Time-course changes in circulating branched-chain amino acid levels and metabolism in obese Yucatan minipig

Abstract

A B S T R A C TObjectives: High-fat high-sucrose diet (HFHS) overfeeding is one of the main factors responsible for the increased prevalence of metabolic disorders. Elevated levels of branched-chain amino acids (BCAAs) have been associated with metabolic dysfunctions, including insulin resistance (IR). The aim of this study was to elucidate whether elevated BCAA levels are the cause or the consequence of IR and to determine the mechanisms and tissues involved in such a phenotype. Methods: We performed a 2-mo follow-up on minipigs overfed an HFHS diet and focused on kinetics fasting and postprandial (PP) BCAA levels and BCAA catabolism in key tissues. Results: The study of the fasting BCAA elevation reveals that BCAA accumulation in the plasma compartment is well correlated with IR markers and body weight. Furthermore, the PP excursion of BCAA levels after the last HFHS meal was exacerbated when compared with that of the first meal, suggesting a reduced amino acid oxidation potential. Although only minor changes in BCAA metabolism were observed in liver, muscle, and the visceral adipose tissue, the oxidative deamination potential of the subcutaneous adipose tissue was blunted after 60 d of HFHS feeding. Conclusions: To our knowledge, the present results demonstrated for the first time in a swine model of obesity and IR, the existence of a phenotype related to high-circulating BCAA levels and metabolic dysregulation. The oxidative BCAA capacity reduction specifically in the subcutaneous adipose tissue emerges, at least in the present swine model, as the more plausible metabolic explanation for the elevated blood BCAA phenotype.© 2017 Elsevier Inc. All rights reserved. IntroductionThe consumption of high-energy diets rich in fat, sugars, or both is increasing worldwide, paralleling the increases in obesity and metabolic diseases like type 2 diabetes mellitus and cardiovascular diseases [1]. High-fat high-sugar (HFHS) diets are highly palatable and have a poorly controlled intake [2]. Despite the high interindividual variability in the sensitivity to weight and adiposity gains, HFHS overfeeding is one of the main factors responsible for the increased prevalence of adiposity and metabolic disorders involving insulin resistance (IR) and leading to chronic metabolic diseases [3].Among the most recently studied metabolic dysfunctions and plasma metabolites alterations associated with IR occurrence, the place of branched-chain amino acids (BCAA) is questioned [4]. An increased level of plasma BCAA is observed in individuals who are insulin resistant and shown to be altered simultaneously with IR and diabetes installation [5]. To date, the underlying mechanisms explaining these increased BCAA levels is still under debate [6,7] and whether the increased level of BCAA should be considered as causal of IR or a consequence of its installation remains controversial [7]. Indeed, a BCAA-altered metabolism in adipose tissue (AT) associated with a reduction of the capacity of the BCAA catabolic enzymes has been clearly shown in ca...

Peripheral Blood Mononuclear Cell Metabolism Acutely Adapted to Postprandial Transition and Mainly Reflected Metabolic Adipose Tissue Adaptations to a High-Fat Diet in Minipigs

“…Interestingly, the increased transamination potential during the first weeks of HFHS feeding could be the consequence of a metabolic adaptation to the progressively increase in BCAA levels. However, by the end of the trial, the potential to catabolise BCAA was blunted, in agreement with a defective oxidative deamination observed in the adipose tissue of HFHS-fed minipigs [ 25 ].…”

“…BCAA related-enzyme activities and mRNA levels were also reduced by the end of the trial, supporting the idea of a progressively reduction of BCAA catabolism from obese minipigs. We and other have shown that in obese and insulin resistant animal models, BCAA circulating levels increased with time [ 25 , 43 ]. Interestingly, the increased transamination potential during the first weeks of HFHS feeding could be the consequence of a metabolic adaptation to the progressively increase in BCAA levels.…”

“…Plasma insulin levels were assessed using a commercial ELISA kit (Mercodia, Uppsala, Sweden). Branched-chain amino acids (BCAA) were assessed enzymatically as described in Polakof et al 2017 [ 25 ].…”

“…The homogenate was centrifuged for 20 min at 10,000× g and the supernatant immediately used. Enzyme activities were determined by spectrophotometry using a microplate reader (Infinite ® 200 PRO NanoQuant, Tecan, Grödig, Austria), based on mini-pigs methods adapted to PBMC [ 23 , 25 , 26 ], including hexokinase (HK), pyruvate kinase (PK), glucose-6-phosphate dehydrogenase (G6PD), malate dehydrogenase (MDH), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH), glutaminase P-dependent, branched-chain amino acid aminotransferase (BCAT) and aspartate aminotransferase (AspAT).…”

Postprandial NMR-Based Metabolic Exchanges Reflect Impaired Phenotypic Flexibility across Splanchnic Organs in the Obese Yucatan Mini-Pig

“…It is as yet unclear at which stage during overfeeding these adaptive processes can be regarded as part of normal metabolic flexibility or whether they reflects negative side effects in the spectrum of the metabolic syndrome [ 2 ]. Thus, we have recently shown that in mini-pigs overfed with a high fat–high sucrose (HFHS) diet for two months, major modifications in the postprandial metabolism occur after only one week of feeding [ 3 , 4 , 5 , 6 ].…”