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Non-alcoholic fatty liver disease (NAFLD) is a complex cardiometabolic disease associated with premature mortality. The diagnosis of NAFLD 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 and a cohort of patients undergoing bariatric surgery. Our instrument for genetically-predicted NAFLD (the study exposure) included all independent genetic variants (n=7 SNPs) from a recent genome-wide association study on NAFLD. The study outcomes included 123 blood lipids, lipoproteins and metabolites measured in 24,925 individuals from 10 European cohorts. After correction for multiple testing, we identified a positive effect of NAFLD on plasma tyrosine levels but not on other metabolites. The association between NAFLD and tyrosine levels was consistent across MR methods and 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 = 2.19e-05). In a sample of 138 patients undergoing bariatric surgery, compared to patients without NAFLD, blood tyrosine levels were higher in those with NAFLD, but were comparable among patients with or without non-alcoholic steatohepatitis. This analysis revealed a potentially causal effect of NAFLD on blood tyrosine levels, suggesting that blood tyrosine levels may represent a new biomarker of NAFLD.Graphical abstract

Background: Observational studies have linked obesity and especially abdominal obesity to non-alcoholic fatty liver disease (NAFLD). These traits are also associated with type 2 diabetes (T2D) and coronary artery disease (CAD) but the causal factor(s) underlying these associations remain unexplored. Multivariable Mendelian randomization (MVMR) is a method that uses multiple genetic variants associated with traits of interest to simultaneously estimate the causal effect of each of these traits on outcomes of interest. Methods: We used a MVMR study design to determine whether obesity (defined using body mass index [BMI]) and abdominal obesity (defined using waist circumference) were causally associated with NAFLD using publicly available genome-wide association study (GWAS) summary statistics of the UK Biobank (n>450,000) and a GWAS meta-analysis of NAFLD (8434 cases and 770,180 control). A MVMR study design was also used to determine the respective causal contributions of waist circumference and NAFLD to T2D and CAD using GWAS summary statistics of the DIAGRAM (74,124 cases and 824,006 controls) and CARDIoGRAMplusC4D (122,733 cases and 424,528 controls) consortia.Results: In univariable Mendelian randomization analyses, both BMI and waist circumference were associated with NAFLD. NAFLD was not associated with obesity or abdominal obesity. In MVMR analyses, waist circumference was associated with NAFLD when accounting for BMI (OR per 1-standard deviation increase = 2.35 95% CI=1.31-4.22, p=4.1e-03) and BMI was not associated with NAFLD when accounting for waist circumference (0.87 95% CI=0.54-1.38, p=5.5e-01). In MVMR analyses accounting for NAFLD, waist circumference remained strongly associated with both T2D (2.65 95% CI=2.32-3.04, p=5.7e-45) and CAD (1.49 95% CI=1.37-1.62, p=8.3e-21).Conclusions: These results identified abdominal obesity as a strong, independent and causal contributor to NAFLD, T2D and CAD, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases.

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.

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

Background and aim: Metabolomic studies have shown that circulating amino acid levels are altered in the context of obesity. The branched-chain amino acids (BCAAs, namely leucine, isoleucine and valine) have been the most studied because of their consistent positive association with adiposity and their ability to prospectively predict type 2 diabetes and cardiovascular diseases (1). Circulating glutamate has been much less investigated, but some have shown that its specific association with central fat accumulation was stronger than that of BCAAs (2). This study aimed to evaluate the relationship between circulating glutamate and abdominal obesity and the impact of genetic factors on this association. Methods: In the TwinsUK cohort, we selected individuals for whom both metabolomics and DXA trunk fat measurements were available (n=4 665). We used linear regression to assess the correlation between glutamate level and trunk fat. Those with a trunk fat mass greater than 15 kg were considered abdominally obese. We compared the odds of presenting abdominal obesity in each circulating glutamate quintile with logistic regression models. Monozygotic twin pairs discordant for trunk fat were selected to identify analyte differences driven by non-genetic factors. All analyses were also performed with BCAAs for comparison. Results: Circulating glutamate was positively and significantly associated with trunk fat (β: 0.28, 95%CI: 0.26-0.31). Individuals in the highest circulating glutamate quintile had a more than 8-fold higher risk of being characterized by abdominal obesity compared to those in the lowest quintile (OR: 8.44, 95%CI: 6.17-11.55). In the 54 monozygotic twin pairs discordant for trunk fat, the heavier twin had significantly higher glutamate level compared to the leaner co-twin (p-value: 4.05e-07). In all these analyses, the results for glutamate were more significant than with any of the BCAAs. Conclusion: There is a positive relationship between circulating glutamate and trunk fat that is partially independent of genetic background. This often-overlooked metabolite might represent an interesting biomarker of abdominal obesity. References: (1) Newgard (2017). Metabolomics and Metabolic Diseases: Where Do We Stand? Cell Metab, 25(1), 43-56, (2) Kimberly et al. (2017). Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis. JCI Insight, 2(9).

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.

Background: Various observational studies have reported that circulating levels of the amino acid glutamate was significantly associated with central fat accumulation in men and women. This is the case in the Framingham Heart Study Generation 3 for waist circumference, in the TwinsUK cohort for trunk fat and in a cohort of 1449 Japanese for visceral adipose tissue area measured by computed tomography. However, whether the association between abdominal adiposity and circulating glutamate is causal, as well as the direction of this association, is unknown. Here, we aimed to determine whether obesity and abdominal obesity were causally associated with circulating glutamate levels. Methods: We used a two-sample bi-directional inverse-variance weighted Mendelian randomization study design (IVW-MR). We derived summary statistics for our exposures and outcomes from published genome-wide association studies from the GIANT consortium (n = 681 275) and blood metabolites (n = 7 804). We identified independent genetic variants (r2 < 0.1) associated with body mass index (BMI) and waist-to-hip ratio adjusted for BMI (WHRadjBMI, p < 5x10-8) as well as circulating glutamate (p < 5x10-5). Results: We found no causal association between circulating glutamate levels and BMI (beta = 0.082, SE = 0.0413, p = 0.0471) or WHRadjBMI (beta = -0.00106, SE = 0.0401, p = 0.979). However, there was a positive effect of BMI (beta = 0.0608, SE = 0.0150, p = 5.19x10-5) and WHRadjBMI (beta = 0.0701, SE = 0.0198, p = 3.98x10-4) on circulating glutamate level. Conclusion: This Mendelian randomization analysis suggests that obesity and abdominal obesity are causally related to elevated circulating glutamate levels. Glutamate levels are not causally related to adiposity. Whether the downregulation of branched-chain amino acid catabolism in adipose tissue reported in obesity underlies this association should be explored.

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