOR[69][70] which then stimulates the activity of p70S6K via PDK1[71] and p70S6K then positively controls muscle protein synthesis.[19] Furthermore, leucine is able to induce activity of the eukaryotic initiation factor (eIF, specifically eIF4E) and suppresses its inhibitory binding protein (4E-BP1) which enhances protein translation[72][73] and has been confirmed following oral intake of leucine.[74] Modulation of eIF in this manner enhances muscle protein synthesis induced by p70S6K, and mTOR activation is a common anabolic pathway that is also tied into exercise (not activated acutely, but after a 1-2 hour time delay),[75][76] insulin,[77] and a caloric excess.[78]

Similar to the other branched chain amino acids and different than insulin, leucine does not stimulate Akt/PKB activity, but activates mTOR through an alternative mechanism.[18][19] Akt is able to enhance eIF2B which also positively promotes muscle protein synthesis induced by p70S6K[79][80] and as such the lack of activation of Akt by leucine is theoretically less potent than if Akt signalling was also promoted like insulin.

mTOR activation from leucine has been confirmed in the tissue of humans following oral supplementation[81][82] as well as p70S6K activation.[18] Akt activation has been investigated, and there has been a failure to find any alteration in activity in human muscle[18] which suggests that the release of insulin from the pancreas induced by leucine (noted to occur in humans[83] and insulin activates Akt) may not be relevant.

Leucine is able to stimulate mTOR activity and its subsequent protein synthesis signaling. Although Akt/PKB positively influences mTOR activity (so when Akt is activated, it activates mTOR) leucine appears to work via a different pathway and activate mTOR without affecting Akt. Regardless, anything that activates mTOR will then activate p70S6K and then promote muscle protein synthesis

This anabolic effect of leucine appears to favor skeletal muscle more than hepatic (liver) tissue[84] and appears to be augmented by physical exercise (muscle contractions)[85] with some studies suggesting preloading leucine to a workout is more effective than other times (in acutely increasing protein synthesis).[86][87]

Leucine appears to be the most potent of all amino acids in stimulating muscle protein synthesis.[88]



Leucine is known to promote muscle protein synthesis at low concentrations in vitro while requiring higher concentrations to attenuate atrophy, despite synthesis rates plateuing.[89]

This muscle preserving effect has been noted in disease states characterized by muscular wasting such as cancer[90] as well as sepsis, burns, and trauma.[91] In these scenarios the benefits appear to be dose-dependent.




Hyper(aminoacid)emia is a term used to refer to an excess (hyper-) of amino acids in the blood (-emia), and similar to that hyperleucinemia refers to an excess of leucine in particular.

In older men, leucine has been found to increase muscle protein synthesis independent of hyperaminoacidemia.[27]



Sarcopenia is characterized by a decrease in skeletal muscle mass protein content and an increase in skeletal muscle fat content that occurs with aging. One of the reasons as to why sarcopenia may occur is due to a decrease in the metabolic response to L-Leucine's muscle preserving effects that occurs with cellular aging[93]. This effect can be negated in part by the addition of L-Leucine to protein containing foods.[94][95][96]


Nutrient-Nutrient Interactions



When the insulin receptor is activated, it can activate mTOR vicariously through Akt.[97] While Akt positively influences protein synthesis induced by S6K1 (which is activated when mTOR is activated[81][82]), leucine supplementation does not appear to directly activate Akt like insulin does in vitro.[18][19] Leucine infusions in humans have been noted to not activate Akt significantly in skeletal muscle[18] which suggests that the insulin secretion induced by leucine[83] is insufficient to stimulate Akt.

Leucine has been found to work synergistically with ingested glucose in reducing blood glucose secondary to releasing more pancreatic insulin secretion.[98][50] Interestingly, leucine is not additive with yohimbine in inducing insulin secretion due to overlapping mechanisms.[50]

Leucine appears to be synergistic with dietary carbohydrate in promoting insulin secretion from the pancreas, and appears to be synergistic with insulin in promoting muscle protein synthesis



Resveratrol is a wine phenolic that is known to interact with sirtuin proteins (mostly SIRT1) which is similar to leucine; the metabolites of KIC and HMB at 0.5mM are able to induce SIRT1 to 30-100% of baseline which is a comparable potency to 2-10μM resveratrol[32] although the combination of leucine (0.5mM) or HMB (0.5μM) and resveratrol (200nM) is able to synergistically induce SIRT1 and SIRT3 activity in both adipocytes and skeletal muscle cells.[99] KIC appears to be a more potent stimulator than HMB,[32] and synergism appears to be greater with leucine than with HMB (possibly indicative of KIC metabolism).[99]

When rats are fed the combination of leucine (24g/kg, up to 200% of the control diet) or HMB (2 or 10g/kg) with resveratrol (12.5 or 225mg/kg) and then sacrificed in a fasted state, the reductions in fat mass and body weight appear to also be synergistic.[99]

It has been noted that incubation of resveratrol with leucine or HMB actually increases AMPK activity (42-55%, respectively) and promoted a modest (18%) increase in fat oxidation despite incubation with 5mM glucose.[99]

Resveratrol and leucine both appear to positively influence mitochondrial biogenesis via SIRT1 activation, and they both appear synergistic in doing so when incubated or ingested together



Citrulline appears to restore muscle protein synthesis rates[100][101] and muscular function[102] during aging and malnourishment in rats, and this appears to be mediated via the mTORc1 pathway (abolished by the mTORc1 inhibitor known as rapamycin).[103][104]

For human studies, supplementation of 0.18g/kg citrulline for a week has failed to significantly modify leucine oxidation rates or whole body protein synthesis[105] but elsewhere at the same dose has been noted to improve nitrogen balance in humans in the fed state.[106] The reason for this discrepancy is unknown.

There is not too much evidence looking at the direct activation of citrulline on mTOR, but it appears to weakly induce proteins after mTOR (including 4E-BP1) to a degree lesser than leucine.[100] It is plausible that citrulline augments mTOR signalling since its benefits are mTOR dependent, in which case it should be synergistic with leucine; this has not been directly investigated.

Citrulline may positively mediate leucine's signalling through mTOR, which theoretically suggests that they are synergistic. The application of the combination towards weight lifters has not yet been investigated, so the synergism is currently just a hypothesis rather than a demonstrated fact


Safety and Toxicity



In a small study in 5 healthy men given graded leucine intake up to 1,250mg/kg (25-fold the estimated average requirement) noted that oral doses of 500-1,250 caused increases in serum ammonia and due to this the upper limited was said to be established at 500mg/kg (for a 150lb human, 34g).[107]

1.^Isabelle Rieu, Michèle Balage, Claire Sornet, Christophe Giraudet, Estelle Pujos, Jean Grizard, Laurent Mosoni, Dominique DardevetLeucine supplementation improves muscle protein synthesis in elderly men independently of hyperaminoacidaemiaJ Physiol.(2006 Aug 15)
2.^Y Boirie, P Gachon, B BeaufrèreSplanchnic and whole-body leucine kinetics in young and elderly menAm J Clin Nutr.(1997 Feb)
3.^Churchward-Venne TA, Breen L, Di Donato DM, Hector AJ, Mitchell CJ, Moore DR, Stellingwerff T, Breuille D, Offord EA, Baker SK, Phillips SMLeucine supplementation of a low-protein mixed macronutrient beverage enhances myofibrillar protein synthesis in young men: a double-blind, randomized trialAm J Clin Nutr.(2014 Feb)
4.^Churchward-Venne TA, Burd NA, Mitchell CJ, West DW, Philp A, Marcotte GR, Baker SK, Baar K, Phillips SMSupplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in menJ Physiol.(2012 Jun 1)
5.^Caoileann H Murphy, Nelson I Saddler, Michaela C Devries, Chris McGlory, Steven K Baker, Stuart M PhillipsLeucine supplementation enhances integrative myofibrillar protein synthesis in free-living older men consuming lower- and higher-protein diets: a parallel-group crossover studyAm J Clin Nutr.(2016 Dec)
6.^Benjamin T Wall, Henrike M Hamer, Anneke de Lange, Alexandra Kiskini, Bart B L Groen, Joan M G Senden, Annemie P Gijsen, Lex B Verdijk, Luc J C van LoonLeucine co-ingestion improves post-prandial muscle protein accretion in elderly menClin Nutr.(2013 Jun)
8.^Holmes HC, Burns SP, Chalmers RA, Bain MS, Iles RAKetogenic flux from lipids and leucine, assessment in 3-hydroxy-3-methylglutaryl CoA lyase deficiencyBiochem Soc Trans.(1995 Aug)
13.^Wullschleger S, Loewith R, Hall MNTOR signaling in growth and metabolismCell.(2006 Feb 10)
14.^Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DMmTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machineryCell.(2002 Jul 26)
15.^Dann SG, Selvaraj A, Thomas GmTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancerTrends Mol Med.(2007 Jun)
16.^Byfield MP, Murray JT, Backer JMhVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinaseJ Biol Chem.(2005 Sep 23)
17.^Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas GAmino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinaseProc Natl Acad Sci U S A.(2005 Oct 4)
18.^Greiwe JS, Kwon G, McDaniel ML, Semenkovich CFLeucine and insulin activate p70 S6 kinase through different pathways in human skeletal muscleAm J Physiol Endocrinol Metab.(2001 Sep)
19.^Blomstrand E, Eliasson J, Karlsson HK, Köhnke RBranched-chain amino acids activate key enzymes in protein synthesis after physical exerciseJ Nutr.(2006 Jan)
22.^Gulati P, Gaspers LD, Dann SG, Joaquin M, Nobukuni T, Natt F, Kozma SC, Thomas AP, Thomas GAmino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34Cell Metab.(2008 May)
23.^Mercan F, Lee H, Kolli S, Bennett AMNovel role for SHP-2 in nutrient-responsive control of S6 kinase 1 signalingMol Cell Biol.(2013 Jan)
24.^Fornaro M, Burch PM, Yang W, Zhang L, Hamilton CE, Kim JH, Neel BG, Bennett AMSHP-2 activates signaling of the nuclear factor of activated T cells to promote skeletal muscle growthJ Cell Biol.(2006 Oct 9)
25.^Zito CI, Qin H, Blenis J, Bennett AMSHP-2 regulates cell growth by controlling the mTOR/S6 kinase 1 pathwayJ Biol Chem.(2007 Mar 9)
28.^Verdin E, Hirschey MD, Finley LW, Haigis MCSirtuin regulation of mitochondria: energy production, apoptosis, and signalingTrends Biochem Sci.(2010 Dec)
29.^Bordone L, Guarente LCalorie restriction, SIRT1 and metabolism: understanding longevityNat Rev Mol Cell Biol.(2005 Apr)
30.^Guarente L, Picard FCalorie restriction--the SIR2 connectionCell.(2005 Feb 25)
33.^Bruckbauer A, Gouffon J, Rekapalli B, Zemel MBThe effects of dairy components on energy partitioning and metabolic risk in mice: a microarray studyJ Nutrigenet Nutrigenomics.(2009)
37.^Uberall F, Hellbert K, Kampfer S, Maly K, Villunger A, Spitaler M, Mwanjewe J, Baier-Bitterlich G, Baier G, Grunicke HHEvidence that atypical protein kinase C-lambda and atypical protein kinase C-zeta participate in Ras-mediated reorganization of the F-actin cytoskeletonJ Cell Biol.(1999 Feb 8)
38.^Nishitani S, Matsumura T, Fujitani S, Sonaka I, Miura Y, Yagasaki KLeucine promotes glucose uptake in skeletal muscles of ratsBiochem Biophys Res Commun.(2002 Dec 20)
40.^Tessari P, Inchiostro S, Biolo G, Duner E, Nosadini R, Tiengo A, Crepaldi GHyperaminoacidaemia reduces insulin-mediated glucose disposal in healthy manDiabetologia.(1985 Nov)
44.^O'Neill HMAMPK and Exercise: Glucose Uptake and Insulin SensitivityDiabetes Metab J.(2013 Feb)
46.^Tremblay F, Brûlé S, Hee Um S, Li Y, Masuda K, Roden M, Sun XJ, Krebs M, Polakiewicz RD, Thomas G, Marette AIdentification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistanceProc Natl Acad Sci U S A.(2007 Aug 28)
48.^Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi MA rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1Mol Endocrinol.(2000 Jun)
53.^Yang J, Wong RK, Park M, Wu J, Cook JR, York DA, Deng S, Markmann J, Naji A, Wolf BA, Gao ZLeucine regulation of glucokinase and ATP synthase sensitizes glucose-induced insulin secretion in pancreatic beta-cellsDiabetes.(2006 Jan)
54.^Yang J, Wong RK, Wang X, Moibi J, Hessner MJ, Greene S, Wu J, Sukumvanich S, Wolf BA, Gao ZLeucine culture reveals that ATP synthase functions as a fuel sensor in pancreatic beta-cellsJ Biol Chem.(2004 Dec 24)
55.^Bränström R, Efendić S, Berggren PO, Larsson ODirect inhibition of the pancreatic beta-cell ATP-regulated potassium channel by alpha-ketoisocaproateJ Biol Chem.(1998 Jun 5)
57.^Malaisse WJ, Hutton JC, Carpinelli AR, Herchuelz A, Sener AThe stimulus-secretion coupling of amino acid-induced insulin release: metabolism and cationic effects of leucineDiabetes.(1980 Jun)
58.^Devedjian JC, Pujol A, Cayla C, George M, Casellas A, Paris H, Bosch FTransgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasisDiabetologia.(2000 Jul)
59.^Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li DQ, Nagaraj V, Reinbothe TM, Tuncel J, Eliasson L, Groop L, Rorsman P, Salehi A, Lyssenko V, Luthman H, Renström EOverexpression of alpha2A-adrenergic receptors contributes to type 2 diabetesScience.(2010 Jan 8)
60.^Shimodahira M, Fujimoto S, Mukai E, Nakamura Y, Nishi Y, Sasaki M, Sato Y, Sato H, Hosokawa M, Nagashima K, Seino Y, Inagaki NRapamycin impairs metabolism-secretion coupling in rat pancreatic islets by suppressing carbohydrate metabolismJ Endocrinol.(2010 Jan)
61.^Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, Berthault MF, Magnan C, Cerasi E, Kaiser N, Leibowitz GmTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetesDiabetes.(2008 Apr)
63.^K Hara, K Yonezawa, Q P Weng, M T Kozlowski, C Belham, J AvruchAmino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanismJ Biol Chem.(1998 Jun 5)
64.^X Wang, L E Campbell, C M Miller, C G ProudAmino acid availability regulates p70 S6 kinase and multiple translation factorsBiochem J.(1998 Aug 15)
65.^H L Fox, P T Pham, S R Kimball, L S Jefferson, C J LynchAmino acid effects on translational repressor 4E-BP1 are mediated primarily by L-leucine in isolated adipocytesAm J Physiol.(1998 Nov)
68.^J C Anthony, F Yoshizawa, T G Anthony, T C Vary, L S Jefferson, S R KimballLeucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathwayJ Nutr.(2000 Oct)
69.^Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SRLeucine stimulates translation initiation in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathwayJ Nutr.(2000 Oct)
70.^Drummond MJ, Fry CS, Glynn EL, Dreyer HC, Dhanani S, Timmerman KL, Volpi E, Rasmussen BBRapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesisJ Physiol.(2009 Apr 1)
72.^Fischer PMCap in hand: targeting eIF4ECell Cycle.(2009 Aug 15)
73.^Kimball SR, Jefferson LSRegulation of protein synthesis by branched-chain amino acidsCurr Opin Clin Nutr Metab Care.(2001 Jan)
77.^Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DHInsulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40Nat Cell Biol.(2007 Mar)
78.^Elmadhun NY, Lassaletta AD, Chu LM, Sellke FWMetformin alters the insulin signaling pathway in ischemic cardiac tissue in a swine model of metabolic syndromeJ Thorac Cardiovasc Surg.(2013 Jan)
80.^Browne GJ, Proud CGRegulation of peptide-chain elongation in mammalian cellsEur J Biochem.(2002 Nov)
82.^Alvestrand A, Hagenfeldt L, Merli M, Oureshi A, Eriksson LSInfluence of leucine infusion on intracellular amino acids in humansEur J Clin Invest.(1990 Jun)
83.^Yang J, Chi Y, Burkhardt BR, Guan Y, Wolf BALeucine metabolism in regulation of insulin secretion from pancreatic beta cellsNutr Rev.(2010 May)
85.^Tipton KD, Elliott TA, Ferrando AA, Aarsland AA, Wolfe RRStimulation of muscle anabolism by resistance exercise and ingestion of leucine plus proteinAppl Physiol Nutr Metab.(2009 Apr)
86.^Tipton KD, Elliott TA, Cree MG, Aarsland AA, Sanford AP, Wolfe RRStimulation of net muscle protein synthesis by whey protein ingestion before and after exerciseAm J Physiol Endocrinol Metab.(2007 Jan)
87.^Tipton KD, Rasmussen BB, Miller SL, Wolf SE, Owens-Stovall SK, Petrini BE, Wolfe RRTiming of amino acid-carbohydrate ingestion alters anabolic response of muscle to resistance exerciseAm J Physiol Endocrinol Metab.(2001 Aug)
90.^Peters SJ, van Helvoort A, Kegler D, Argilès JM, Luiking YC, Laviano A, van Bergenhenegouwen J, Deutz NE, Haagsman HP, Gorselink M, van Norren KDose-dependent effects of leucine supplementation on preservation of muscle mass in cancer cachectic miceOncol Rep.(2011 Jul)
92.^Nicastro H, Artioli GG, Costa Ados S, Solis MY, da Luz CR, Blachier F, Lancha AH JrAn overview of the therapeutic effects of leucine supplementation on skeletal muscle under atrophic conditionsAmino Acids.(2011 Feb)
93.^Fujita S, Volpi EAmino acids and muscle loss with agingJ Nutr.(2006 Jan)
96.^Rieu I, Sornet C, Bayle G, Prugnaud J, Pouyet C, Balage M, Papet I, Grizard J, Dardevet DLeucine-supplemented meal feeding for ten days beneficially affects postprandial muscle protein synthesis in old ratsJ Nutr.(2003 Apr)
98.^Kalogeropoulou D, Lafave L, Schweim K, Gannon MC, Nuttall FQLeucine, when ingested with glucose, synergistically stimulates insulin secretion and lowers blood glucoseMetabolism.(2008 Dec)
99.^Bruckbauer A, Zemel MB, Thorpe T, Akula MR, Stuckey AC, Osborne D, Martin EB, Kennel S, Wall JSSynergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and miceNutr Metab (Lond).(2012 Aug 22)
101.^Osowska S, Duchemann T, Walrand S, Paillard A, Boirie Y, Cynober L, Moinard CCitrulline modulates muscle protein metabolism in old malnourished ratsAm J Physiol Endocrinol Metab.(2006 Sep)
102.^Faure C, Raynaud-Simon A, Ferry A, Daugé V, Cynober L, Aussel C, Moinard CLeucine and citrulline modulate muscle function in malnourished aged ratsAmino Acids.(2012 Apr)
104.^Cynober L, de Bandt JP, Moinard CLeucine and citrulline: two major regulators of protein turnoverWorld Rev Nutr Diet.(2013)
106.^Rougé C, Des Robert C, Robins A, Le Bacquer O, Volteau C, De La Cochetière MF, Darmaun DManipulation of citrulline availability in humansAm J Physiol Gastrointest Liver Physiol.(2007 Nov)
107.^Elango R, Chapman K, Rafii M, Ball RO, Pencharz PBDetermination of the tolerable upper intake level of leucine in acute dietary studies in young menAm J Clin Nutr.(2012 Oct)