Leucine is an essential branched-chain amino acid (BCAA) associated with skeletal muscle growth and maintenance, energy production, and generation of neurotransmitter and gluconeogenic precursors ⁽³⁵⁾. It stimulates protein synthesis by activating the mTOR pathway ⁽¹⁾, and is thought to enhance muscle anabolic signaling ⁽¹¹⁾.

Animal models indicate that BCAA metabolism-related gene expression is regulated during adipocyte differentiation and influenced by nutrient levels, and leucine supplementation induces Bcat2 and Bckdha genes during early and late differentiation ⁽³⁵⁾. Insulin sensitivity was improved in mice fed a high-fat diet by decreasing adiposity, rather than through direct action on peripheral target organs ⁽³⁶⁾. Supplementation also improved lipid and glucose metabolism and restored leptin sensitivity in previously obese animals ⁽¹⁹⁾. However, in already-obese rats, leucine worsened adiposity by encouraging hypothalamic gene expression that favored fat accumulation ⁽³⁷⁾. In another study, it did not reduce food intake or induce an anorectic pattern of hypothalamic gene expression ⁽³⁸⁾. Co-ingesting leucine and glycine markedly attenuated glucose response, with only a modest increase in insulin response, suggesting their effects on glucose metabolism are partially insulin-independent ⁽³⁹⁾. Leucine along with subtherapeutic levels of a PDE5 inhibitor altered lipid metabolism from storage to oxidation, improved glycemic control, and reversed hepatic steatosis induced by high-fat feeding ⁽⁴⁰⁾.

Leucine supplementation speeds connective tissue repair and muscle regeneration by attenuating transforming growth factor-beta type I receptor and activating Smad2/3 ⁽⁴¹⁾. Antiatrophic effects were not mediated by its metabolite, beta-hydroxy-beta-methyl butyrate, and did not occur in dexamethasone-treated rats ⁽⁴²⁾.

The ability of leucine to improve anemia in ribosomal protein-deficient cells occurs independently of TP53 ⁽²³⁾. In Diamond-Blackfan anemia patients, leucine modulated protein synthesis by enhancing translation leading to improved hemoglobin levels ⁽⁷⁾. In the skeletal muscle of cirrhotic patients, an oral leucine-enriched BCAA mixture increased autophagy and reversed impaired mTOR1 signaling ⁽²⁴⁾. Leucine may have a protective role in attenuating macrophage foam-cell formation, a hallmark of early atherogenesis, via mechanisms related to the metabolism of cholesterol, triglycerides, and energy production ⁽⁴⁹⁾.