Adipose Tissue Branched Chain Amino Acid (BCAA) Metabolism Modulates Circulating BCAA Levels

Abstract

Whereas the role of adipose tissue in glucose and lipid homeostasis is widely recognized, its role in systemic protein and amino acid metabolism is less well-appreciated. In vitro and ex vivo experiments suggest that adipose tissue can metabolize substantial amounts of branched chain amino acids (BCAAs). However, the role of adipose tissue in regulating BCAA metabolism in vivo is controversial. Interest in the contribution of adipose tissue to BCAA metabolism has been renewed with recent observations demonstrating down-regulation of BCAA oxidation enzymes in adipose tissue in obese and insulin-resistant humans. Using gene set enrichment analysis, we observe alterations in adipose-tissue BCAA enzyme expression caused by adipose-selective genetic alterations in the GLUT4 glucosetransporter expression. We show that the rate of adipose tissue BCAA oxidation per mg of tissue from normal mice is higher than in skeletal muscle. In mice overexpressing GLUT4 specifically in adipose tissue, we observe coordinate down-regulation of BCAA metabolizing enzymes selectively in adipose tissue. This decreases BCAA oxidation rates in adipose tissue, but not in muscle, in association with increased circulating BCAA levels. To confirm the capacity of adipose tissue to modulate circulating BCAA levels in vivo, we demonstrate that transplantation of normal adipose tissue into mice that are globally defective in peripheral BCAA metabolism reduces circulating BCAA levels by 30% (fasting)-50% (fed state). These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adiposetissue BCAA enzymes may modulate circulating BCAA levels.The branched chain amino acids (BCAAs) 2 , leucine, isoleucine, and valine, are three of the nine essential amino acids and are relatively abundant in the food supply accounting for ϳ20% of total protein intake (1). In contrast to the other 17 amino acids, which are predominantly metabolized in the liver, BCAAs are poorly metabolized during first pass through the liver as the liver expresses only low levels of the mitochondrial branched chain aminotransferase (BCAT2 or BCATm), the first enzyme in the catabolism of BCAAs in most peripheral tissues (2, 3). BCAAs are therefore in a unique position among amino acids to signal to the periphery and the brain the amino acid content of a meal. Circulating BCAAs, acting as nutrient signals, regulate protein synthesis, and degradation, and insulin secretion, and have been implicated in central nervous system control of food intake and energy balance (4 -7). Our knowledge of the physiologic mechanisms which regulate circulating BCAA levels remains incomplete. In this study, we provide evidence that adipose tissue contributes to the regulation of circulating BCAAs.Over the last two decades, adipose tissue has emerged as a key endocrine organ and a regulator of integrated fuel homeostasis. Whereas its role in glucose and lipid homeostasis is widely recognized, its role in systemic protein ...

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

“…Based on whole tissue estimates of BCKD complex activity, WAT leucine kinetics, and BCAA oxidation rates in tissue preparations, WAT could be an important contributor to regulation of whole body BCAA homeostasis (7, 37a, 38, 43). This is supported by a recent study demonstrating that gene expression of BCKD enzyme components was higher in perigonadal WAT compared with gastrocnemius skeletal muscle, and valine oxidation rate was higher in perigonadal WAT compared with gastrocnemius muscle explants (22). In that same study, adipose transplantation experiments demonstrated the potential importance of WAT in modulating systemic BCAA concentrations.…”

Roux-en-Y Gastric Bypass Surgery, but Not Calorie Restriction, Reduces Plasma Branched-Chain Amino Acids in Obese Women Independent of Weight Loss or the Presence of Type 2 Diabetes

“…Increased protein consumption containing these essential amino acids may raise their plasma levels, but some data suggest that protein intake and circulating BCAA levels are not necessarily correlated (16,17). Alternatively, downregulation of catabolic enzymes in adipose or other tissues might be involved (8,9). In a parallel study, we analyzed the transcriptome in visceral and subcutaneous adipose tissue samples by RNA sequencing in the cohort of the current study (18).…”

“…Why levels of circulating BCAAs are elevated in obesity is unclear. Evidence has been provided for a role of white adipose tissue BCAA metabolism in the modulation of circulating BCAA levels (8,9).…”

The relationship between BMI and metabolomic profiles: a focus on amino acids

“…Some of the possible mechanisms that have been suggested include reduced activities of key BCAA catabolic enzymes in liver and adipose tissue (27,28) , and differential rates of protein turnover. However, more evidence is required in order to fully understand changes in flux through metabolic pathways that may lead to increased levels of BCAA and related metabolites in insulin resistant individuals.…”