Branched chain amino acids—friend or foe in the control of energy substrate turnover and insulin sensitivity?

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

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Altered Dairy Protein Intake Does Not Alter Circulatory Branched Chain Amino Acids in Healthy Adults: A Randomized Controlled Trial

Nutrients ◽

10.3390/nu10101510 ◽

2018 ◽

Vol 10 (10) ◽

pp. 1510 ◽

Cited By ~ 9

Author(s):

Utpal Prodhan ◽

Amber Milan ◽

Eric Thorstensen ◽

Matthew Barnett ◽

Ralph Stewart ◽

...

Keyword(s):

Amino Acids ◽

Insulin Sensitivity ◽

Protein Intake ◽

Branched Chain Amino Acids ◽

Healthy Adults ◽

Model Assessment ◽

Dairy Intake ◽

Branched Chain ◽

Dairy Protein ◽

The Impact

Dairy, as a major component of a high protein diet, is a critical dietary source of branched chain amino acids (BCAA), which are biomarkers of health and diseases. While BCAA are known to be key stimulators of protein synthesis, elevated circulatory BCAA is an independent risk factor for type 2 diabetes mellitus. This study examined the impact of altered dairy intake on plasma BCAA and their potential relationship to insulin sensitivity. Healthy adults (n = 102) were randomized to receive dietary advice to reduce, maintain, or increase habitual dairy intake for 1 month. Food intake was recorded with food frequency questionnaires. Self-reported protein intake from dairy was reported to be reduced (−14.6 ± 3.0 g/day), maintained (−4.0 ± 2.0 g/day) or increased (+13.8 ± 4.1 g/day) according to group allocation. No significant alterations in circulating free amino acids (AA), including BCAA, were measured. Insulin sensitivity, as assessed by homeostatic model assessment-insulin resistance (HOMA-IR), was also unaltered. A significant change in dairy protein intake showed no significant effect on fasting circulatory BCAA and insulin sensitivity in healthy populations.

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Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice

Metabolism ◽

10.1016/j.metabol.2014.03.006 ◽

2014 ◽

Vol 63 (6) ◽

pp. 841-850 ◽

Cited By ~ 44

Author(s):

Fei Xiao ◽

Junjie Yu ◽

Yajie Guo ◽

Jiali Deng ◽

Kai Li ◽

...

Keyword(s):

Amino Acids ◽

Insulin Sensitivity ◽

Glucose Metabolism ◽

Branched Chain Amino Acids ◽

Branched Chain

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

Journal of Nutritional Science ◽

10.1017/jns.2015.37 ◽

2016 ◽

Vol 5 ◽

Cited By ~ 17

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.

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The effect of physical activity level and exercise training on the association between plasma branched-chain amino acids and intrahepatic lipid content in participants with obesity

International Journal of Obesity ◽

10.1038/s41366-021-00815-4 ◽

2021 ◽

Author(s):

Froukje Vanweert ◽

Sebastiaan C. Boone ◽

Bram Brouwers ◽

Dennis O. Mook-Kanamori ◽

Renée de Mutsert ◽

...

Keyword(s):

Physical Activity ◽

Amino Acids ◽

Insulin Sensitivity ◽

Exercise Training ◽

Physical Activity Level ◽

Branched Chain Amino Acids ◽

Activity Level ◽

Post Exercise ◽

Branched Chain ◽

Intrahepatic Lipid

Abstract Aims To evaluate whether the association between plasma branched-chain amino acids (BCAA) and intrahepatic lipid (IHL) was affected by physical activity level. Furthermore, to investigate if a conventional exercise training program, a subcategory of physical activity, could lower plasma BCAA along with alterations in IHL content in patients with type 2 diabetes (T2DM) and people with nonalcoholic fatty liver (NAFL). Methods To investigate the effect of physical activity on the association between plasma BCAA and IHL content, linear regression analyses were performed in 1983 individuals from the Netherlands Epidemiology of Obesity (NEO) stratified by physical activity frequency. Furthermore, the effect of a 12-week supervised combined aerobic resistance-exercise program on plasma BCAA, insulin sensitivity (hyperinsulinemic–euglycemic clamp), and IHL (proton-magnetic resonance spectroscopy (1H-MRS)) was investigated in seven patients with T2DM, seven individuals with NAFL and seven BMI-matched control participants (CON). Results We observed positive associations between plasma valine, isoleucine and leucine level, and IHL content (1.29 (95% CI: 1.21, 1.38), 1.52 (95% CI: 1.43, 1.61), and 1.54 (95% CI: 1.44, 1.64) times IHL, respectively, per standard deviation of plasma amino acid level). Similar associations were observed in less active versus more active individuals. Exercise training did not change plasma BCAA levels among groups, but reduced IHL content in NAFL (from 11.6 ± 3.0% pre-exercise to 8.1 ± 2.0% post exercise, p < 0.05) and CON (from 2.4 ± 0.6% pre-exercise to 1.6 ± 1.4% post exercise, p < 0.05), and improved peripheral insulin sensitivity in NAFL as well by ~23% (p < 0.05). Conclusions The association between plasma BCAA levels and IHL is not affected by physical activity level. Exercise training reduced IHL without affecting plasma BCAA levels in individuals with NAFL and CON. We conclude that exercise training-induced reduction in IHL content is not related to changes in plasma BCAA levels. Trial registration Trial registry number: NCT01317576.

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Oral administration of α-ketoglutarate enhances nitric oxide synthesis by endothelial cells and whole-body insulin sensitivity in diet-induced obese rats

Experimental Biology and Medicine ◽

10.1177/1535370219865229 ◽

2019 ◽

Vol 244 (13) ◽

pp. 1081-1088

Author(s):

Carmen D Tekwe ◽

Kang Yao ◽

Jian Lei ◽

Xilong Li ◽

Anand Gupta ◽

...

Keyword(s):

Nitric Oxide ◽

Amino Acids ◽

Endothelial Cells ◽

Insulin Sensitivity ◽

Branched Chain Amino Acids ◽

Whole Body ◽

Nitric Oxide Synthesis ◽

High Fat ◽

Obese Rats ◽

Branched Chain

Obesity is a risk factor for many chronic diseases, including hypertension, type-2 diabetes, and cancer. Interestingly, concentrations of branched-chain amino acids (BCAAs) in plasma are commonly associated with endothelial dysfunction in humans and animals with obesity. Because L-leucine inhibits nitric oxide synthesis by endothelial cells (EC), we hypothesized that dietary supplementation with AKG (a substrate for BCAA transaminase) may stimulate BCAA catabolism in the small intestine and extra-intestinal tissues, thereby reducing the circulating concentrations of BCAAs and increasing nitric oxide synthesis by endothelial cells. Beginning at four weeks of age, male Sprague-Dawley rats were fed a low-fat or a high-fat diet for 15 weeks. At 19 weeks of age, lean or obese rats continued to be fed for 12 weeks their respective diets and received drinking water containing 0 or 1% AKG ( n = 8/group). At 31 weeks of age, the rats were euthanized to obtain tissues. Food intake did not differ ( P > 0.05) between rats supplemented with or without AKG. Oral administration of AKG (250 mg/kg BW per day) reduced ( P < 0.05) concentrations of BCAAs, glucose, ammonia, and triacylglycerols in plasma, adiposity, and glutamine:fructose-6-phosphate transaminase activity in endothelial cells, and enhanced ( P < 0.05) concentrations of the reduced form of glutathione in tissues, nitric oxide synthesis by endothelial cells, and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in both low-fat and high-fat rats. AKG administration reduced ( P < 0.05) white adipose tissue weights of rats in the low-fat and high-fat groups. These novel results indicate that AKG can reduce adiposity and increase nitric oxide production by endothelial cells in diet-induced obese rats. Impact statement Obesity is associated with elevated concentrations of branched-chain amino acids, including L-leucine. L-Leucine inhibits the synthesis of nitric oxide from L-arginine by endothelial cells, contributing to impairments in angiogenesis, blood flow, and vascular dysfunction, as well as insulin resistance. Reduction in the circulating levels of branched-chain amino acids through dietary supplementation with α-ketoglutarate to promote their transamination in the small intestine and other tissues can restore nitric oxide synthesis in the vasculature and reduce the weights of white adipose tissues, thereby improving metabolic profiles and whole-body insulin sensitivity (indicated by oral glucose tolerance test) in diet-induced obese rats. Our findings provide a simple and effective nutritional means to alleviate metabolic syndrome in obese subjects. This is highly significant to combat the current obesity epidemic and associated health problems in humans worldwide.

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Abstract MP125: Branched-chain Keto Acids, Not Branched-chain Amino Acids, Impairs Cardiac Insulin Sensitivity by Disrupting Insulin Signaling in the Mitochondria

Circulation Research ◽

10.1161/res.127.suppl_1.mp125 ◽

2020 ◽

Vol 127 (Suppl_1) ◽

Author(s):

Qutuba Karwi ◽

Golam Mezbah Uddin ◽

Cory S Wagg ◽

Gary D Lopaschuk

Keyword(s):

Insulin Resistance ◽

Amino Acids ◽

Insulin Sensitivity ◽

Glucose Oxidation ◽

Branched Chain Amino Acids ◽

Mitochondrial Translocation ◽

Oxidation Rates ◽

Keto Acids ◽

Branched Chain ◽

Branched Chain Keto Acids

Alterations in branched-chain amino acids (BCAA) oxidation have been linked to the development of cardiac insulin resistance and its negative impact on cardiac function. However, it is not clear if these detrimental effects are due to the accumulation of BCAAs or branched-chain keto acids (BCKAs). It is also unknown how impaired BCAAs oxidation mediates cardiac insulin resistance. To examine this, we specifically deleted mitochondrial branched-chain aminotransferase (BCATm) in the heart to selectively increase in BCAAs and decrease in BCKAs in the heart. BCATm -/- mice had normal cardiac function compared to their wildtype littermates (WT Cre+/+ ). However, there was a significant increase in insulin-stimulated cardiac glucose oxidation rates in BCATm -/- mice, independent of any changes in glucose uptake or glycolytic rates. This enhancement in cardiac insulin sensitivity was associated with an increase in the phosphorylation of Akt and activation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. To determine the impact of reversing these events, we examined the effects of increasing cardiac BCKAs on cardiac insulin sensitivity. We perfused isolated working mice hearts with high levels of BCKAs (α;-keto-isocaproate 80 μM, α;-keto-β;-methylvalorate 100μM, α;-keto-isovalorate 70 μM), levels that can be seen during diabetes and obesity. The BCKAs completely blunted insulin-stimulated glucose oxidation rates. We also found that BCKAs abolished insulin-stimulated mitochondrial translocation of Akt, an effect which was associated with PDH deactivation. We conclude that the accumulation of BCKAs, and not BCAAs, is a major contributor to cardiac insulin resistance via abrogating mitochondrial translocation of Akt.

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