Leucine Supplementation: A Novel Strategy for Modulating Lipid Metabolism and Energy Homeostasis

Abstract

Lipid metabolism is an important and complex biochemical process involved in the storage of energy and maintenance of normal biological functions. Leucine, a branched amino acid, has anti-obesity effects on glucose tolerance, lipid metabolism, and insulin sensitivity. Leucine also modulates mitochondrial dysfunction, representing a new strategy to target aging, neurodegenerative disease, obesity, diabetes, and cardiovascular disease. Although various studies have been carried out, much uncertainty still exists and further studies are required to fully elucidate the relationship between leucine and lipid metabolism. This review offers an up-to-date report on leucine, as key roles in both lipid metabolism and energy homeostasis in vivo and in vitro by acceleration of fatty acid oxidation, lipolysis, activation of the adenosine 5'-monophosphate-activated protein kinase (AMPK)-silent information regulator of transcription 1 (SIRT1)-proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, synthesis, and/or secretion of adipokines and stability of the gut microbiota.

Keywords: adipokine; energy axis; leucine; lipid metabolism; microbiota.

Figure 1

Leucine catabolism. After leucine ingestion, the reversible transamination of leucine to α-ketoisocaproate (KIC) occurs, through branched-chain amino acid (BCAA) transferase (BCAT) present in various tissues, and then approximately 5% of KIC is converted into β-hydroxy-β-methylbutyrate (HMB) by the cytosolic enzyme KIC dioxygenase, and about 95% ingested KIC is metabolized into isovaleryl-CoA, which is catalyzed predominantly by the mitochondrial branched chain a-keto acid dehydrogenase (BCKD).

Figure 2

Dietary leucine effects on lipid metabolism in adipose tissues. After ingestion, leucine binds to Sestrin2, and then activates mammalian target of rapamycin complex 1 (mTORC1), facilitates lipolysis, and inhibits fatty acid synthesis by modulating the substrates such as translational inhibitor 4E-binding protein-1 (4EBP1) and S6 kinase 1 (S6K1). It also regulates adipokine synthesis/secretion and adenosine 5′-monophosphate-activated protein kinase (AMPK)–silent information regulator of transcription 1 (SIRT1)–proliferator-activated receptor γ coactivator-1α (PGC-1α) energy axis in adipose tissue, thus modulating mitochondrial biogenesis, promoting browning and fatty acid oxidation.

Figure 3

The SIRT1–AMPK–PGC-1α axis is involved in the leucine regulation in energy metabolism.