Glutamate and obesity - what is the link?

PURPOSE OF REVIEW: Many studies using metabolomics have tried to unravel the metabolic signature of obesity and understand the pathophysiology of this complex and heterogeneous disease. Circulating levels of the amino acid glutamate have been consistently associated with obesity and more specifically with measurements of abdominal fat accumulation. The purpose of this narrative review is to highlight recent studies documenting this association. RECENT FINDINGS: Circulating glutamate concentrations have been positively correlated with measurements of central fat accumulation such as waist circumference and visceral adipose tissue area. Moreover, elevated glutamate levels have been linked to a higher prevalence of type 2 diabetes, cardiovascular diseases and nonalcoholic fatty liver disease. The association with adiposity is detected in early life, and genetic predisposition does not appear as a major driver. Glutamate levels reflect in vivo synthesis rather than dietary intake. However, interventions generating metabolic improvements such as incretin receptor agonist treatment or dietary improvements may reduce plasma levels of this amino acid. SUMMARY: Recent findings confirm the consistent association between circulating glutamate and abdominal obesity and its cardiometabolic complications. The pathophysiological pathways underlying this phenomenon are still unclear. Furthermore, studies are needed to establish the usefulness of this analyte as a biomarker of abdominal obesity.

Association between Circulating Amino Acids and COVID-19 Severity.

The severity of the symptoms associated with COVID-19 is highly variable, and has been associated with circulating amino acids as a group of analytes in metabolomic studies. However, for each individual amino acid, there are discordant results among studies. The aims of the present study were: (i) to investigate the association between COVID-19-symptom severity and circulating amino-acid concentrations; and (ii) to assess the ability of circulating amino-acid levels to predict adverse outcomes (intensive-care-unit admission or hospital death). We studied a sample of 736 participants from the Biobanque Québécoise COVID-19. All participants tested positive for COVID-19, and the severity of symptoms was determined using the World-Health-Organization criteria. Circulating amino acids were measured by HPLC-MS/MS. We used logistic models to assess the association between circulating amino acids concentrations and the odds of presenting mild vs. severe or mild vs. moderate symptoms, as well as their accuracy in predicting adverse outcomes. Patients with severe COVID-19 symptoms were older on average, and they had a higher prevalence of obesity and type 2 diabetes. Out of 20 amino acids tested, 16 were significantly associated with disease severity, with phenylalanine (positively) and cysteine (inversely) showing the strongest associations. These associations remained significant after adjustment for age, sex and body mass index. Phenylalanine had a fair ability to predict the occurrence of adverse outcomes, similar to traditionally measured laboratory variables. A multivariate model including both circulating amino acids and clinical variables had a 90% accuracy at predicting adverse outcomes in this sample. In conclusion, patients presenting severe COVID-19 symptoms have an altered amino-acid profile, compared to those with mild or moderate symptoms.

Mendelian randomization prioritizes abdominal adiposity as an independent causal factor for liver fat accumulation and cardiometabolic diseases.

Background: Observational studies have linked adiposity and especially abdominal adiposity to liver fat accumulation and non-alcoholic fatty liver disease. These traits are also associated with type 2 diabetes and coronary artery disease but the causal factor(s) underlying these associations remain unexplored. Methods: We used a multivariable Mendelian randomization study design to determine whether body mass index and waist circumference were causally associated with non-alcoholic fatty liver disease using publicly available genome-wide association study summary statistics of the UK Biobank (n = 461,460) and of non-alcoholic fatty liver disease (8434 cases and 770,180 control). A multivariable Mendelian randomization study design was also used to determine the respective causal contributions of waist circumference and liver fat (n = 32,858) to type 2 diabetes and coronary artery disease. Results: Using multivariable Mendelian randomization we show that waist circumference increase non-alcoholic fatty liver disease risk even when accounting for body mass index (odd ratio per 1-standard deviation increase = 2.35 95% CI = 1.31-4.22, p = 4.2e-03), but body mass index does not increase non-alcoholic fatty liver disease risk when accounting for waist circumference (0.86 95% CI = 0.54-1.38, p = 5.4e-01). In multivariable Mendelian randomization analyses accounting for liver fat, waist circumference remains strongly associated with both type 2 diabetes (3.27 95% CI = 2.89-3.69, p = 3.8e-80) and coronary artery disease (1.66 95% CI = 1.54-1.8, p = 3.4e-37). Conclusions: These results identify waist circumference as a strong, independent, and causal contributor to non-alcoholic fatty liver disease, type 2 diabetes and coronary artery disease, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases.

Large-scale analysis of circulating glutamate and adipose gene expression in relation to abdominal obesity.

Circulating levels of the amino acid glutamate are associated with central fat accumulation, yet the pathophysiology of this relationship remains unknown. We aimed to (i) refine and validate the association between circulating glutamate and abdominal obesity in a large twin cohort, and (ii) investigate whether transcriptomic profiles in adipose tissue could provide insight into the biological mechanisms underlying the association. First, in a cohort of 4665 individuals from the TwinsUK resource, we identified individuals with abdominal obesity and compared prevalence of the latter across circulating glutamate quintiles. Second, we used transcriptomic signatures generated from adipose tissue, both subcutaneous and visceral, to investigate associations with circulating glutamate levels. Individuals in the top circulating glutamate quintile had a sevenfold higher prevalence of abdominal obesity compared to those in the bottom quintile. The adipose tissue transcriptomic analyses identified GLUL, encoding Glutamate-Ammonia Ligase, as being associated with circulating glutamate and abdominal obesity, with pronounced signatures in the visceral depot. In conclusion, circulating glutamate is positively associated with the prevalence of abdominal obesity which relates to dysregulated GLUL expression specifically in visceral adipose tissue.

Mendelian Randomization Analysis Identifies Blood Tyrosine Levels as a Biomarker of Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is a complex disease associated with premature mortality. Its diagnosis is challenging, and the identification of biomarkers causally influenced by NAFLD may be clinically useful. We aimed at identifying blood metabolites causally impacted by NAFLD using two-sample Mendelian randomization (MR) with validation in a population-based biobank. Our instrument for genetically predicted NAFLD included all independent genetic variants from a recent genome-wide association study. The outcomes included 123 blood metabolites from 24,925 individuals. After correction for multiple testing, a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites was identified. This association was consistent across MR methods and was robust to outliers and pleiotropy. In observational analyses performed in the Estonian Biobank (10,809 individuals including 359 patients with NAFLD), after multivariable adjustment, tyrosine levels were positively associated with the presence of NAFLD (odds ratio per 1 SD increment = 1.23 [95% confidence interval = 1.12-1.36], p = 2.19 × 10-5). In a small proof-of-concept study on bariatric surgery patients, blood tyrosine levels were higher in patients with NAFLD than without. This study revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting it may represent a new biomarker of NAFLD.

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

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.

Circulating glutamate concentration as a biomarker of visceral obesity and associated metabolic alterations.

BACKGROUND: Visceral adipose tissue (VAT) area is a strong predictor of obesity-related cardiometabolic alterations, but its measurement is costly, time consuming and, in some cases, involves radiation exposure. Glutamate, a by-product of branched-chain-amino-acid (BCAA) catabolism, has been shown to be increased in visceral obese individuals. In this follow-up data analysis, we aimed to investigate the ability of plasma glutamate to identify individuals with visceral obesity and concomitant metabolic alterations. METHODS: Measurements of adiposity, targeted blood metabolomics and cardiometabolic risk factors were performed in 59 healthy middle-aged women. Visceral and subcutaneous adipose tissue areas were measured by computed tomography (CT) whereas body fat and lean mass were assessed by dual-energy x-ray absorptiometry (DEXA). RESULTS: The univariate Pearson correlation coefficient between glutamate and VAT area was r = 0.46 (p < 0.001) and it was r = 0.36 (p = 0.006) when adjusted for total body fat mass. Glutamate allowed to identify individuals with VAT areas ≥100 cm2 (ROC_AUC: 0.78, 95% CI: 0.66-0.91) and VAT ≥130 cm2 (ROC_AUC: 0.71, 95% CI: 0.56-0.87). The optimal glutamate concentration threshold determined from the ROC curve (glutamate ≥34.6 µmol/L) had a greater sensitivity than the metabolic syndrome (MetS) and the hypertriglyceridemic waist (HTW) phenotype to identify individuals with VAT ≥100 cm2 (83% for glutamate vs 52% for the MetS and 35% for the HTW). Variance analysis showed that women with a high circulating glutamate level (≥34.6 µmol/L) had an altered metabolic profile, particularly regarding total triglyceride levels and the amount of triglycerides and cholesterol in very-low-density lipoproteins (all p < 0.01). CONCLUSION: Circulating glutamate is strongly associated with VAT area and may represent a potential screening tool for visceral obesity and alterations of the metabolic profile.

Androgens and the Regulation of Adiposity and Body Fat Distribution in Humans.

The sexual dimorphism in human body fat distribution suggests a causal role for sex hormones. This is of particular importance when considering the role of excess visceral adipose tissue accumulation as a critical determinant of obesity-related cardiometabolic alterations. Scientific literature on the modulation of body fat distribution by androgens in humans is abundant, remarkably inconsistent and difficult to summarize. We reviewed relevant literature on this topic, with a particular emphasis on androgen replacement, androgen effects on selected parameters of adipose tissue function and adipose tissue steroid-converting enzymes. In men, low androgenic status mostly reflected by reduced total testosterone is a frequent feature of visceral obesity and the metabolic syndrome. Regarding testosterone therapy, however, studies must be appreciated in the context of current controversies on their cardiovascular effects. Analyses of available studies suggest that decreases in waist circumference in response to testosterone are more likely observed in men with low levels of testosterone and high BMI at study onset. In women with androgen excess, higher testosterone and free testosterone levels are fairly consistent predictors of increased abdominal and/or visceral adipose tissue accumulation, which is not the case in nonhyperandrogenic women. Regarding mechanisms, androgens decrease adipogenesis and markers of lipid storage in vitro in men and women. Evidence also suggest that local steroid transformations by adipose tissue steroid-converting enzymes expressed in a depot-specific fashion may play a role in androgen-mediated modulation of body fat distribution. Accumulating evidence shows that androgens are critical modulators of body fat distribution in both men and women. © 2018 American Physiological Society. Compr Physiol 8:1253-1290, 2018.