Levels Of Branched-chain Amino Acids Research Articles

Association of Elevated Serum Branched-chain Amino Acid Levels With Longitudinal Skeletal Muscle Loss.

Branched-chain amino acids (BCAA) are substrates for protein synthesis. Although their intake may contribute to an increase in skeletal muscle mass, elevated serum BCAA levels have been reported to be associated with insulin resistance, potentially resulting in decreased skeletal muscle mass. This study aimed to explore the association between elevated serum BCAA levels and longitudinal skeletal muscle loss. A cohort analysis was conducted, in which serum amino acids were analyzed in healthy individuals who underwent a medical health checkup at Kameoka Municipal Hospital (HOZUGAWA study), Japan. Seventy-one participants (37 men and 34 women) underwent follow-up checkups after the baseline visit. The follow-up duration was 1.2 ± .4 years. The relationship between fasting baseline serum BCAA levels and lifestyle factors, body composition, blood test results, dietary history, and changes in skeletal muscle mass was evaluated. In both men and women, serum BCAA levels were positively correlated with body weight, body mass index, skeletal muscle mass index (SMI), and serum triglycerides but inversely correlated with serum high-density lipoprotein cholesterol. In men, fasting serum BCAA levels were inversely associated with the rate of change in SMI (adjusted β = -.529, P = .006), and elevated BCAA levels were independently associated with a longitudinal decrease in skeletal muscle mass (odds ratio: 1.740; 95% confidence interval: 1.023-2.960 per 50 nmol/mL serum BCAAs increase). Increased circulating BCAAs could be an indicator of skeletal muscle loss in men.

Elevated BCAA catabolism reverses the effect of branched-chain ketoacids on glucose transport in mTORC1-dependent manner in L6 myotubes.

Plasma levels of branched-chain amino acids (BCAA) and their metabolites, branched-chain ketoacids (BCKA), are increased in insulin resistance. We previously showed that ketoisocaproic acid (KIC) suppressed insulin-stimulated glucose transport in L6 myotubes, especially in myotubes depleted of branched-chain ketoacid dehydrogenase (BCKD), the enzyme that decarboxylates BCKA. This suggests that upregulating BCKD activity might improve insulin sensitivity. We hypothesised that increasing BCAA catabolism would upregulate insulin-stimulated glucose transport and attenuate insulin resistance induced by BCKA. L6 myotubes were either depleted of BCKD kinase (BDK), the enzyme that inhibits BCKD activity, or treated with BT2, a BDK inhibitor. Myotubes were then treated with KIC (200 μM), leucine (150 μM), BCKA (200 μM), or BCAA (400 μM) and then treated with or without insulin (100 nM). BDK depletion/inhibition rescued the suppression of insulin-stimulated glucose transport by KIC/BCKA. This was consistent with the attenuation of IRS-1 (Ser612) and S6K1 (Thr389) phosphorylation but there was no effect on Akt (Ser473) phosphorylation. The effect of leucine or BCAA on these measures was not as pronounced and BT2 did not influence the effect. Induction of the mTORC1/IRS-1 (Ser612) axis abolished the attenuating effect of BT2 treatment on glucose transport in cells treated with KIC. Surprisingly, rapamycin co-treatment with BT2 and KIC further reduced glucose transport. Our data suggests that the suppression of insulin-stimulated glucose transport by KIC/BCKA in muscle is mediated by mTORC1/S6K1 signalling. This was attenuated by upregulating BCAA catabolic flux. Thus, interventions targeting BCAA metabolism may provide benefits against insulin resistance and its sequelae.

The effects of endurance physical exercise with fat-free milk intake as a therapy for metabolic syndrome and/or sarcopenia

Background: Nutrition and exercise are important factors for addressing metabolic syndrome and sarcopenia as they are related to insulin secretion. Proteins, particularly branched-chain amino acids (BCAAs), have insulinotropic effects, while exercise reduces insulin secretion. It is thus important to investigate the effects of protein intake and exercise alone and in combination to determine suitable dietary and exercise therapies for treating metabolic syndrome and sarcopenia. Methods: Eight healthy young adult female volunteers participated in a crossover trial consisting of two 5-day experiments. Days 1 and 2 comprised a body-weight-maintained adjustment period during which the participants consumed control diets (energy, 2,010 kcal; protein, 51.9 g). Days 3 to 5 comprised the treatment period during which the participants consumed experimental diets (energy, 2,010 kcal; protein 82.3 g) containing 402 kcal of fat-free milk, and either performed only normal daily activities (non-Ex) or performed normal daily activities and exercised on a bicycle with an ergometer at a target intensity of about 50% of the maximal oxygen intake, expending 402 kcal of additional energy (Ex). Total urine samples were collected during the daytime (6:45 to 18:45) and nighttime (18:45 to 6:45 the next morning). Fasting blood samples were collected early in the morning before and after the treatment period. Results: Plasma valine, leucine, and BCAA levels were significantly elevated after both the non-Ex and Ex periods. Serum insulin levels were significantly elevated only after the non-Ex period. Urinary C-peptide immunoreactivity excretion levels increased significantly during the non-Ex period, but they decreased significantly during the Ex period. After the Ex period, the serum triglyceride and remnant lipoprotein-cholesterol (RLP-C) levels were significantly decreased. Homeostatic model assessment for insulin resistance (HOMA-IR) and atherosclerosis index (AI) values were slightly, yet significantly, increased after the non-Ex period, but were unchanged after the Ex period. The degree of change (Δ) in the RLP-C level significantly and positively correlated with the Δ HOMA-IR and Δ AI.

Gas chromatography-mass spectrometry-based quantitative method using tert-butyldimethylsilyl derivatization for plasma levels of free amino acids and related metabolites in Japanese Black cattle.

The quantification of amino acid and related metabolite levels is important for evaluating amino acid metabolism and function in animals. However, a useful quantitative method is not enough. In this study, we developed and validated tert-butyldimethylsilyl derivatization method using gas chromatography-mass spectrometry to quantify plasma levels of free amino acids and related metabolites in Japanese Black cattle. Of the 51 metabolites examined, 24, including 20 amino acids, one amine, and three keto acids, could be quantified. Compared with the trimethylsilyl derivatization method using gas chromatography-mass spectrometry, which has been used for untargeted metabolomic analysis, the present method had higher analytical reliability. This method is advantageous for assessing branched-chain amino acid (BCAA) metabolism because it enables the quantification of not only BCAA levels (valine, leucine, and isoleucine) but also their bioactive metabolite keto acid levels (2-ketoisovaleric acid, 2-ketoisocaproic acid, and 2-keto-3-methylvaleric acid) in the plasma. In addition, this method can quantify the plasma levels of not only tryptophan but also its bioactive metabolites kynurenine and serotonin. These results suggest that this quantitative method has the potential to further our understanding of amino acid metabolic processes and their functions in Japanese Black cattle.

The role of branched-chain amino acids and their downstream metabolites in mediating insulin resistance.

Elevated levels of circulating branched-chain amino acids (BCAAs) and their associated metabolites have been strongly linked to insulin resistance and type 2 diabetes. Despite extensive research, the precise mechanisms linking increased BCAA levels with these conditions remain elusive. In this review, we highlight the key organs involved in maintaining BCAA homeostasis and discuss how obesity and insulin resistance disrupt the intricate interplay among these organs, thus affecting BCAA balance. Additionally, we outline recent research shedding light on the impact of tissue-specific or systemic modulation of BCAA metabolism on circulating BCAA levels, their metabolites, and insulin sensitivity, while also identifying specific knowledge gaps and areas requiring further investigation. Finally, we summarize the effects of BCAA supplementation or restriction on obesity and insulin sensitivity.

Role of Branched and Aromatic Amino Acids, Diet Inflammatory Index, and Anthropometric Indices on Mental Health.

Mental health disorders are one of the most important and increasing health problems in the youth of today's societies. Some dietary intake and body mass status are factors that affect mental health. This study aimed to investigate the relationship between the intake of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) and anthropometric and dietary inflammatory indices with mental health, including depression, anxiety, and stress. In this case-control study, the data of 138 teenage girls aged 13-18 years were collected. Three-day 24-hour food recall and standard anthropometric methods were used to calculate the dietary inflammation intake score of normal and energy-adjusted diets. Mental health disorders were diagnosed by the DASS-21 questionnaire. Statistical analysis used Student's t-test, correlation, and multiple regression were used to analyze the data based on the study's statistical requirements. Based on the findings, 59 (42%) of the girls had mental disorders, and 79 (58%) were healthy. The average weight of stressed people was significantly higher than that of healthy people, and the BMI of anxious people was significantly higher than that of nonanxious people (P < 0.05). A significant positive correlation was found between stress and weight and energy intake. Additionally, there was a significant negative correlation between BCAAs and mental health. The average intake of BCAAs was significantly lower in patients (P = 0.01). The trend analysis showed significantly lower BCAA levels among the 4th quartile of mental disorders. No significant relationship was observed between DII, AAA, and anthropometric indices. After adjustment of the results, no relationship was observed between mental health and the studied factors. BCAA might be related to mental health. Further studies in different age and sex groups are highly recommended.

Branched-chain amino acid catabolic defect promotes α-cell proliferation via activating mTOR signaling

Elevated circulating level of branched-chain amino acids (BCAAs) is closely related to the development of type 2 diabetes. However, the role of BCAA catabolism in various tissues in maintaining glucose homeostasis remains largely unknown. Pancreatic α-cells have been regarded as amino acid sensors in recent years. Therefore, we generated α-cell specific branched-chain alpha-ketoacid dehydrogenase E1α subunit (BCKDHA) knockout (BCKDHA-αKO) mice to decipher the effects of BCAA catabolism in α-cells on whole-body energy metabolism. BCKDHA-αKO mice showed normal body weight, body fat, and energy expenditure. Plasma glucagon level and glucose metabolism also remained unchanged in BCKDHA-αKO mice. Whereas, the deletion of BCKDHA led to increased α-cell number due to elevated cell proliferation in neonatal mice. In vitro, only leucine among BCAAs promoted aTC1-6 cell proliferation, which was blocked by the agonist of BCAA catabolism BT2 and the inhibitor of mTOR Rapamycin. Like Rapamycin, BT2 attenuated leucine-stimulated phosphorylation of S6 in αTC1-6 cells. Elevated phosphorylation level of S6 protein in pancreatic α-cells was also observed in BCKDHA-αKO mice. These results suggest that local accumulated leucine due to defective BCAA catabolism promotes α-cell proliferation through mTOR signaling, which is insufficient to affect glucagon secretion and whole-body glucose homeostasis.

Response of Neuropeptides to Hunger Signals in Teleost

Introduction: The perception of hunger is a complex physiological process that requires precise coordination between the central and peripheral tissues. Methods: In this study, tilapia fasted for 24 h was chosen to establish a hunger model to study the mechanism of homeostasis recovery under the joint regulation of the central nervous system (CNS) and peripheral tissues. Results: The gastric and intestinal contents of tilapia were predominantly depleted after a fasting period of 9 h and 24 h, respectively. The serum glucose level significantly decreased at the 9-h and 24-h fasting, respectively, and the glucokinase-dependent glucosensing mechanism in the liver was identified as well as the significant activation of phospho-AMPK. However, fasting for 24 h did not activate glucosensing mechanisms and AMPK signaling pathways in the hypothalamus. On the other hand, significant reductions were observed in the mRNA levels of the lipid synthesis-related genes fas and accα, and the serum triglyceride levels as well. The mRNA levels of npy, agrp, pomc, and cart in the hypothalamus fluctuated during the fasting period without significant differences. With in situ hybridization npy signals upregulated in the ventral zone of posterior periventricular nucleus after 24-h fasting, pomc signals enhanced in the lateral tuberal nucleus. Based on the serum metabolomic analysis, the levels of branched-chain amino acids, butyrate, and short-chain acylcarnitine decreased, while those of medium- and long-chain acylcarnitine increased. Conclusion: Fasting for 24 h resulted in changes in npy and pomc signals within the hypothalamus and triggered the glucosensing mechanism in the liver of tilapia. This study is beneficial for elucidating the response of neuropeptides in the CNS to the changes of nutritional factors when hungry.

Investigation of Metabolite Differences in Salted Shrimp Varieties during Fermentation.

Fermentation of salted shrimp involves the interaction of multiple factors. However, studies of the effects of shrimp variety and fermentation temperature on metabolites generated during fermentation are limited. Therefore, we investigated the effects of the shrimp variety, fermentation temperature, and fermentation period on the composition of fermented salted shrimp. Four different varieties of salted shrimp, namely, Detteugijeot (SSA), Red shrimp jeot (SSB), Chujeot (SSC), and Yukjeot (SSD), were prepared and stored at 5 and 10 °C for 5 months. The pH values ranged from 6.71 to 6.99, with SSD showing the lowest pH at both temperatures. Although total nitrogen content remained relatively constant, amino nitrogen exhibited an upward trend after 2 months and was particularly increased at 10 °C. This increase was attributed to variations in microorganisms and enzymes in the salted shrimp. Except for proline, citrulline, and ornithine, amino acid levels increased during fermentation with the highest amounts detected in SSA. Additionally, the levels of glutamic acid and branched-chain amino acids were found to be sensitive to fermentation temperature. Amino acid levels were apparently affected by species-specific metabolic pathways of the microorganisms present in each salted shrimp. Compared to the other varieties, SSB had significantly higher contents of adenosine triphosphate and hypoxanthine. A high hypoxanthine content could contribute to increased bitterness and an umami taste profile. Furthermore, the correlation between salted shrimp and metabolites was unique in SSB, whereas partial clustering was observed between the SSA and SSC.

Acute and sub-acute metabolic change in different brain regions induced by moderate blunt traumatic brain injury.

The objective of the study was to observe the effect of moderate closed-head injury on hippocampal, thalamic, and striatal tissue metabolism with time. Closed head injury is responsible for metabolic changes. These changes can be permanent or temporary, depending on the injury's impact. For the experiment, 20 rats were randomly divided into four groups, each containing five animals. Animals were subjected to injury using a modified Marmarou's weight drop device; hippocampal, thalamic, and striatal tissue samples were collected after 1 day, 3 days, and 7 days of injury. NMR spectra were acquired following sample processing. Changes in myo-inositol, creatine, glutamate, succinate, lactate, and N-acetyl aspartic acid in hippocampal tissues were observed at day 3 PI. The tyrosine level in the hippocampus was altered at day 7 PI. While thalamic and striatal tissue samples showed altered levels of branched-chain amino acids and myo-inositol at day 1PI. Taurine, gamma amino butyric acid (GABA), choline, and alpha keto-glutarate levels were found to be significantly altered in striatal tissues at days 1 and 3PI. Acetate and GABA levels were altered in the thalamus on day 1 PI. The choline level in the thalamus was found to alter at all-time points after injury. The alteration in these metabolites may be due to the alteration in their respective pathways. Neurotransmitter and energy metabolism pathways were found to be altered in all three brain regions after TBI. This study may help better understand the effect of injury on the metabolic balance of a specific brain region and recovery.

Serum branched chain amino acids: an effective indicator of diabetic kidney disease.

In recent years, there has been a growing association between elevated circulating levels of branched-chain amino acids (BCAA) and diabetes mellitus. However, the relationship between serum BCAA levels and diabetic kidney disease (DKD) remains ambiguous. This study aims to investigate serum BCAA levels in DKD patients at various stages and assess the correlation between BCAA and clinical characteristics. We enrolled patients with type 2 diabetes mellitus (T2DM) who were admitted to our hospital and categorized them into three groups based on different DKD stages: normal proteinuria, microproteinuria, and macroalbuminuria groups. Forty healthy volunteers were included as the control group, and we measured serum BCAA concentrations using liquid chromatography-mass spectrometry (LC-MS). Subsequently, we conducted correlation and regression analyses to assess the associations between BCAA and clinical indicators. Serum BCAA levels were significantly elevated in T2DM patients compared to healthy controls. However, these levels exhibited a gradual decline with the progression of DKD. Furthermore, after adjusting for age, gender, and disease duration, we observed an independent association between serum albumin, urinary transferrin, and urinary microalbumin with BCAA. Our findings suggest a noteworthy decline in serum BCAA levels alongside the advancement of DKD. Additionally, serum BCAA exhibits an independent correlation with renal function indicators. These observations point to the possibility that serum BCAA concentrations in individuals with T2DM hold promise as a crucial predictor for both the initiation and progression of DKD.

Reducing branched-chain amino acids improves cardiac stress response in mice by decreasing histone H3K23 propionylation.

Identification of branched-chain amino acid (BCAA) oxidation enzymes in the nucleus led us to predict that they are a source of the propionyl-CoA that is utilized for histone propionylation and, thereby, regulate gene expression. To investigate the effects of BCAAs on the development of cardiac hypertrophy and failure, we applied pressure overload on the heart in mice maintained on a diet with standard levels of BCAAs (BCAA control) versus a BCAA-free diet. The former was associated with an increase in histone H3K23-propionyl (H3K23Pr) at the promoters of upregulated genes (e.g., cell signaling and extracellular matrix genes) and a decrease at the promoters of downregulated genes (e.g., electron transfer complex [ETC I-V] and metabolic genes). Intriguingly, the BCAA-free diet tempered the increases in promoter H3K23Pr, thus reducing collagen gene expression and fibrosis during cardiac hypertrophy. Conversely, the BCAA-free diet inhibited the reductions in promoter H3K23Pr and abolished the downregulation of ETC I-V subunits, enhanced mitochondrial respiration, and curbed the progression of cardiac hypertrophy. Thus, lowering the intake of BCAAs reduced pressure overload-induced changes in histone propionylation-dependent gene expression in the heart, which retarded the development of cardiomyopathy.

Branched-Chain Amino Acid Accumulation Fuels the Senescence-Associated Secretory Phenotype.

The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine play critical roles in protein synthesis and energy metabolism. Despite their widespread use as nutritional supplements, BCAAs' full effects on mammalian physiology remain uncertain due to the complexities of BCAA metabolic regulation. Here a novel mechanism linking intrinsic alterations in BCAA metabolism is identified to cellular senescence and the senescence-associated secretory phenotype (SASP), both of which contribute to organismal aging and inflammation-related diseases. Altered BCAA metabolism driving the SASP is mediated by robust activation of the BCAA transporters Solute Carrier Family 6 Members 14 and 15 as well as downregulation of the catabolic enzyme BCAA transaminase 1 during onset of cellular senescence, leading to highly elevated intracellular BCAA levels in senescent cells. This, in turn, activates the mammalian target of rapamycin complex 1 (mTORC1) to establish the full SASP program. Transgenic Drosophila models further indicate that orthologous BCAA regulators are involved in the induction of cellular senescence and age-related phenotypes in flies, suggesting evolutionary conservation of this metabolic pathway during aging. Finally, experimentally blocking BCAA accumulation attenuates the inflammatory response in a mouse senescence model, highlighting the therapeutic potential of modulating BCAA metabolism for the treatment of age-related and inflammatory diseases.

Impaired cardiac BCAA catabolism associated with impaired myocardial efficiency during exercise in a porcine model with multiple risk factors

Abstract Background Diabetes mellitus (DM), chronic kidney disease (CKD) and consumption of a high-fat diet (HFD), are well known risk factors for diastolic heart failure. We recently developed a multiple comorbidity swine model (MCS), with DM (streptozotocin), HFD and CKD (kidney embolization), and showed that 6 months of sustained hyperglycemia, hypercholesterolemia and kidney dysfunction resulted in inflammation and oxidative stress associated with coronary microvascular dysfunction and left ventricular diastolic dysfunction. Additionally, MCS animals showed impaired myocardial efficiency during exercise as demonstrated by increased myocardial oxygen consumption (Fig. A), suggesting an impairment in myocardial mitochondrial function. Purpose Here we used a combined omics (single nuclei RNA sequencing and proteomics) approach to study the molecular pathways involved in mitochondrial dysfunction. Methods 15 MCS and 10 healthy control female swine were included in the study. Proteome analysis and single nuclei RNA sequencing, was performed on frozen left ventricle myocardial samples. Results Proteome analysis of MCS hearts showed reduced expression of branched-chain amino acid (BCAA) catabolism proteins (Fig. B), most notably BCAT2, MCCC1 and MCCC2. Single nuclei RNA sequencing of a subgroup of the same animals demonstrated a downregulation of these genes specifically in cardiomyocyte subpopulations. Besides being a source of ATP, via oxidative phosphorylation in mitochondria, BCAAs, encompassing essential amino acids (leucine, valine and isoleucine), act as signaling molecules. Thus, increased BCAA levels reduce insulin sensitivity, modulate mitochondrial substrate utilization and impair mitochondrial function, resulting in increased mitochondrial production of reactive oxygen species (ROS). These findings are consistent with our data in the MCS swine indicating that impaired BCAA metabolism was found in the myocardium of animals with comorbidities and were associated with increased ROS levels (8-isoprostane 12.9±0.8 pg/mg protein in MCS vs 10.3±0.5 in healthy animals, P=0.02 by T-test) and impaired myocardial efficiency during exercise (Fig. A). Conclusion Taken together, these findings suggest an essential role of altered BCAA cardiomyocyte metabolism resulting in mitochondrial dysfunction, increased oxidative stress and subsequent alterations in the myocardial function.Fig.

Abstract 16868: Genetic Regulation of Branched-Chain Amino Acid Levels Does Not Increase Type 2 Diabetes Risk

Introduction: The branched-chain amino acids (BCAAs) valine, leucine, and isoleucine are associated with incident type 2 diabetes (T2D). Prior genetic studies have provided conflicting results as to whether the BCAAs are causally related to T2D but are limited by a small number of genetic instruments associated with BCAA levels. Hypothesis: We hypothesized that polygenic predictors that capture a broad set of genetic mechanisms regulating BCAA levels would clearly define the etiological relationship with T2D. Methods: We constructed and validated instrumental variables for each BCAA using well-powered datasets and tested their association with T2D using two-sample inverse variance weighted (IWV) Mendelian randomization (MR). Sensitivity analyses were performed to ensure the accuracy of the findings. We also tested whether instrumental variables for T2D, fasting insulin, and body mass index (BMI) were associated with BCAA levels. Finally, logistic regression was used to test whether a polygenic risk score (PRS) for T2D was associated with measured BCAA levels among 1220 participants in the Framingham offspring study (FOS) without prevalent T2D. Results: There were no significant associations with T2D for valine (beta=0.17 change in log-odds per standard deviation change in valine, [95% CI, -0.28 - 0.62], p=0.45), leucine (beta=0.19 [-0.30 - 0.68] p=0.45) or isoleucine (beta=0.02 [-0.54 - 0.59], p=0.94). In contrast, T2D was associated with each BCAA (valine: beta=0.08 per standard deviation change in levels per log-odds change in type 2 diabetes, [0.05 - 0.10], p=1.8x10 -9 ), (leucine: beta= 0.06 [0.04 - 0.09], p=4.5x10 -8 ) and isoleucine (beta= 0.06 [0.04 - 0.08], p=2.8x10 -8 ). The T2D associations were replicated in an independent population but not in a second population where T2D cases were removed. Similarly, a T2D PRS was associated with measured BCAA levels in the FOS study but not when incident T2D cases were removed. Positive associations were seen for fasting insulin and BMI, and the BCAAs by MR, and, in multivariable MR analyses, T2D and fasting insulin had independent associations with each BCAA. Conclusions: These data suggest that BCAAs are not mediators of T2D risk but may rather serve as biomarkers of T2D and higher insulin levels.

Abstract 16157: Impaired Branched Chain Amino Acid Metabolism in Porcine Right Atrial Dysfunction

Background: Right atrial (RA) dysfunction is prevalent and an early predictor of mortality in pulmonary arterial hypertension (PAH). At present, the underlying pathobiology of RA dysfunction is not well defined, and thus approaches are needed to delineate potential therapeutic pathways to hopefully improve outcomes in PAH. Methods: Surgical pulmonary artery banding induced right ventricular and right atrial dysfunction in male piglets. 6 weeks post-banding, cardiovascular magnetic resonance imaging quantified cardiac structure/function. Right atrial and ventricular tissue was subjected to quantitative proteomics and targeted metabolomics. Results: PAB piglets had decreased RA ejection fraction (RAEF) and increased RA end-systolic volume. Pathway analysis revealed proteins responsible for branched chain amino acid (BCAA) degradation, including MCEE (Methylmalonyl CoA Epimerase), DLD (Dihydrolipoamide Dehydrogenase), HIBADH (3-hydroxyisobutyrate Dehydrogenase), ACAT1 (Acetyl-CoA Acetyltransferase 1), and IVD (Isovaleryl-CoA Dehydrogenase), were reduced in PAB RAs, which was not observed in RV tissue. Targeted metabolomics analysis demonstrated BCAAs were elevated in the RA of PAB piglets and BCAA levels were strongly and inversely associated with RAEF. Conclusions: Deranged BCAA metabolism is uniquely observed in the dysfunctional RA, which offers a new therapeutic target for this important clinical problem.

Abstract 13276: Metabolic Pathways and Risk Biomarkers for Incident Heart Failure

Introduction: Metabolomic profiling provides important information about heart failure (HF) risk. Metabolites reporting on muscle fuel substrate including branched-chain amino acids (BCAAs) and ketones have been implicated in HF pathogenesis and as circulating biomarkers of risk. We sought to identify the role of these known metabolites and identify novel metabolites and related pathways associated with incident HF in a large population-based cohort. Methods: Metabolomic profiling has been performed in the UK Biobank cohort using the Nightingale NMR platform. Principal component analysis (PCA) was used for dimensionality reduction and to identify shared metabolic pathways. Cox proportional hazard models were used to test the association between each PCA factor, and of individual metabolites heavily loaded on significant factors, with time to incident HF. Results: Of n=118,021 participants with metabolomic profiling data, n=3,865 (3.3%) developed incident HF (mean [SD] follow-up: 12.5 [1.3] years). The 107 metabolite biomarkers clustered into 12 PCA factors (Table 1). Nine factors were associated with incident HF in adjusted models. Factor 5 (BCAAs, aromatic acids) was not associated with incident HF in adjusted models. However, higher levels of each individual BCAA were associated with decreased risk of incident HF, with valine as the most protective (HR 0.91 [CI 0.88-0.95], q = 3x10 -6 ). Factors 2 (large HDL) and 6 (ketones) were associated with increased risk of incident HF, while factors 4 (small HDL) and 9 (omega-3 fatty acids) were associated with decreased risk of incident HF. Conclusions: In a large population-based cohort, we found that higher baseline levels of ketones and large HDL were associated with increased risk of incident HF, while higher levels of BCAAs, small HDL, and omega-3 fatty acids were associated with decreased risk of incident HF. These results highlight known and new metabolic pathways and related circulating biomarkers of HF risk.

Abstract 12466: Targeted Quantitative Plasma Metabolomics Identifies Metabolite Signatures That Distinguish Heart Failure With Reduced and Preserved Ejection Fraction

Background: Despite recent advances, heart failure (HF) remains a high burden disease and is largely treated with a “one-size-fits-all” approach. Two phenotypes are recognized: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). To develop HF disease-specific approaches to define and guide treatment, distinguishing biomarkers are needed. Methods: We conducted quantitative, targeted LC/MS plasma metabolomics on 787 samples collected by the Penn Medicine BioBank from patients with HFrEF (n=219), HFpEF (n=357), and matched non-failing Controls (n=211). Sample collection time from last meal was not controlled. A total of 97 metabolites were analyzed, comprising 30 amino acids, 8 organic acids, and 59 acylcarnitines classified by carbon length. Results: 3-hydroxybutyrate (3-HBA) was uniquely and significantly elevated in the HFrEF group [mean +/- SEM: HFpEF, 108.7(+/-7.15); HFrEF, 148.0(+/-12.4); Control, 86.29(+/-8.01); p &lt;.0001]. The 3-HBA metabolite C4-OH butyryl-carnitine also showed a similar HFrEF-specific pattern. Consistent with previous studies, long/very-long chain acylcarnitines were elevated in the HFrEF group to a much greater extent than the HFpEF group compared to Controls. Branched-chain amino acid (BCAA) levels were not different across the groups; however, acylcarnitine species indicative of BCAA degradation, including C04 Isobutyryl, C04-DC Methylmalonyl, C04-DC Succinyl, and C05 2-Methylbutyryl, were significantly elevated in both HF groups compared to Controls. Lastly, we found that the amino acid, asymmetric dimethylarginine, which promotes endothelial dysfunction and vasoconstriction, was uniquely elevated in the HFpEF cohort [mean +/- SEM: HFpEF, 1.236(+/- .019); HFrEF, 1.105(+/- .027); Control, 1.077(+/- .022); p &lt; .0001]. Conclusions: Taken together, these results identify plasma metabolite signatures that potentially distinguish between HFrEF and HFpEF and suggest patterns of metabolic re-programming in extra-cardiac tissue in the context of heart failure. Future studies will be necessary to define the utility of these metabolites as biosignatures to help guide therapeutics and to identify the underlying physiology responsible for these observations.

Weight-loss Independent Clinical and Metabolic Biomarkers Associated with Type 2 Diabetes Remission Post-bariatric/metabolic Surgery

PurposeRemission of type 2 diabetes (T2D) can be achieved by many, but not all, people following bariatric/metabolic surgery. The mechanisms underlying T2D remission remain incompletely understood. This observational study aimed to identify novel weight-loss independent clinical, metabolic and genetic factors that associate with T2D remission using comprehensive phenotyping.Materials and MethodsTen patients without T2D remission (non-remitters) were matched to 10 patients with T2D remission (remitters) for age, sex, type of surgery, body weight, BMI, post-operative weight loss, duration from surgery and duration of T2D. Detailed body composition assessed using magnetic resonance imaging, gut hormones, serum metabolomics, insulin sensitivity, and genetic risk scores for T2D and anthropometric traits were assessed.ResultsRemitters had significantly greater β-cell function and circulating acyl ghrelin levels, but lower visceral adipose tissue (VAT): subcutaneous adipose tissue (SAT) ratio than non-remitters. Branched-chain amino acids (BCAAs) and VLDL particle size were the most discriminant metabolites between groups. A significant positive correlation between, VAT area, VAT:SAT ratio and circulating levels of BCAAs was observed, whereas a significant negative correlation between BCAAs and β-cell function was revealed.ConclusionWe highlight a potentially novel relationship between VAT and BCAAs, which may play a role in glucoregulatory control. Improvement in β-cell function, and the role ghrelin plays in its recovery, is likely another key factor influencing T2D remission post-surgery. These findings suggest that adjunctive approaches that target VAT loss and restoration of BCAA metabolism might achieve higher rates of long-term T2D remission post-surgery.Graphical

Genetic and Lifestyle-Related Factors Influencing Serum Hyper-Propionylcarnitine Concentrations and Their Association with Metabolic Syndrome and Cardiovascular Disease Risk.

The genetic and environmental determinants of serum propionylcarnitine concentrations (PC) remain largely unexplored. This study investigated the impact of genetic and environmental factors on serum propionylcarnitine levels in middle-aged and elderly participants from the Ansan/Ansung cohort of the Korean Genome and Epidemiology Study. Our goal was to understand the role of PC on the risk of metabolic syndrome (MetS) leading to cardiovascular disease, particularly concerning branched-chain amino acid (BCAA) metabolism. We analyzed participants' demographic, lifestyle, and biochemical data with and without MetS. Serum metabolite concentrations, including carnitine, acylcarnitine, and amino acid concentrations, were measured, and the components of MetS were evaluated. Genetic variants associated with low and high PC were selected using genome-wide association studies after adjusting for MetS-related parameters. Further, genetic variants and lifestyle factors that interacted with the polygenic risk score (PRS) were analyzed. Participants with MetS were older and less educated, and their alcohol intake was higher than non-MetS participants. PC was significantly associated with the MetS risk and increased the serum levels of BCAAs and other amino acids. Higher PC positively correlated with MetS components, insulin resistance, and cardiovascular risk factors. Intake of calcium, sodium, and vitamin D were inversely associated with PC, but coffee consumption was positively linked to PC. Multiple C2 And Transmembrane Domain Containing-1 (MCTP1)_rs4290997, Kinesin Family Member-7 (KIF7)_rs2350480, Coagulation Factor-II (F2)_rs2070850, Peroxisomal Biogenesis Factor-3 (PEX3)_rs223231, TBC1 Domain Family Member-22A (TBC1D22A)_rs910543, and Phospholipase A2 Group-IV-C (PLA2G4C)_rs7252136 interact with each other to have a threefold influence on PC. The PRS for the six-genetic variant model also interacted with age; the diet rich in beans, potato, and kimchi; and smoking status, influencing PC. In conclusion, elevated PC was associated with MetS and cardiovascular disease risk, suggesting their potential as disease biomarkers.