Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease

Karlsson, Torgny; Rask‐Andersen, Mathias; Pan, Gang; Höglund, Julia; Wadelius, Claes; Ek, Weronica E.; Johansson, Åsa

doi:10.1038/s41591-019-0563-7

Cited by 220 publications

(183 citation statements)

References 43 publications

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“…The latter might be likely due to limited statistical power since more recent genome-wide association analysis using data from UK Biobank (N > 300k) showed significant associations (p < 5e-8, retrieved via www.phenoscanner.medscl.cam.ac.uk 54 on 15/09/2019) with several refined anthropometric traits, in particular measures of fat-free mass, with the exact same missense SNV (rs4680) as has been used to annotate X-11593 as O-methylascorbate. However, neither the COMT locus nor the SNV appeared to be significant when using predicted VAT mass as an outcome in a genome-wide association study 6 . To conclude, our female-specific observation of VAT-associated levels of O-methylascorbate maybe explainable by a common genetic architecture of anthropometric traits and intermediary metabolism but further studies are needed to disentangle the relationship in more detail.…”

Section: Scientific Reports |mentioning

confidence: 86%

“…Accumulation of visceral adipose tissue (VAT) has been associated with metabolic and cardiovascular diseases (CVD) 3 and is suspected to account for sex-specific differences in disease risks 4,5 . A more recent genetic approach has established a causal link between VAT and metabolic diseases with an astonishingly sex-difference, the odds for having T2DM being about 3-fold higher in women compared to men for the same absolute increase in VAT 6 . Nevertheless, in both sexes accumulation of VAT was strongly related to a higher risk of CVD including myocardial infarction or hypertension as well as mortality [7][8][9] .…”

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confidence: 99%

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Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population

Otto

Budde

Kastenmüller

et al. 2020

Sci Rep

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obesity is one of the major risk factor for cardiovascular and metabolic diseases. A disproportional accumulation of fat at visceral (VAt) compared to subcutaneous sites (SAt) has been suspected as a key detrimental event. We used non-targeted metabolomics profiling to reveal metabolic pathways associated with higher VAt or SAt amount among subjects free of metabolic diseases to identify possible contributing metabolic pathways. The study population comprised 491 subjects [mean (standard deviation): age 44.6 yrs (13.0), body mass index 25.4 kg/m² (3.6), 60.1% females] without diabetes, hypertension, dyslipidemia, the metabolic syndrome or impaired renal function. We associated MRi-derived fat amounts with mass spectrometry-derived metabolites in plasma and urine using linear regression models adjusting for major confounders. We tested for sex-specific effects using interactions terms and performed sensitivity analyses for the influence of insulin resistance on the results. VAT and SAT were significantly associated with 155 (101 urine) and 49 (29 urine) metabolites, respectively, of which 45 (27 urine) were common to both. Major metabolic pathways were branched-chain amino acid metabolism (partially independent of insulin resistance), surrogate markers of oxidative stress and gut microbial diversity, and cortisol metabolism. We observed a novel positive association between VAt and plasma levels of the potential pharmacological agent piperine. Sex-specific effects were only a few, e.g. the female-specific association between VAT and O-methylascorbate. In brief, higher VAT was associated with an unfavorable metabolite profile in a sample of healthy, mostly non-obese individuals from the general population and only few sex-specific associations became apparent. equal amount of unknown compounds showed significant associations with VAT, including those related to either cortisol or piperine in the derived metabolic network (Fig. 3).Plasma and urine metabolites associated with SAT. Almost all association between SAT and metabolites were already described for VAT. Within each fluid, only two significant observations were unique to SAT (Figs. 1 and 2). Cortisol (inversely) and N1-methyl-2-pyridone-5-carboxamide (positively) levels in plasma as well as 3′-sialyllactose and the unknown compound X-12840 (both positively) levels in urine associated with SAT.

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Section: Scientific Reports |mentioning

confidence: 86%

mentioning

confidence: 99%

Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population

Otto

Budde

Kastenmüller

et al. 2020

Sci Rep

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“…In addition to lipid metabolism and inflammation, the difference in the role of sex hormones between men and women may be another potential mechanism. On the one hand, sex hormones can affect the distribution of body fat, and as we know, the increase of visceral fat is a risk factor for various chronic diseases (35); on the other hand, sex hormones can indirectly affect human behavior, such as dietary preference or physical activity level, which may also affect the prevalence of chronic diseases to some extent. A systematic review confirms that hyperandrogenism may increase the risk of type 2 diabetes in women while decreasing risk in men (36).…”

Section: Discussionmentioning

confidence: 99%

Women Are at a Higher Risk of Chronic Metabolic Diseases Compared to Men With Increasing Body Mass Index in China

et al. 2020

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Background: Chronic non-communicable diseases are the major causes of mortality in the world. However, few studies have investigated the association between multi-categories BMI and chronic diseases from perspective of sex stratification. This study aimed to investigate the risk of chronic diseases at different BMI levels, and to further explore whether BMI-health risk associations differ by sex. Methods: In total, 21,134 participants aged 19-65 years (60.4% men) from the Tianjin People's Hospital, Tianjin Union Medical Center-Health Management Center were recruited for this cross-sectional study. Sex-specific percentiles of BMI were calculated and divided into 11 categories according to the 2000 CDC growth charts. Health-related indicators, such as hyperglycemia, hypertension, non-alcoholic fatty liver diseases (NAFLD), hyperuricemia, etc., were used as dependent variables in this study. Statistical differences were tested by unpaired Mann-Whitney U-test and chi-squared test. Logistic regression models were used to examine the associations between BMI and health-related indicators.

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“…There is also evidence for regional differences in the adipocytes capacity to sequester fatty acids from chylomicrons (meal-derived), very-low density lipoproteins (VLDL, secreted by the liver) and from circulating free fatty acids (FFA) (Koutsari et al, 2008;McQuaid et al, 2010;Votruba et al, 2007). It has been postulated that these alterations in lipid metabolism (McQuaid et al, 2011;Spalding et al, 2017) may partly explain the apparent contribution of visceral (VAT) (Karlsson et al, 2019) and abdominal subcutaneous (ASAT) adipose tissue depots to the pathogenesis of insulin resistance and other cardiometabolic diseases, and the possible protective role of glutealfemoral adipose tissue (GFAT) in disease pathogenesis (Lee et al, 2013;McQuaid et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Proteome analysis of human visceral and subcutaneous adipocytes identifies depot-specific heterogeneity at metabolic control points

Raajendiran

Souza

Ooi

et al. 2020

Preprint

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Adipose tissue is a primary regulator of energy balance and metabolism. The distribution of adipose tissue depots is of clinical interest because the accumulation of upper-body subcutaneous (ASAT) and visceral adipose tissue (VAT) is associated with cardiometabolic diseases, whereas lower-body gluteal-femoral adipose tissue (GFAT) appears to be protective. There is heterogeneity in morphology and metabolism of adipocytes obtained from different regions of the body, but detailed knowledge of the constituent proteins in each depot is lacking. Here, we determined the human adipocyte proteome from ASAT, VAT and GFAT using high-resolution SWATH mass spectrometry proteomics. We quantified 4220 proteins in adipocytes, and 2329 proteins were expressed in all three adipose depots. Comparative analysis revealed significant differences between adipocytes from different regions (6 and 8% when comparing VAT vs. ASAT and GFAT, 3% when comparing ASAT vs. GFAT), with marked differences in proteins that regulate metabolic functions. The VAT adipocyte proteome was overrepresented with proteins of glycolysis, lipogenesis, oxidative stress and mitochondrial dysfunction. The GFAT adipocyte proteome predicted activation of PPARa, fatty acid and BCAA oxidation, enhanced TCA cycle flux and oxidative phosphorylation, which was supported by metabolomic data obtained from adipocytes from the same patient donors. Together, this proteomic analysis provides an important resource and novel insights that enhance the understanding of metabolic heterogeneity in the regional adipocytes of humans. 0.0 0.5 1.0 1.5 2.0 2.5 GPD2 GSR PRDX5 CAT SOD2 MAOA OGDH DHODH CYB5R3 CYB5A CYC1 PARK7 HSD17B10 VDAC1 VDAC2 VDAC3

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Contribution of genetics to visceral adiposity and its relation to cardiovascular and metabolic disease

Cited by 220 publications

References 43 publications

Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population

Associations between adipose tissue volume and small molecules in plasma and urine among asymptomatic subjects from the general population

Women Are at a Higher Risk of Chronic Metabolic Diseases Compared to Men With Increasing Body Mass Index in China

Proteome analysis of human visceral and subcutaneous adipocytes identifies depot-specific heterogeneity at metabolic control points

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