Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: An untargeted metabolomic approach

Hanzu, Felicia A.; Vinaixa, María; Papageorgiou, Anna; Parrizas, Marcelina; Correig, X.; Delgado, Salvadora; Carmona, Francesc; Samino, Sara; Vidal, Josep; Gomis, Ramón

doi:10.1002/oby.20541

Cited by 27 publications

(25 citation statements)

References 42 publications

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“…More recently, it has been shown that obesity blunts amino acid metabolism in adipose tissue and profoundly affects BCAA catabolism. In subcutaneous and visceral adipose tissue obtained during surgery, essential amino acids, leucine, glutamine and serine and 2-ketoisocaproic acid differed significantly between obese and lean subjects [41]. In our earlier study of MZ twin pairs discordant for obesity, serum levels of insulin secretionenhancing BCAA were increased in obese male co-twins and adipose tissue transcription profiles exposed significant down-regulation of genes involved with mitochondrial BCAA catabolism [3,42] indicating that the increase in plasma BCAA levels may be due to their decreased oxidation in the peripheral tissues.…”

Section: Discussionmentioning

confidence: 91%

Abdominal obesity and circulating metabolites: A twin study approach

et al. 2016

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Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors.Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r g ) and environmental (r e ) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs. Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r g = 0.40), glycoprotein (r g = 0.37), serum triglycerides (r g = 0.36), BCAAs (r g = 0.30-0.40), HDL Keywords:Twin study Bivariate twin model 2 0 1 6 ) 1 1 Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. Genetic correlation Serum metabolites Obesity measures M E T A B O L I S M C L I N I C A L A N D E X P E R I M E N T A L 6 5 (

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Section: Discussionmentioning

confidence: 91%

Abdominal obesity and circulating metabolites: A twin study approach

et al. 2016

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“…Metabolomics based on gas chromatography techniques has been previously tested in adipose tissue from differential locations [9]. Although it is robust, this technique shows a relatively low number of potential candidates when compared with liquid chromatography coupled with high-precision mass spectrometry.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

et al. 2016

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Aims/hypothesis We aimed to investigate the potential mechanisms involved in the compromised adipogenesis of visceral (VAT) vs subcutaneous adipose tissue (SAT) using comparative metabolomics. Based on the differentially identified metabolites, we focused on the relationship between the active form of vitamin B 6 (pyridoxal 5-phosphate [PLP]), known to be generated through pyridoxal kinase (PDXK), and adipogenesis. Methods Non-targeted metabolomics analyses were performed in paired VAT and SAT (n = 14, discovery cohort). PDXK gene expression was evaluated in two validation cohorts of paired SAT and VAT samples in relation to obesity status and insulin sensitivity, and mechanistically after weight loss in vivo and in 3T3-L1 cells in vitro.Results Comparative metabolomics showed that PLP was significantly decreased in VAT vs SAT. Concordantly, PDXK mRNA levels were significantly decreased in VAT vs SAT, specifically in adipocytes. The decrease was specially marked in obese individuals. PDXK mRNA levels showed a strong association with adipogenic, lipid-droplet-related and lipogenic genes. At a functional level, systemic insulin sensitivity positively associated with PDXK expression, and surgically-induced weight loss (improving insulin sensitivity) led to increased SAT PDXK mRNA levels in parallel with adipogenic genes. In human pre-adipocytes, PDXK mRNA levels increased during adipocyte differentiation and after administration of peroxisome proliferator-activated receptor-γ agonists, and decreased under inflammatory stimuli. Mechanistic studies in 3T3-L1 cells showed that PLP administration resulted in increased adipogenic mRNA markers during early adipogenesis, whereas the PLP antagonist 4-deoxypyridoxine exerted opposite effects. Conclusions/interpretation Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.

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“…While many studies have focused on plasma metabolite alterations in obesity, insulin resistance, and type 2 diabetes, only a few studies have considered body fat distribution, other markers of cardiometabolic risk (13,44,55), and possible depot-specific alterations in BCAA-catabolizing enzymes (15,19). In addition, only one study has performed metabolomicsbased AA analysis including human visceral and subcutaneous adipose tissue from nonobese and obese individuals (13).…”

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confidence: 99%

“…In addition, only one study has performed metabolomicsbased AA analysis including human visceral and subcutaneous adipose tissue from nonobese and obese individuals (13). Thus, we attempted to identify which features of the plasma metabolite signature of obesity were related to visceral obesity and cardiometabolic risk factors and assessed possible depot-specific alterations in expression and protein levels of BCAAcatabolizing enzymes in visceral and subcutaneous adipose tissue.…”

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confidence: 99%

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

Boulet

Chevrier

Grenier-Larouche

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

117

106

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profiling of obese individuals revealed altered concentrations of many metabolites, especially branched-chain amino acids (BCAA), possibly linked to altered adipose tissue BCAA catabolism. We tested the hypothesis that some features of this metabolite signature relate closely to visceral obesity and concomitant alterations in cardiometabolic risk factors. We also postulated that alterations in BCAA-catabolizing enzymes are predominant in visceral adipose tissue. Fifty-nine women (BMI 20 -41 kg/m 2 ) undergoing gynecologic surgery were recruited and characterized for overall and regional adiposity, blood metabolite levels using targeted metabolomics, and cardiometabolic risk factors. Adipose samples (visceral and subcutaneous) were obtained and used for gene expression and Western blot analyses. Obese women had significantly higher circulating BCAA and kynurenine/tryptophan (Kyn/Trp) ratio than lean or overweight women (P Ͻ 0.01). Principal component analysis confirmed that factors related to AA and the Kyn/Trp ratio were positively associated with BMI, fat mass, visceral or subcutaneous adipose tissue area, and subcutaneous adipocyte size (P Յ 0.05). AA-related factor was positively associated with HOMA-IR (P Յ 0.01). Factors reflecting glycerophospholipids and sphingolipids levels were mostly associated with altered blood lipid concentrations (P Յ 0.05). Glutamate level was the strongest independent predictor of visceral adipose tissue area (r ϭ 0.46, P Ͻ 0.001). Obese women had lower expression and protein levels of BCAA-catabolizing enzymes in visceral adipose tissue than overweight or lean women (P Յ 0.05). We conclude that among metabolites altered in obesity plasma concentrations of BCAA and the Kyn/Trp ratio are closely related to increased adiposity. Alterations in expression and protein levels of BCAA-catabolizing enzymes are predominant in visceral adipose tissue.

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Obesity rather than regional fat depots marks the metabolomic pattern of adipose tissue: An untargeted metabolomic approach

Cited by 27 publications

References 42 publications

Abdominal obesity and circulating metabolites: A twin study approach

Abdominal obesity and circulating metabolites: A twin study approach

Metabolomics uncovers the role of adipose tissue PDXK in adipogenesis and systemic insulin sensitivity

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

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