Circulating glutamate level as a potential biomarker for abdominal obesity and metabolic risk

doi:10.1016/j.numecd.2019.08.015

Nutrition, Metabolism and Cardiovascular Diseases

Volume 29, Issue 12, December 2019, Pages 1353-1360

https://doi.org/10.1016/j.numecd.2019.08.015 Get rights and content

Highlights

•
Glutamate is a by-product of the catabolism of branched-chain amino acids.
•
Circulating glutamate level is associated with waist circumference, in both sexes.
•
It is a potential screening tool for abdominal obesity and metabolic dysfunction.

Abstract

Background and aim

Circulating level of glutamate, a by-product of the catabolism of branched-chain amino acids, has been positively correlated with visceral adipose tissue accumulation and waist circumference (WC). The aim of the present study was to assess the potential of using glutamate level to identify individuals with abdominal obesity and a high cardiometabolic risk.

Methods and results

The study sample included 99 men and 99 women. Fasting serum glutamate was measured using the Biocrates p180 kit. Anthropometric and metabolic variables were used to identify individuals with abdominal obesity (WC ≥ 95 cm in both sexes), the hypertriglyceridemic waist (HTW) phenotype and the metabolic syndrome (MetS). Mean (±SD) age was 34.1 ± 10.1 years, mean BMI was 29.0 ± 6.2 kg/m² and mean WC was 92.7 ± 16.5 cm. Glutamate was strongly correlated with WC (r = 0.66 for men; r = 0.76 for women, both p < 0.0001) and multiple markers of metabolic dysfunction, particularly fasting triglyceride level (r = 0.59 for men; r = 0.57 for women, both p < 0.0001), HDL-cholesterol level (r = −0.45, p < 0.0001 in both sexes) and the HOMA-IR index (r = 0.65 for men; r = 0.60 for women, both p < 0.0001). Logistic regressions showed that glutamate had an excellent accuracy to identify individuals with abdominal obesity (ROC_AUC: 0.90 for both sexes), a good accuracy to identify those with the HTW phenotype (ROC_AUC: 0.82 for men; 0.85 for women) and fair-to-good accuracy for the MetS (ROC_AUC: 0.78 for men; 0.89 for women).

Conclusion

Glutamate level may represent an interesting potential biomarker of abdominal obesity and metabolic risk.

Graphical abstract

Introduction

Obesity, which is defined as abnormal or excessive fat accumulation, is associated with an increased prevalence of cardiovascular diseases, diabetes and some cancers [1]. One of the main determinants of metabolic health is the amount of fat accumulated around organs of the abdominal cavity, known as visceral adipose tissue (VAT) [2]. Direct quantification of VAT accumulation requires imaging methods, which are expensive, time consuming and, in some cases, involve radiation. Therefore, anthropometric measurements are often used as surrogates of VAT, the most common being the waist circumference (WC) [2].

In recent years, the 3 branched-chain amino acids (BCAAs, namely leucine, isoleucine and valine) have been extensively studied for their implication in obesity and concomitant metabolic dysfunctions. Reviews of this literature are now available, notably by Newgard who summarized the current body of evidence showing that BCAAs are associated with obesity, diabetes and cardiovascular diseases, and that they are predictive of diabetes development and treatment outcomes [3].

The amino acid glutamate, a by-product of the catabolism of all 3 BCAAs, has attracted less attention, but there is growing evidence that it could also represent a promising marker of metabolic dysfunction. Its measurement is less frequent than that of the BCAAs, but most studies that did measure it yielded consistent results. Kimberly et al. investigated the metabolite profile of non-alcoholic steatohepatitis in the Framingham Heart Study (FHS) 3rd generation (n = 997) [4]. They reported that glutamate was a stronger predictor of WC than the 3 BCAAs (age and sex adjusted β = 0.28 for glutamate vs 0.18 for isoleucine, 0.16 for valine and 0.13 for leucine, all p < 0.0001). In the study of the offspring cohort from the FHS (n = 1015), Cheng and collaborators [5] reported a trend towards a positive association between glutamate and WC (age and sex adjusted r² = 0.05, p = 0.07). In the same study, Cheng et al. reported that in the Malmo Diet and Cancer cohort (n = 746), the association between glutamate and WC was significant even when adjusted for age, sex and body mass index (BMI) (r² = 0.17, p < 0.0001). Moreover, Zhao et al. showed that glutamate was positively and significantly associated with WC in a sample of 431 normoglycemic American Indians (β = 2.33, p = 0.0003 when adjusted for sex, age, relatedness, site, lifestyle and socioeconomic status; β = 2.31, p = 0.0002 when further adjusted for dietary intake and the homeostatic model assessment of insulin resistance [HOMA-IR] index) [6].

Fewer studies investigated the relationship between amino acids and VAT specifically. The first to do so was Yamakado et al., in 2012, who studied nearly 1500 Japanese participants [7]. In the univariate correlation analysis, glutamate was the amino acid most strongly associated with VAT area (r = 0.49, p-value not available). This has since been confirmed by 2 other studies: by our team in 2015 [8] and by Takashina et al., in 2016 [9]. In both cases, glutamate was the strongest correlate of VAT among all the amino acid tested (r = 0.46, p < 0.001 in Boulet et al. and r = 0.57, p < 0.05 in Takashina et al.). Furthermore, in a secondary analysis of the sample from 2015, we showed that the correlation between circulating glutamate and VAT was independent of total fat mass measured by Dual Energy X-ray Absorptiometry (r = 0.36, p = 0.006) [10].

More studies are needed before concluding on the possibility of identifying high risk individuals using amino acid levels, either individually or in combinations. In the present study, we aimed to evaluate the potential of using circulating glutamate as a biomarker of abdominal obesity and metabolic risk.

Section snippets

Study population

The original cohort from which the present sample was drawn included 664 individuals recruited between May 2004 and April 2007 in the Quebec City metropolitan area [11]. All participants were Caucasian and were between 18 and 55 years of age. Participants were invited to come to the laboratory to fill a lifestyle and demographic questionnaire. Blood samples and anthropometric measurements were taken by a nurse and a trained research assistant, respectively. A subsample of 100 obese and 100

Sample characteristics

The characteristics of the sample are shown in Table 2. Mean (±SD) age was 34.1 ± 10.1 years, mean BMI was 29.0 ± 6.2 kg/m² and mean WC was 92.7 ± 16.5 cm. Overall, 47.5% of the sample had abdominal obesity, 19.2% had the HTW phenotype and 33.0% presented the MetS. Glutamate had the lowest plasma level of all the amino acids evaluated with a mean of 42.93 ± 27.65 μmol/L (other amino acids not shown).

Although BMI did not significantly differ between sexes (p = 0.77), mean WC was significantly

Discussion

We aimed to evaluate the potential of circulating glutamate as a biomarker of abdominal obesity and metabolic risk. Among those selected, we report that glutamate was the amino acid most strongly correlated with WC and multiple markers of metabolic dysfunction, particularly total TG level, HDL-C level and the HOMA-IR index. We demonstrate that glutamate concentration used as a single variable has an excellent ability to identify individuals with abdominal obesity and a fair-to-good ability to

Disclosures

AT receives funding from Johnson & Johnson Medical Companies and Medtronic Canada for studies unrelated to this project.

MCV is Tier 1 Canada Research Chair in Genomics Applied to Nutrition and Metabolic Health.

Acknowledgements

The authors would like to express their gratitude to the participants involved in the study for their excellent collaboration. We would like to thank Marie-Eve Bouchard, Steve Amireault, Diane Drolet and Dominique Beaulieu for their collaboration to the recruitment of the participants, the study coordination and data collection.

References (24)

C.B. Newgard
Metabolomics and metabolic diseases: where do we stand?
Cell Metabol
(2017)
S. Lemieux et al.
A single threshold value of waist girth identifies normal-weight and overweight subjects with excess visceral adipose tissue
Am J Clin Nutr
(1996)
J.V. Carter et al.
ROC-ing along: evaluation and interpretation of receiver operating characteristic curves
Surgery
(2016)
H. Nagao et al.
Increased dynamics of tricarboxylic acid cycle and glutamate synthesis in obese adipose tissue: in vivo metabolic turnover analysis
J Biol Chem
(2017)
WHO
Obesity and overweight
A. Tchernof et al.
Pathophysiology of human visceral obesity: an update
Physiol Rev
(2013)
W.T. Kimberly et al.
Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis
JCI Insight
(2017)
S. Cheng et al.
Metabolite profiling identifies pathways associated with metabolic risk in humans
Circulation
(2012)
Q. Zhao et al.
Metabolic profiles of obesity in American Indians: the strong Heart family study
PLoS One
(2016)
M. Yamakado et al.
Plasma amino acid profile is associated with visceral fat accumulation in obese Japanese subjects
Clin Obes
(2012)

M.M. Boulet et al.

Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk

Am J Physiol Endocrinol Metab

(2015)

C. Takashina et al.

Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance

Nutr Metab

(2016)

Cited by (25)

Impacts of glutamate, an exercise-responsive metabolite on insulin signaling
2024, Life Sciences
Disruption of the insulin signaling pathway leads to insulin resistance (IR). IR is characterized by impaired glucose and lipid metabolism. Elevated levels of circulating glutamate are correlated with metabolic indicators and may potentially predict the onset of metabolic diseases. Glutamate receptor antagonists have significantly enhanced insulin sensitivity, and improved glucose and lipid metabolism. Exercise is a well-known strategy to combat IR. The aims of our narrative review are to summarize preclinical and clinical findings to show the correlations between circulating glutamate levels, IR and metabolic diseases, discuss the causal role of excessive glutamate in IR and metabolic disturbance, and present an overview of the exercise-induced alteration in circulating glutamate levels.
A literature search was conducted to identify studies on glutamate, insulin signaling, and exercise in the PubMed database. The search covered articles published from December 1955 to January 2024, using the search terms of “glutamate”, “glutamic acid”, “insulin signaling”, “insulin resistance”, “insulin sensitivity”, “exercise”, and “physical activity”.
Elevated levels of circulating glutamate are correlated with IR. Excessive glutamate can potentially hinder the insulin signaling pathway through various mechanisms, including the activation of ectopic lipid accumulation, inflammation, and endoplasmic reticulum stress. Glutamate can also modify mitochondrial function through Ca²⁺ and induce purine degradation mediated by AMP deaminase 2. Exercise has the potential to decrease circulating levels of glutamate, which can be attributed to accelerated glutamate catabolism and enhanced glutamate uptake.
Glutamate may act as a mediator in the exercise-induced improvement of insulin sensitivity.
Serum metabolomics profiling of improved metabolic syndrome is characterized by decreased pro-inflammatory biomarkers: A longitudinal study in Chinese male adults
2023, Nutrition Research
Metabolic syndrome (MetS) is a serious global health concern. The objective of this study is to dynamically investigate the changes of metabolic profiles and metabolites in Chinese male MetS subjects after an 18 months diet and exercise intervention. Fifty male MetS patients defined according to International Diabetes Federation 2005 guidelines were subjected to diet and exercise counseling for 18 months. Serum samples were taken at baseline, 12 months, and 18 months, respectively, for clinical evaluation and metabolomics analyses. Diet and exercise intervention for 18 months achieved significant improvements in the metabolic profiles of all participants. Nineteen subjects (38.0%) exhibited MetS remission at the end of the study. A total of 812 relative features were characterized and 61 were successfully identified. Furthermore, 17 differential metabolites were of significance at both time points (baseline-12 months, baseline-18 months) and presented nonlinear trends through time. Eight metabolites (47.1%) were predominantly converged to inflammation and oxidative stress. Pro-inflammatory biomarkers were remarkably decreased after 18 months of intervention, and prostaglandin E2, neuroprotectin D1, and taxiphyllin in combination were firstly found to demonstrate a fair discriminative power (area under curve = 0.911) to predict the improvement of MetS undergone diet and exercise intervention. The significant shift of metabolomic profiling after 18 months of lifestyle counseling provide a novel insight and reveal that earlier inflammation control may be of potential benefit in MetS management.
A novel approach to repositioning memantine for metabolic syndrome-induced steatohepatitis: Modulation of hepatic autophagy, inflammation, and fibrosis
2023, Life Sciences
This study investigated the possible hepatoprotective effects of memantine, compared to pioglitazone, in rat steatohepatitis, emphasizing its role in modulating hepatic autophagy.
Metabolic syndrome (MetS) was provoked in adult male Wistar rats by a high fructose/fat/salt regimen for eight weeks. Then, rats were administered either memantine or pioglitazone daily for 10 weeks (both at 20 mg/kg, orally). An oral glucose tolerance test (OGTT) was done at the end of the study, and serum liver enzymes, lipids, and fasting blood glucose were measured. Also, hepatic contents of inflammatory, oxidative, and autophagy markers were quantified. Additionally, histopathological examinations of general hepatic structure and glycogen content were performed.
Compared to the MetS rats, memantine normalized fasting serum insulin, Homeostatic Model Assessment (HOMA-IR), serum lipids, and liver enzymes (ALT and AST). Memantine also markedly reduced hepatic inflammatory markers; NF-κB and TNF-α. In addition, hepatic NRF2 and GSH were augmented, while hepatic MDA was reduced by memantine. Interestingly, livers of the memantine group showed elevated Beclin1 and LC3 and reduced p62 contents compared to the MetS group indicating that memantine preserved hepatic autophagy. Histopathological examination revealed that memantine ameliorated hepatic steatosis and inflammation. Pioglitazone also mitigated most of the steatohepatitis-related changes, however, memantine was more effective in most of the studied parameters.
The hepatoprotective effect of memantine against steatohepatitis is mediated, at least partly, through conserving hepatic autophagy along with anti-inflammatory, antioxidant, and anti-fibrotic effects.
Metabolomic biomarkers of the mediterranean diet in pregnant individuals: A prospective study
2023, Clinical Nutrition
Metabolomic profiling is a systematic approach to identifying biomarkers for dietary patterns. Yet, metabolomic markers for dietary patterns in pregnant individuals have not been investigated. The aim of this study was to identify plasma metabolomic markers and metabolite panels that are associated with the Mediterranean diet in pregnant individuals.
This is a prospective study of 186 pregnant individuals who had both dietary intake and metabolomic profiles measured from the Fetal Growth Studies-Singletons cohort. Dietary intakes during the peri-conception/1st trimester and the second trimester were accessed at 8–13 and 16–22 weeks of gestation, respectively. Adherence to the Mediterranean diet was measured by the alternate Mediterranean Diet (aMED) score. Fasting plasma samples were collected at 16–22 weeks and untargeted metabolomics profiling was performed using the mass spectrometry-based platforms. Metabolites individually or jointly associated with aMED scores were identified using linear regression and least absolute shrinkage and selection operator (LASSO) regression models with adjustment for potential confounders, respectively.
Among 459 annotated metabolites, 64 and 41 were individually associated with the aMED scores of the diet during the peri-conception/1st trimester and during the second trimester, respectively. Fourteen metabolites were associated with the Mediterranean diet in both time windows. Most Mediterranean diet-related metabolites were lipids (e.g., acylcarnitine, cholesteryl esters (CEs), linoleic acid, long-chain triglycerides (TGs), and phosphatidylcholines (PCs), amino acids, and sugar alcohols. LASSO regressions also identified a 10 metabolite-panel that were jointly associated with aMED score of the diet during the peri-conception/1st trimester (AUC: 0.74; 95% CI: 0.57, 0.91) and a 3 metabolites-panel in the 2nd trimester (AUC: 0.68; 95% CI: 0.50, 0.86).
We identified plasma metabolomic markers for the Mediterranean diet among pregnant individuals. Some of them have also been reported in previous studies among non-pregnant populations, whereas others are novel. The results from our study warrant replication in pregnant individuals by future studies.
This study was registered at ClinicalTrials.gov.
Serum metabolites associated with increased insulin resistance and low cardiorespiratory fitness in overweight adolescents
2022, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
It is a precursor of succinyl-CoA, homocysteine, creatine, and carnitine and can be obtained from food or gastrointestinal microbes. Methionine plays a crucial role in the immune system, since its catabolism leads to an increase in the production of glutathione, taurine, and other metabolites [22]. A study showed that children with obesity have lower concentrations of methionine than children with normal weight [23].
Obesity affects metabolism, increasing the risk of developing non-communicable diseases in adolescence, due to excess adipose tissue and low cardiorespiratory fitness (CRF). The metabolomics approach allows the elucidation of metabolites, which may have the concentrations altered by several factors, such as body composition (BC). We aimed to analyze the metabolomic profile of normal-weight and overweight adolescents and associate the metabolites with clinical markers related to BC, insulin resistance (IR), and CRF.
The sample was composed of 57 adolescents and divided into two groups: the normal-weight group (NWG, n = 24) and the overweight group (OWG, n = 33). They underwent blood collection and anthropometric, BC, and CRF assessment. Blood serum samples were analyzed by ¹H-NMR spectroscopy (600 MHz). The OWG presented higher values of body weight (BW), body mass index (BMI), waist circumference (WC), fasting glucose, insulin, IR, cholesterol, and percentage of fat mass (%FM) and lower levels of peak oxygen consumption ( $V$ O₂ peak) compared with the NWG. The OWG presented lower concentrations of 3-hydroxyisovalerate, glutamate, and methionine as well as higher concentrations of aspartate, asparagine, creatine, glycerol, myo-inositol, proline, pyruvate, tyrosine, and valerate compared with the NWG. The concentrations of glutamate, myo-inositol, creatine, methionine, and valerate correlated with %FM; pyruvate and valerate positively correlated with IR; and glutamate, tyrosine, and valerate negatively correlated with CRF.
Changes in the BC lead to changes in the metabolomic profile of adolescents, and the altered metabolites are associated with increased IR and low CRF. These results indicate new targets for health monitoring and prevention of cardiovascular and metabolic diseases in adolescents.
Plasma amino acid profile, a biomarker for visceral adipose tissue that can substitute for waist circumference in Japanese Americans
2021, Obesity Research and Clinical Practice
Citation Excerpt :
In 1969, Felig et al. first reported the observation of higher branched-chain amino acids (BCAA), tyrosine, phenylalanine, and decreased glycine levels in obese subjects [7]. Since then, more studies have further investigated the link between amino acid (AA) profiles and obesity [8–13]. In particular, two studies have been conducted in individuals of Japanese descent [9,10]; however, they were cross-sectional, limiting assessment of potential causal relationships.
Greater visceral fat area (VFA) is associated with cardiometabolic outcomes. We sought to identify cross-sectional and longitudinal associations between amino acid (AA) levels and VFA in Japanese-Americans.
From the cohort of 342 Japanese-American participants (51% men) in a study of diabetes risk factors who were free from diabetes, we measured levels of 20 AA by mass spectrometry, height, weight, waist circumference (WC), VFA, subcutaneous fat area by single-slice CT at the umbilicus. Using AA significantly associated with VFA in univariate analyses, we created a VFA prediction index, termed the 4A index. We compared area under receiver-operating characteristic curve (AUROC) of the 4A index to WC and an existing AA index (Yamakado et al. Clin Obes 2012) in classifying VFA at different cutoff values. We fit age-adjusted linear regression models to evaluate associations between AA levels and change in VFA over 5 years.
All 20 AA levels significantly detected VFA excess, but WC was better. The 4A index performed better than Yamakado index at classifying VFA ≥ 100 cm² (0.798, 0.807 vs. 0.677, 0.671 for men and women, p < 0.0033) and VFA ≥ sex-specific median values (0.797, 0.786 vs. 0.676, 0.629 for men and women, p < 0.0017). AA significantly associated with change in VFA over 5 years were asparagine, glutamate, glutamine, glycine, methionine, proline, threonine in men; and histidine, isoleucine, tyrosine in women (p < 0.05).
The 4A index can serve as a biomarker for VFA in Japanese-Americans and be considered for this purpose when WC is not available.

View all citing articles on Scopus

View full text

© 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Circulating glutamate level as a potential biomarker for abdominal obesity and metabolic risk

Highlights

Abstract

Background and aim

Methods and results

Conclusion

Graphical abstract

Introduction

Section snippets

Study population

Sample characteristics

Discussion

Disclosures

Acknowledgements

Cell Metabol

Am J Clin Nutr

Surgery

J Biol Chem

Obesity and overweight

Pathophysiology of human visceral obesity: an update

Physiol Rev

Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis

JCI Insight

Metabolite profiling identifies pathways associated with metabolic risk in humans

Circulation

Metabolic profiles of obesity in American Indians: the strong Heart family study

PLoS One

Plasma amino acid profile is associated with visceral fat accumulation in obese Japanese subjects

Clin Obes

Alterations of plasma metabolite profiles related to adipose tissue distribution and cardiometabolic risk

Am J Physiol Endocrinol Metab

Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance

Nutr Metab