Leucine | Supplementopedia

Overview

Leucine is an essential branched‑chain amino acid (BCAA) that cannot be synthesized by humans and must be obtained from the diet. It is a key building block of proteins and serves as a primary signal for muscle protein synthesis, making it a central nutrient for maintaining and building lean tissue.

Benefits

Muscle Protein Synthesis (MPS): Research consistently links leucine supplementation to enhanced MPS and improved recovery after resistance training, largely through activation of the mTORC1 pathway (Phillips et al., 2020).
Sarcopenia: In older adults, leucine‑rich diets help attenuate age‑related sarcopenia and preserve functional strength (Kumar et al., 2022).
Glucose Homeostasis: Leucine also supports glucose homeostasis by stimulating insulin secretion and enhancing peripheral glucose uptake, which can aid metabolic control in pre‑diabetic populations (Gao & Wang, 2021).
Cognitive Benefits: Emerging data suggest modest cognitive benefits via increased brain‑derived neurotrophic factor (BDNF) expression, though evidence remains preliminary (Zhang et al., 2023).
Clinical Nutrition: In clinical nutrition, leucine-enriched formulas improve wound healing and reduce muscle loss during immobilization or critical illness (Wang et al., 2021).

How It Works

Protein Synthesis Signaling: Leucine functions as both a substrate for protein synthesis and a potent signaling molecule.
mTORC1 Activation: After cellular uptake via the LAT1 transporter, leucine directly binds to the regulatory protein Sestrin2, relieving its inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). Activated mRNA‑binding protein 4E‑BP1 and S6K1 then promote translation initiation, driving muscle protein synthesis.
Insulin Secretion: Leucine also stimulates pancreatic β‑cells, enhancing insulin release through the mTOR‑dependent pathway, thereby improving glucose uptake in skeletal muscle via GLUT4 translocation.
Neuroprotective Effects: In the brain, leucine crosses the blood‑brain barrier, where it modulates neurotransmitter synthesis and may up‑regulate BDNF via the mTOR‑dependent neuroplasticity pathway.
Overall Actions: Collectively, these mechanisms explain leucine’s anabolic, metabolic, and neuro‑protective actions.

Dosage

Resistance Training: For healthy adults engaged in resistance training, 2–3 g of free‑form leucine per serving (total 5–10 g per day when combined with other BCAAs) is widely used to maximize MPS without excessive nitrogen load.
Timing: Timing strategies include 2 g taken pre‑workout or immediately post‑exercise, when muscle cells are most receptive to anabolic signaling.
Older Adults: Older adults (>65 y) may benefit from 3–5 g per meal to counteract anabolic resistance, as demonstrated in the “LEU‑SEN” trials.
Clinical Settings: In clinical settings (e.g., sarcopenia, post‑surgical recovery), 2.5 g three times daily (≈7.5 g/day) has been shown safe and effective.
Athletes: Athletes should avoid exceeding 30 g/day to prevent potential metabolic disturbances.

Safety & Side Effects

General Tolerance: Leucine is generally well‑tolerated at typical supplemental doses (≤15 g/day).
Side Effects: Mild adverse effects include gastrointestinal discomfort (bloating, nausea) when taken on an empty stomach.
High Intake Risks: High chronic intakes (>30 g/day) may impair ammonia detoxification, increase plasma ammonia, and exacerbate hepatic or renal dysfunction in susceptible individuals.
Contraindications: Contraindications include severe liver disease, advanced renal failure (eGFR < 30 mL/min/1.73 m²), and inborn errors of branched‑chain amino‑acid metabolism (e.g., maple‑syrup urine disease).
Drug Interactions: Leucine may potentiate insulin‑secretagogue drugs (e.g., sulfonylureas) and should be used with caution in patients on insulin therapy.
Pregnancy/Lactation: Pregnant or lactating women should limit intake to ≤2 g/day unless directed by a healthcare professional.

Chemistry

Molecular Formula and Weight: Leucine (L‑leucine) is a non‑polar, essential α‑amino acid with the molecular formula C₆H₁₃NO₂ and a molecular weight of 131.17 g·mol⁻¹.
IUPAC Name: Its IUPAC name is (2S)-2‑amino‑4‑methylpentanoic acid.
Side Chain: The side chain consists of an isobutyl group (–CH₂‑CH(CH₃)₂) attached to the α‑carbon, conferring its characteristic branched‑chain structure.
Zwitterion Form: At physiological pH (~7.4) leucine exists as a zwitterion (–NH₃⁺ and –COO⁻).
Solubility: The amino acid is moderately soluble in water (≈22 g/L at 25 °C) and highly soluble in ethanol and methanol.
Optical Activity: Its optical activity (L‑configuration) is the biologically active form used in protein synthesis.
Functional Roles: The side‑chain hydrophobicity contributes to its role as a key regulator of the mTOR pathway, while the α‑amino group participates in peptide bond formation.

Sources & Quality

Dietary Sources: Dietary leucine is abundant in animal proteins (e.g., whey, chicken, beef, fish) and in plant sources such as soy, lentils, and peanuts.
Commercial Production: Commercially, leucine is typically produced by microbial fermentation (e.g., Corynebacterium glutamicum or E. coli engineered strains) followed by crystallization, yielding a high‑purity (>98 %) free‑form amino acid.
Alternative Synthesis: Chemical synthesis via the Strecker or reductive amination pathways is also employed, though fermentation is preferred for food‑grade products due to lower impurity risk.
Supplement Quality: For supplements, manufacturers must verify identity and purity through HPLC, assess for heavy‑metal contamination, and ensure compliance with USP or EFSA standards.
Third-Party Certifications: Look for third‑party certifications (e.g., NSF, Informed‑Choice) to guarantee consistent quality and minimal adulteration.