Interaction of Branched Chain Amino Acids with Lipid Metabolism in Adipose Tissue

2015 ◽  
pp. 22-40
Author(s):  
H. M. Goodman ◽  
L. Blinder ◽  
G. P. Frick
Keyword(s):  
Amino Acids ◽  
Adipose Tissue ◽  
Lipid Metabolism ◽  
Branched Chain Amino Acids ◽  
Branched Chain

scholarly journals Chronic Dietary Branched-Chain Amino Acids Induced Lipid Oxidation and Blunted Insulin-Stimulated Glucose Production in Mice With NAFLD

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 529-529
Author(s):  
Chaitra Surugihalli ◽  
Vaishna Muralidaran ◽  
Kruti Patel ◽  
Tabitha Gregory ◽  
Nishanth Sunny
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Oxidation ◽  
Glucose Production ◽  
Branched Chain Amino Acids ◽  
Hepatic Insulin Resistance ◽  
High Fat ◽  
Branched Chain

Abstract Objectives Elevated circulating branched-chain amino acids (BCAAs) during insulin resistance are strong predictors of type 2 diabetes mellitus onset. Defects in BCAA degradation are evident in several tissues during insulin resistance and non-alcoholic fatty liver disease (NAFLD). Furthermore, alterations in BCAA metabolism are associated with changes in several aspects lipid metabolism, including lipogenesis, ketogenesis and mitochondrial TCA cycle activity. Considering the crosstalk between BCAAs and lipid metabolism, we hypothesized that chronic supplementation of BCAAs will modulate hepatic insulin resistance and mitochondrial lipid oxidation during NAFLD. Methods Mice (C57BL/6N) were reared on either a low-fat (LF; 10% fat kcal), high-fat (HF; 60% fat kcal or high-fat diet supplemented with BCAA (HFBA; 150% BCAA) for 24 weeks. Metabolic profiling was conducted under fed or overnight fasted (14–16 hrs) conditions. A subset of overnight fasted mice from the HF and HFBA groups were subjected to hyperinsulinemic euglycemic clamps, following implantation of jugular vein catheters. Results Feeding HF and HFBA diets resulted in NAFLD. Circulating BCAAs were higher in ‘fed’ mice consuming HFBA diet (e.g., Valine, µM ± SEM; 311 ± 38 in HF, 432 ± 34 in HFBA, P ≤ 0.05). Overnight fasting significantly reduced BCAA levels in all groups, but the fasting levels of BCAAs remained similar between groups. Fed-to-fasted fold changes in blood glucose, serum insulin and c-peptide were higher in HFBA mice (P ≤ 0.05). Insulin stimulated suppression of glucose production (% ± SEM; HF = 38 ± 11, HFBA = 16 ± 16) was blunted in HFBA mice.  Furthermore, fed-to-fasted expression of hepatic genes involved in lipid oxidation, including LCAD, MCAD, PPARa and CPT1a were significantly higher (P ≤ 0.05) in the HFBA mice. Conclusions In summary, chronic BCAA supplementation induced hepatic lipid oxidation gene expression, without any apparent improvements in insulin sensitivity. In conclusion, while the induction of lipid oxidation by BCAAs could explain certain beneficial effects associated with their supplementation, the longer-term impact of the BCAAs on insulin sensitivity need to be further explored. Funding Sources National Institutes of Health (NIH) grant RO1-DK-112865

scholarly journals Associations between plasma branched-chain amino acids, β-aminoisobutyric acid and body composition

2016 ◽  
Vol 5 ◽  
Author(s):  
Annemarie Rietman ◽  
Takara L. Stanley ◽  
Clary Clish ◽  
Vamsi Mootha ◽  
Marco Mensink ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Body Composition ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Cardiometabolic Risk ◽  
Branched Chain Amino Acids ◽  
Multivariate Modelling ◽  
Matsuda Index ◽  
Branched Chain

AbstractPlasma branched-chain amino acids (BCAA) are elevated in obesity and associated with increased cardiometabolic risk. β-Aminoisobutyric acid (B-AIBA), a recently identified small molecule metabolite, is associated with decreased cardiometabolic risk. Therefore, we investigated the association of BCAA and B-AIBA with each other and with detailed body composition parameters, including abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). A cross-sectional study was carried out with lean (n 15) and obese (n 33) men and women. Detailed metabolic evaluations, including measures of body composition, insulin sensitivity and plasma metabolomics were completed. Plasma BCAA were higher (1·6 (se 0·08) (×107) v. 1·3 (se 0·06) (×107) arbitrary units; P = 0·005) in obese v. lean subjects. BCAA were positively associated with VAT (R 0·49; P = 0·0006) and trended to an association with SAT (R 0·29; P = 0·052). The association between BCAA and VAT, but not SAT, remained significant after controlling for age, sex and race on multivariate modelling (P < 0·05). BCAA were also associated with parameters of insulin sensitivity (Matsuda index: R −0·50, P = 0·0004; glucose AUC: R 0·53, P < 0·001). BCAA were not associated with B-AIBA (R −0·04; P = 0·79). B-AIBA was negatively associated with SAT (R −0·37; P = 0·01) but only trended to an association with VAT (R 0·27; P = 0·07). However, neither relationship remained significant after multivariate modelling (P > 0·05). Plasma B-AIBA was associated with parameters of insulin sensitivity (Matsuda index R 0·36, P = 0·01; glucose AUC: R −0·30, P = 0·04). Plasma BCAA levels were positively correlated with VAT and markers of insulin resistance. The results suggest a possible complex role of adipose tissue in BCAA homeostasis and insulin resistance.

scholarly journals Short-term dietary reduction of branched-chain amino acids reduces meal-induced insulin secretion and modifies microbiome composition in type 2 diabetes: a randomized controlled crossover trial

2019 ◽  
Vol 110 (5) ◽  
pp. 1098-1107 ◽  
Author(s):  
Yanislava Karusheva ◽  
Theresa Koessler ◽  
Klaus Strassburger ◽  
Daniel Markgraf ◽  
Lucia Mastrototaro ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acids ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Crossover Trial ◽  
Branched Chain Amino Acids ◽  
Short Term ◽  
Microbiome Composition ◽  
Branched Chain

ABSTRACT Background Epidemiological studies have shown that increased circulating branched-chain amino acids (BCAAs) are associated with insulin resistance and type 2 diabetes (T2D). This may result from altered energy metabolism or dietary habits. Objective We hypothesized that a lower intake of BCAAs improves tissue-specific insulin sensitivity. Methods This randomized, placebo-controlled, double-blinded, crossover trial examined well-controlled T2D patients receiving isocaloric diets (protein: 1 g/kg body weight) for 4 wk. Protein requirements were covered by commercially available food supplemented ≤60% by an AA mixture either containing all AAs or lacking BCAAs. The dietary intervention ensured sufficient BCAA supply above the recommended minimum daily intake. The patients underwent the mixed meal tolerance test (MMT), hyperinsulinemic-euglycemic clamps (HECs), and skeletal muscle and white adipose tissue biopsies to assess insulin signaling. Results After the BCAA− diet, BCAAs were reduced by 17% during fasting (P < 0.001), by 13% during HEC (P < 0.01), and by 62% during the MMT (P < 0.001). Under clamp conditions, whole-body and hepatic insulin sensitivity did not differ between diets. After the BCAA− diet, however, the oral glucose sensitivity index was 24% (P < 0.01) and circulating fibroblast-growth factor 21 was 21% higher (P < 0.05), whereas meal-derived insulin secretion was 28% lower (P < 0.05). Adipose tissue expression of the mechanistic target of rapamycin was 13% lower, whereas the mitochondrial respiratory control ratio was 1.7-fold higher (both P < 0.05). The fecal microbiome was enriched in Bacteroidetes but depleted of Firmicutes. Conclusions Short-term dietary reduction of BCAAs decreases postprandial insulin secretion and improves white adipose tissue metabolism and gut microbiome composition. Longer-term studies will be needed to evaluate the safety and metabolic efficacy in diabetes patients. This trial was registered at clinicaltrials.gov as NCT03261362.

scholarly journals The branched‐chain amino acids valine and leucine have differential effects on hepatic lipid metabolism

2020 ◽  
Vol 34 (7) ◽  
pp. 9727-9739
Author(s):  
Christopher A. Bishop ◽  
Matthias B. Schulze ◽  
Susanne Klaus ◽  
Karolin Weitkunat
Keyword(s):  
Amino Acids ◽  
Lipid Metabolism ◽  
Branched Chain Amino Acids ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid ◽  
Differential Effects ◽  
Branched Chain

scholarly journals Impact of Branched Chain Amino Acids on Mitochondrial Metabolism and Insulin Signaling in Mouse Hepatocytes (P08-111-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Meghan Maguire ◽  
Chaitra Surugihalli ◽  
Azuri Hughes ◽  
Nishanth Sunny
Keyword(s):  
Insulin Resistance ◽  
Amino Acids ◽  
Lipid Metabolism ◽  
Mitochondrial Function ◽  
Insulin Signaling ◽  
Branched Chain Amino Acids ◽  
Turnover Rates ◽  
Alcoholic Fatty Liver ◽  
Gene And Protein Expression ◽  
Branched Chain

Abstract Objectives Plasma branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) are elevated during insulin resistance and are robust predictors of future onset of type 2 diabetes mellitus (T2DM). Further, recent evidence points to a significant cross talk between BCAAs and lipid metabolism, which is disrupted during lipid metabolic disorders. Indeed, dysfunctional mitochondrial lipid metabolism is a central feature of non-alcoholic fatty liver disease (NAFLD). Considering the metabolic and molecular mechanisms of BCAA action on central metabolic pathways, we hypothesized that excess BCAAs during insulin resistance can interfere with mitochondrial function, by altering lipid oxidation, gluconeogenesis, and insulin signaling in the liver. Methods Mice (C57BL/6) were either fed a control (10% kcal from fat) or high fat (HF; 60% kcal from fat) diet for 16 weeks. Mice were then overnight fasted and challenged with either a saline or BCAA infusion (15.59 µmole/hour) for 8-hrs. Glucose and ketone turnover rates were determined from the dilution of [13C6]glucose and [13C4]3-hydroxybutyrate tracers. Plasma and tissues were collected and stored for metabolic profiling and gene and protein expression analysis. Results Infusion of BCAAs in mice resulted in a 2-fold elevation of circulating BCAAs (Control 179 ± 7 µM vs. 375 ± 21 µM, P < 0.01, HF 119 ± 4 µM vs. 265 ± 13 µM, P < 0.01). Elevated levels of BCAAs in circulation were associated with an increase in blood glucose levels in control mice (108 ± 7 µM vs. 127 ± 7 µM, p = 0.09). However, this response was absent in HF-fed mice (152 ± 7 µM vs. 155 ± 10 µM, P = 0.85). Surprisingly, ketone turnover rates (µmoles/min) were significantly reduced with BCAA infusion in the control mice (2.5 ± 0.2 vs. 1.6 ± 0.1, P < 0.01), but remained unchanged with BCAA infusion in HF-fed mice (1.9 ± 0.3 vs. 2.0 ± 0.3). The infusion of BCAAs also induced the phosphorylation of Akt in control mice (P < 0.01), but this effect was blunted in HF-fed mice. Conclusions Our results suggest that excess BCAAs can modulate hepatic mitochondrial function and insulin signaling. Chronic exposure to elevated levels of circulating BCAAs could exacerbate metabolic dysfunction during NAFLD by altering normal hepatic mitochondrial function. Funding Sources National Institutes of Health R01.

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