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1.
Mol Nutr Food Res ; : e1900732, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31389129

RESUMO

SCOPE: Akkermansia muciniphila (A. muciniphila) is an intestinal commensal with anti-inflammatory properties both in the intestine and other organs. The aim is to investigate the effects of oral administration of A. muciniphila on lipid metabolism, immunity, and cuff-induced neointima formation in hyperlipidemic APOE*3-Leiden (E3L).CETP mice. METHODS AND RESULTS: Hyperlipidemic male E3L.CETP mice are daily treated with 2 × 108 CFU A. muciniphila by oral gavage for 4 weeks and the effects are determined on plasma lipid levels, immune parameters, and cuff-induced neointima formation and composition. A. muciniphila administration lowers body weight and plasma total cholesterol and triglycerides levels. A. muciniphila influences the immune cell composition in mesenteric lymph nodes, as evident from an increased total B cell population, while reducing the total T cell and neutrophil populations. Importantly, A. muciniphila reduces the expression of the activation markers MHCII on dendritic cells and CD86 on B cells. A. muciniphila also increases whole blood ex vivo lipopolysaccharide-stimulated IL-10 release. Finally, although treatment with A. muciniphila improves lipid metabolism and immunity, it does not affect neointima formation or composition. CONCLUSIONS: Four weeks of treatment with A. muciniphila exerts lipid-lowering and immunomodulatory effects, which are insufficient to inhibit neointima formation in hyperlipidemic E3L.CETP mice.

2.
Sci Rep ; 9(1): 9996, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292457

RESUMO

Cholesteryl ester transfer protein (CETP) is mainly expressed by Kupffer cells in the liver. A reduction of hepatic triglyceride content (HTGC) by pioglitazone or caloric restriction is accompanied by a decrease in circulating CETP. Since GLP-1 analogues also reduce HTGC, we assessed whether liraglutide decreases CETP. Furthermore, we investigated the association between HTGC and CETP in a population-based cohort. In a placebo-controlled trial, 50 patients with type 2 diabetes were randomly assigned to treatment with liraglutide or placebo added to standard care. In this trial and in 1,611 participants of the Netherlands Epidemiology of Obesity (NEO) study, we measured HTGC and circulating CETP by proton magnetic resonance spectroscopy and ELISA, respectively. The HTGC was decreased in the liraglutide group (-6.3%; 95%CI of difference [-9.5, -3.0]) but also in the placebo group (-4.0%; 95%CI[-6.0, -2.0]), without between-group differences. CETP was not decreased by liraglutide (-0.05 µg/mL; 95%CI[-0.13, 0.04]) or placebo (-0.04 µg/mL; 95%CI[-0.12, 0.04]). No association was present between HTGC and CETP at baseline (ß: 0.002 µg/mL per %TG, 95%CI[-0.005, 0.009]) and between the changes after treatment with liraglutide (ß: 0.003 µg/mL per %TG, 95%CI[-0.010, 0.017]) or placebo (ß: 0.006 µg/mL per %TG, 95%CI[-0.012,0.024]). Also, in the cohort n o association between HTGC and CETP was present (ß: -0.001 µg/mL per SD TG, 95%CI[-0.005, 0.003]). A reduction of HTGC after treatment with liraglutide or placebo does not decrease circulating CETP. Also, no association between HTGC and CETP was present in a large cohort. These findings indicate that circulating CETP is not determined by HTGC.Clinical Trial Registration: Clinicaltrials.gov (NCT01761318).

3.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
4.
J Am Heart Assoc ; 8(9): e010810, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31017036

RESUMO

Background Identifying associations between serum metabolites and visceral adipose tissue ( VAT ) could provide novel biomarkers of VAT and insights into the pathogenesis of obesity-related diseases. We aimed to discover and replicate metabolites reflecting pathways related to VAT . Methods and Results Associations between fasting serum metabolites and VAT area (by computed tomography or magnetic resonance imaging) were assessed with cross-sectional linear regression of individual-level data from participants in MESA (Multi-Ethnic Study of Atherosclerosis; discovery, N=1103) and the NEO (Netherlands Epidemiology of Obesity) study (replication, N=2537). Untargeted 1H nuclear magnetic resonance metabolomics profiling of serum was performed in MESA, and metabolites were replicated in the NEO study using targeted 1H nuclear magnetic resonance spectroscopy. A total of 30 590 metabolomic spectral variables were evaluated. After adjustment for age, sex, race/ethnicity, socioeconomic status, smoking, physical activity, glucose/lipid-lowering medication, and body mass index, 2104 variables representing 24 nonlipid and 49 lipid/lipoprotein subclass metabolites remained significantly associated with VAT ( P=4.88×10-20-1.16×10-3). These included conventional metabolites, amino acids, acetylglycoproteins, intermediates of glucose and hepatic metabolism, organic acids, and subclasses of apolipoproteins, cholesterol, phospholipids, and triglycerides. Metabolites mapped to 31 biochemical pathways, including amino acid substrate use/metabolism and glycolysis/gluconeogenesis. In the replication cohort, acetylglycoproteins, branched-chain amino acids, lactate, glutamine (inversely), and atherogenic lipids remained associated with VAT ( P=1.90×10-35-8.46×10-7), with most associations remaining after additional adjustment for surrogates of VAT (glucose level, waist circumference, and serum triglycerides), reflecting novel independent associations. Conclusions We identified and replicated a metabolite panel associated with VAT in 2 community-based cohorts. These findings persisted after adjustment for body mass index and appear to define a metabolic signature of visceral adiposity.

5.
Artigo em Inglês | MEDLINE | ID: mdl-30448542

RESUMO

OBJECTIVE: Proteoglycan 4 (Prg4) has emerged from human association studies as a possible factor contributing to weight gain, dyslipidemia and insulin resistance. In the current study, we investigated the causal role of Prg4 in controlling lipid and glucose metabolism in mice. METHODS: Prg4 knockout (KO) mice and wild-type (WT) littermates were challenged with an obesogenic high-fat diet (45% of total calories as fat) for 16 weeks. To further stimulate the development of metabolic alterations, 10% fructose water was provided starting from week 13. RESULTS: Prg4 deficiency only tended to reduce diet-induced body weight gain, but significantly improved glucose handling (AUC: -29%; p < 0.05), which was also reflected by a tendency towards a reduced HOMA-IR score (-49%; p = 0.06 as compared to WT mice). This coincided with lower hepatic expression of glycolysis (Gck: -30%; p < 0.05) and lipogenesis (Acc: -21%; p < 0.05 and Scd1: -38%; p < 0.001) genes, which translated in significantly lower hepatic triglyceride levels (-56%; p < 0.001) in Prg4 KO mice as compared to WT mice. Prg4 KO mice likely had lower glucose utilization by skeletal muscle as compared to WT mice, judged by a significant reduction in the genes Glut4 (-29%; p < 0.01), Pfkm (-21%; p < 0.05) and Hk2 (-39%; p < 0.001). Moreover, Prg4 KO mice showed a favorable white adipose tissue phenotype with lower uptake of triglyceride-derived fatty acids (-46%; p < 0.05) and lower gene expression of inflammatory markers Cd68, Mcp1 and Tnfα (-65%, -81% and -63%, respectively; p < 0.01) than WT mice. CONCLUSION: Prg4 KO mice are protected from high-fat diet-induced glucose intolerance and fatty liver disease.

6.
Peptides ; 107: 25-31, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30076861

RESUMO

It is debated whether sex differences in adiponectin and leptin are due to sex differences in body fat distribution. In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, associations of measures of body fat and sex with serum adiponectin and leptin concentrations were examined using linear regression analysis (n = 6494, VAT: n = 2516). Sex differences were additionally adjusted for the measure of body fat that was most strongly associated with adiponectin or leptin concentrations. Median adiponectin concentrations in women and men were 10.5 mg/L (IQR, interquartile range: 7.7-13.9) and 6.1 mg/L (IQR: 4.5-8.2), mean difference 4.6 mg/L (95% CI: 4.3, 4.9). Median leptin concentrations in women and men were 19.2 µg/L (IQR: 11.5-30.0) and 7.1 µg/L (IQR: 4.6-11.1), mean difference 15.1 µg/L (95% CI: 14.4, 15.8). VAT was most strongly associated with adiponectin, total body fat percentage was most strongly associated with leptin. After adjustment for VAT, women had 3.8 mg/L (95% CI: 3.3, 4.3) higher adiponectin than men. After adjustment for total body fat percentage, leptin concentrations in women were 0.4 µg/L lower than in men (95% CI: -1.2, 2.0). One genetic variant (rs4731420) was associated with extreme leptin concentrations (>100 µg/L) in women: odds ratio 2.8 (95% CI: 1.7, 4.6). Total body fat percentage was strongly associated with leptin concentrations. Higher leptin concentrations in women than in men were completely explained by differences in total body fat percentage. Visceral fat was associated with adiponectin concentrations, and did not completely explain higher adiponectin concentrations in women than in men.

7.
Int J Obes (Lond) ; 2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30120431

RESUMO

BACKGROUND: The worldwide prevalence of obesity, a major risk factor for numerous debilitating chronic disorders, is increasing rapidly. Although a substantial amount of the variation in body mass index (BMI) is estimated to be heritable, the largest meta-analysis of genome-wide association studies (GWAS) to date explained only ~2.7% of the variation. To tackle this 'missing heritability' problem of obesity, here we focused on the contribution of DNA repeat length polymorphisms which are not detectable by GWAS. SUBJECTS AND METHODS: We determined the cytosine-adenine-guanine (CAG) repeat length in the nine known polyglutamine disease-associated genes (ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, HTT, ATN1 and AR) in two large cohorts consisting of 12,457 individuals and analyzed their association with BMI, using generalized linear mixed-effect models. RESULTS: We found a significant association between BMI and the length of CAG repeats in seven polyglutamine disease-associated genes (including ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP and AR). Importantly, these repeat variations could account for 0.75% of the total BMI variation. CONCLUSIONS: Our findings incriminate repeat polymorphisms as an important novel class of genetic risk factors of obesity and highlight the role of the brain in its pathophysiology.

8.
Methods Mol Biol ; 1730: 247-256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29363078

RESUMO

Short-chain fatty acids, the end products of fermentation of dietary fibers by the gut microbiota, have been shown to exert multiple effects on mammalian metabolism. For the analysis of short-chain fatty acids, gas chromatography-mass spectrometry is a very powerful and reliable method. Here, we describe a fast, reliable, and reproducible method for the separation and quantification of short-chain fatty acids in mouse feces, cecum content, and blood samples (i.e., plasma or serum) using gas chromatography-mass spectrometry. The short-chain fatty acids analyzed include acetic acid, propionic acid, butyric acid, valeric acid, hexanoic acid, and heptanoic acid.

9.
Methods Mol Biol ; 1730: 257-265, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29363079

RESUMO

Our body contains a wide variety of fatty acids that differ in chain length, the degree of unsaturation, and location of the double bonds. As the various fatty acids play distinct roles in health and disease, methods that can specifically determine the fatty acid profile are needed for fundamental and clinical studies. Here we describe a method for the separation and quantification of fatty acids ranging from 8 to 24 carbon chain lengths in blood samples using gas chromatography-mass spectrometry following derivatization using pentafluorobenzyl bromide. This method quantitatively monitors fatty acid composition in a manner that satisfies the requirements for comprehensiveness, sensitivity, and accuracy.

10.
Diabetes ; 66(11): 2915-2926, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28847883

RESUMO

Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL-free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL-free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Análise da Randomização Mendeliana , Adulto , Idoso , Diabetes Mellitus Tipo 2/genética , Feminino , Regulação da Expressão Gênica , Variação Genética , Genoma Humano , Humanos , Masculino , Pessoa de Meia-Idade
11.
Metabolomics ; 13(9): 104, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804275

RESUMO

BACKGROUND: The growing field of metabolomics has opened up new opportunities for prediction of type 2 diabetes (T2D) going beyond the classical biochemistry assays. OBJECTIVES: We aimed to identify markers from different pathways which represent early metabolic changes and test their predictive performance for T2D, as compared to the performance of traditional risk factors (TRF). METHODS: We analyzed 2776 participants from the Erasmus Rucphen Family study from which 1571 disease free individuals were followed up to 14-years. The targeted metabolomics measurements at baseline were performed by three different platforms using either nuclear magnetic resonance spectroscopy or mass spectrometry. We selected 24 T2D markers by using Least Absolute Shrinkage and Selection operator (LASSO) regression and tested their association to incidence of disease during follow-up. RESULTS: The 24 markers i.e. high-density, low-density and very low-density lipoprotein sub-fractions, certain triglycerides, amino acids, and small intermediate compounds predicted future T2D with an area under the curve (AUC) of 0.81. The performance of the metabolic markers compared to glucose was significantly higher among the young (age < 50 years) (0.86 vs. 0.77, p-value <0.0001), the female (0.88 vs. 0.84, p-value =0.009), and the lean (BMI < 25 kg/m2) (0.85 vs. 0.80, p-value =0.003). The full model with fasting glucose, TRFs, and metabolic markers yielded the best prediction model (AUC = 0.89). CONCLUSIONS: Our novel prediction model increases the long-term prediction performance in combination with classical measurements, brings a higher resolution over the complexity of the lipoprotein component, increasing the specificity for individuals in the low risk group.

12.
Metabolomics ; 13(5): 48, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28316560

RESUMO

INTRODUCTION: Brown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [18F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume. OBJECTIVE: We aimed to identify metabolites in serum that are associated with BAT volume and activity in men. METHODS: We assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7-26.6) years, BMI 22.1 (20.5-23.4) kg/m2) who subsequently underwent a cold-induced [18F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort. RESULTS: After correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (ß= 116 (85-148) mL, R2 = 0.81, p = 4.6 × 10-7; ß = 79 (93-119) mL, R2 = 0.57, p = 5.9 × 10-4 and ß= 91 (40-141) mL, R2 = 0.52, p = 1.0 × 10-3, respectively) as well as with BAT activity (ß= 0.20 (0.11-0.29) g/mL, R2 = 0.59, p = 1.9 × 10-4; ß = 0.15 (0.06-0.23) g/mL, R2 = 0.47, p = 2.0 × 10-3 and ß= 0.13 (0.01-0.25) g/mL, R2 = 0.28, p = 0.04, respectively). When tested in three independent replication cohorts (total n = 37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (ß= 0.15 (0.07-0.23) g/mL, R2 = 0.08, p = 4.2 × 10-4). CONCLUSIONS: LysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant.

13.
Br J Pharmacol ; 173(11): 1793-804, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26990179

RESUMO

BACKGROUND AND PURPOSE: High-fat diet consumption results in obesity and chronic low-grade inflammation in adipose tissue. Whereas glucocorticoid receptor (GR) antagonism reduces diet-induced obesity, GR agonism reduces inflammation, the combination of which would be desired in a strategy to combat the metabolic syndrome. The purpose of this study was to assess the beneficial effects of the selective GR modulator C108297 on both diet-induced weight gain and inflammation in mice and to elucidate underlying mechanisms. EXPERIMENTAL APPROACH: Ten-week-old C57Bl/6 J mice were fed a high-fat diet for 4 weeks while being treated with the selective GR modulator C108297, a full GR antagonist (RU486/mifepristone) or vehicle. KEY RESULTS: C108297 and, to a lesser extent, mifepristone reduced body weight gain and fat mass. C108297 decreased food and fructose intake and increased lipolysis in white adipose tissue (WAT) and free fatty acid levels in plasma, resulting in decreased fat cell size and increased fatty acid oxidation. Furthermore, C108297 reduced macrophage infiltration and pro-inflammatory cytokine expression in WAT, as well as in vitro LPS-stimulated TNF-α secretion in macrophage RAW 264.7 cells. However, mifepristone also increased energy expenditure, as measured by fully automatic metabolic cages, and enhanced expression of thermogenic markers in energy-combusting brown adipose tissue (BAT) but did not affect inflammation. CONCLUSIONS AND IMPLICATIONS: C108297 attenuates obesity by reducing caloric intake and increasing lipolysis and fat oxidation, and in addition attenuates inflammation. These data suggest that selective GR modulation may be a viable strategy for the reduction of diet-induced obesity and inflammation.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Inflamação/prevenção & controle , Mifepristona/farmacologia , Obesidade/prevenção & controle , Receptores de Glucocorticoides/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mifepristona/administração & dosagem , Obesidade/metabolismo , Obesidade/patologia , Células RAW 264.7
14.
Nat Commun ; 7: 11122, 2016 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-27005778

RESUMO

Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.


Assuntos
Doenças Cardiovasculares/genética , Lipoproteína(a)/genética , Metabolômica/métodos , Adulto , Idoso , Doenças Cardiovasculares/metabolismo , Mapeamento Cromossômico , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Lipoproteínas VLDL/metabolismo , Espectroscopia de Ressonância Magnética , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Triglicerídeos/metabolismo , Adulto Jovem
15.
Atherosclerosis ; 246: 267-73, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26820801

RESUMO

INTRODUCTION: Adipose tissue has been postulated to contribute substantially to the serum cholesteryl ester transfer protein (CETP) pool. However, in a recent large cohort study waist circumference was not associated with plasma CETP. The aim of the present study was to further examine associations of accurate measures of body fat and body fat distribution with serum CETP concentration. METHODS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, we examined in 6606 participants (aged 45-65 years) the associations of total body fat, body mass index (BMI), waist circumference, waist-to-hip ratio (WHR), abdominal subcutaneous (aSAT) and visceral adipose tissue (VAT) assessed with magnetic resonance imaging (n = 2547) and total and trunk fat mass assessed with dual-energy X-ray absorptiometry (n = 909) with serum CETP concentration. Regression models were adjusted for age, ethnicity, sex, dietary intake of fat and cholesterol, physical activity, smoking and menopausal status. RESULTS: Mean (SD) age was 56 (6) years and BMI 26.3 (4.4) kg/m(2), 56% were women. Mean serum CETP concentration was 2.47 µg/mL. The difference in serum CETP was 0.02 µg/mL (95%CI: -0.01, 0.05) per SD total body fat (8.7%), and 0.02 µg/mL (0.00, 0.04) per SD BMI (4.4 kg/m(2)). Similar associations around the null were observed for waist circumference, WHR, aSAT, VAT, total and trunk fat mass. CONCLUSION: In this population-based study, there was no evidence for clinically relevant associations between several measures of body fat and serum CETP concentration. This finding implies that adipose tissue does not contribute to the CETP pool in serum.


Assuntos
Adiposidade , Proteínas de Transferência de Ésteres de Colesterol/sangue , Gordura Intra-Abdominal/fisiopatologia , Obesidade/sangue , Gordura Subcutânea Abdominal/fisiopatologia , Absorciometria de Fóton , Idoso , Biomarcadores/sangue , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Obesidade/diagnóstico por imagem , Obesidade/epidemiologia , Obesidade/fisiopatologia , Estudos Prospectivos , Gordura Subcutânea Abdominal/diagnóstico por imagem , Circunferência da Cintura , Relação Cintura-Quadril
16.
Arch Biochem Biophys ; 589: 138-44, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26271442

RESUMO

Most studies examining the association between type 2 diabetes (T2D) and amino acids have focused on fasting concentrations. We hypothesized that, besides fasting concentrations, amino acid responses to a standardized meal challenge are also associated with T2D. In a cross-sectional study of 525 participants (165 newly-diagnosed T2D, 186 newly-diagnosed impaired fasting glycaemia, and 174 normal fasting glucose), we examined postprandial amino acid concentrations and the responses (defined as the concentrations and responses 150 min after a standardized meal) of fourteen amino acids in relation to T2D. T2D was associated with lower postprandial concentration of seven amino acids compared to the normal fasting glucose group (lowest effect estimate for serine: -0.54 standard deviations (SD) (95% CI: -0.77, -0.32)), and higher concentrations of phenylalanine, tryptophan, tyrosine and (iso-)leucine (highest effect estimate for (iso-)leucine: 0.44 SD (95% CI: 0.20, 0.67)). Regarding the meal responses, T2D was associated with lower responses of seven amino acids (ranging from -0.55 SD ((95% CI): -0.78, -0.33) for serine to -0.25 SD ((95% CI: -0.45, -0.02) for ornithine). We conclude that T2D is associated with postprandial concentrations of amino acids and a reduced amino acid meal response, indicating that these measures may also be potential markers of T2D.


Assuntos
Aminoácidos/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Período Pós-Prandial , Adulto , Biomarcadores/sangue , Carnitina/análogos & derivados , Carnitina/sangue , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Resistência à Insulina , Masculino , Sono
17.
Arch Biochem Biophys ; 589: 152-7, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26384768

RESUMO

During mild cold exposure, non-shivering thermogenesis increases to maintain core body temperature by increasing utilization of substrates, especially fatty acids (FA), ultimately affecting lipid-associated metabolites. We aimed to investigate whether mild cooling induces changes in other metabolites and whether this response differs between white Caucasians and South Asians, who have a disadvantageous metabolic phenotype. 12 lean male Dutch white Caucasians and 12 matched Dutch South Asians were exposed to mild cold. Before and after 100 min exposure, serum samples were collected for analysis of 163 metabolites and 27 derived parameters using high throughput metabolomics. The overall response to mild cooling between both ethnicities was not different, therefore the data were pooled. After Bonferroni correction, mild cooling significantly changed 44 of 190 (23%) metabolic parameters. Specifically, cooling increased 19 phosphatidylcholine (PC) species, only those containing very long chain FAs, and increased the total class of PC containing mono-unsaturated FAs (+12.5%). Furthermore, cooling increased 10 sphingomyelin species as well as the amino acids glutamine (+18.7%), glycine (+11.6%) and histidine (+10.6%), and decreased short-chain (C3 and C4) acylcarnitines (-17.1% and -19.4%, respectively). In conclusion, mild cooling elicits substantial effects on serum metabolites in healthy males, irrespective of white Caucasian or South Asian ethnicity.


Assuntos
Grupo com Ancestrais do Continente Asiático , Peso Corporal , Temperatura Baixa , Grupo com Ancestrais do Continente Europeu , Metabolômica , Termogênese , Adolescente , Adulto , Carnitina/análogos & derivados , Carnitina/sangue , Ácidos Graxos não Esterificados/sangue , Glicerofosfolipídeos/sangue , Humanos , Masculino , Esfingomielinas/sangue , Adulto Jovem
18.
Arch Biochem Biophys ; 589: 145-51, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26393786

RESUMO

We have previously shown that acute sleep curtailment induces insulin resistance, both in healthy individuals as well as in patients with type 1 diabetes, suggesting a causal role for sleep disturbances in pathogenesis of insulin resistance, independent of endogenous insulin production. However, the underlying mechanisms remain unclear. This study aimed to explore the metabolic pathways affected by sleep loss using targeted metabolomics in human fasting plasma samples. Healthy individuals (n = 9) and patients with type 1 diabetes (n = 7) were studied after a single night of short sleep (4 h) versus normal sleep (8 h) in a cross-over design. Strikingly, one night of short sleep specifically increased the plasma levels of acylcarnitines, essential intermediates in mitochondrial fatty acid oxidation (FAO). Specifically, short sleep increased plasma levels of tetradecenoyl-l-carnitine (C14:1) (+32%, p = 2.67*10(-4)), octadecanoyl-l-carnitine (C18:1) (+22%, p = 1.92*10(-4)) and octadecadienyl-l-carnitine (C18:2) (+27%, p = 1.32*10(-4)). Since increased plasma acylcarnitine levels could be a sign of disturbed FAO, it is possible that sleep curtailment acutely induces inefficient mitochondrial function. Our observations provide a basis for further research into the role of acylcarnitines as a potential mechanistic pathway by which sleep deprivation - even short term - causes adverse metabolic effects, such as insulin resistance.


Assuntos
Carnitina/análogos & derivados , Resistência à Insulina , Sono , Adulto , Carnitina/sangue , Jejum/sangue , Feminino , Humanos , Masculino , Metabolômica
19.
Eur J Hum Genet ; 24(1): 142-5, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26014429

RESUMO

The assignment of causative genes to noncoding variants identified in genome-wide association studies (GWASs) is challenging. We show how combination of knowledge from gene and pathway databases and chromatin interaction data leads to reinterpretation of published quantitative trait loci for blood metabolites. We describe a previously unidentified link between the rs2403254 locus, which is associated with the ratio of 3-methyl-2-oxobutanoate and alpha-hydroxyisovalerate levels, and the distal LDHA gene. We confirmed that lactate dehydrogenase can catalyze the conversion between these metabolites in vitro, suggesting that it has a role in branched-chain amino acid metabolism. Examining datasets from the ENCODE project we found evidence that the locus and LDHA promoter physically interact, showing that LDHA expression is likely under control of distal regulatory elements. Importantly, this discovery demonstrates that bioinformatic workflows for data integration can have a vital role in the interpretation of GWAS results.


Assuntos
Aminoácidos de Cadeia Ramificada/metabolismo , Cetoácidos/metabolismo , L-Lactato Desidrogenase/genética , Locos de Características Quantitativas , Valeratos/metabolismo , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , L-Lactato Desidrogenase/metabolismo , Regiões Promotoras Genéticas , Ligação Proteica
20.
Nutrients ; 7(9): 7676-90, 2015 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-26378572

RESUMO

Obese women with type 2 diabetes mellitus (T2DM) have more inflammation in their subcutaneous white adipose tissue (sWAT) than age-and-BMI similar obese women with normal glucose tolerance (NGT). We aimed to investigate whether WAT fatty acids and/or oxylipins are associated with the enhanced inflammatory state in WAT of the T2DM women. Fatty acid profiles were measured in both subcutaneous and visceral adipose tissue (vWAT) of 19 obese women with NGT and 16 age-and-BMI similar women with T2DM. Oxylipin levels were measured in sWAT of all women. Arachidonic acid (AA) and docosahexaenoic acid (DHA) percentages were higher in sWAT, but not vWAT of the T2DM women, and AA correlated positively to the gene expression of macrophage marker CD68. We found tendencies for higher oxylipin concentrations of the 5-LOX leukotrienes in sWAT of T2DM women. Gene expression of the 5-LOX leukotriene biosynthesis pathway was significantly higher in sWAT of T2DM women. In conclusion, AA and DHA content were higher in sWAT of T2DM women and AA correlated to the increased inflammatory state in sWAT. Increased AA content was accompanied by an upregulation of the 5-LOX pathway and seems to have led to an increase in the conversion of AA into proinflammatory leukotrienes in sWAT.


Assuntos
Araquidonato 5-Lipoxigenase/análise , Ácido Araquidônico/análise , Diabetes Mellitus Tipo 2/enzimologia , Ácidos Docosa-Hexaenoicos/análise , Mediadores da Inflamação/análise , Inflamação/enzimologia , Obesidade Mórbida/enzimologia , Transdução de Sinais , Gordura Subcutânea/enzimologia , Proteínas Ativadoras de 5-Lipoxigenase/genética , Adulto , Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Araquidonato 5-Lipoxigenase/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Dipeptidases/genética , Feminino , Humanos , Inflamação/diagnóstico , Gordura Intra-Abdominal/enzimologia , Leucotrienos/análise , Pessoa de Meia-Idade , Países Baixos , Obesidade Mórbida/diagnóstico , Obesidade Mórbida/genética , Obesidade Mórbida/cirurgia , Regulação para Cima
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