High Leucine Diets Stimulate Cerebral Branched-Chain Amino Acid Degradation and Modify Serotonin and Ketone Body Concentrations in a Pig Model.

Anna G Wessels,Alexandra Schutkowski,Gabriele I Stangl,Jörg Bartelt,Etienne Corrent,Holger Kluge,Bettina König,Andreas Kiowski,Frank Hirche,James D Clelland

doi:10.1371/journal.pone.0150376

Anna G Wessels, Alexandra Schutkowski + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0150376

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Abstract

In addition to its role as an essential protein component, leucine (Leu) displays several other metabolic functions such as activation of protein synthesis. This property makes it an interesting amino acid for the therapy of human muscle atrophy and for livestock production. However, Leu can stimulate its own degradation via the branched-chain keto acid dehydrogenase complex (BCKDH). To examine the response of several tissues to excessive Leu, pigs were fed diets containing two- (L2) and four-fold (L4) higher Leu contents than the recommended amount (control). We found that the L4 diet led to a pronounced increase in BCKDH activity in the brain (2.5-fold, P < 0.05), liver (1.8-fold, P < 0.05) and cardiac muscle (1.7-fold, P < 0.05), whereas we found no changes in enzyme activity in the pancreas, skeletal muscle, adipose tissue and intestinal mucosa. The L2 diet had only weak effects on BCKDH activity. Both high Leu diets reduced the concentrations of free valine and isoleucine in nearly all tissues. In the brain, high Leu diets modified the amount of tryptophan available: for serotonin synthesis. Compared to the controls, pigs treated with the high Leu diets consumed less food, showed increased plasma concentrations of 3-hydroxybutyrate and reduced levels of circulating serotonin. In conclusion, excessive Leu can stimulate BCKDH activity in several tissues, including the brain. Changes in cerebral tryptophan, along with the changes in amino acid-derived metabolites in the plasma may limit the use of high Leu diets to treat muscle atrophy or to increase muscle growth.

Highlights

Leu is one of the branched-chain amino acids (BCAAs) and, in addition to playing a role as a substrate for protein synthesis, it has an important function in the stimulation of protein translation through the activation of mammalian target of rapamycin [1,2]
We showed that pigs fed high Leu diets had lower food intake, which may explain the decline in growth observed in these animals
We further observed an increase in branched-chain keto acid dehydrogenase complex (BCKDH) activity in all tissues except the skeletal muscle and adipose tissue in response to high Leu diets

Summary

Introduction

Leu is one of the branched-chain amino acids (BCAAs) and, in addition to playing a role as a substrate for protein synthesis, it has an important function in the stimulation of protein translation through the activation of mammalian target of rapamycin (mTOR) [1,2]. In pigs, one of the most important production animals and a potential human model, the effects of a high Leu diet on BCKDH activity have been investigated in only the liver and skeletal muscle [8,11]. Pigs do not have a dietary requirement for protein per se, but they do have minimum dietary requirements for the same essential or amino acids as humans, along with an adequate amount of nonessential amino nitrogen from various nonessential amino acids (reviewed in [12]) These features are important in terms of developing possible therapies for humans and with regard to the fact that intake of protein and Leu in industrialized countries is, on average, twice as high as the suggested need for this amino acid [13]

Material and Methods

Study design and diets

Results

Discussion