Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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Effects of the pure flavonoids epicatechin and quercetin on vascular function and cardiometabolic health: a randomized double-blind, placebo-controlled, crossover trial
Dower, J.I. ; Geleijnse, J.M. ; Gijsbers, L. ; Zock, P.L. ; Kromhout, D. ; Hollman, P.C.H. - \ 2015
American Journal of Clinical Nutrition 101 (2015)5. - ISSN 0002-9165 - p. 914 - 921.
homeostasis model assessment - reduces blood-pressure - flavanol-rich cocoa - insulin-resistance - dark chocolate - cardiovascular-disease - hypertensive subjects - endothelial function - plasma epicatechin - catechin contents
BACKGROUND: Prospective cohort studies showed inverse associations between the intake of flavonoid-rich foods (cocoa and tea) and cardiovascular disease (CVD). Intervention studies showed protective effects on intermediate markers of CVD. This may be due to the protective effects of the flavonoids epicatechin (in cocoa and tea) and quercetin (in tea). OBJECTIVE: We investigated the effects of supplementation of pure epicatechin and quercetin on vascular function and cardiometabolic health. DESIGN: Thirty-seven apparently healthy men and women aged 40-80 y with a systolic blood pressure (BP) between 125 and 160 mm Hg at screening were enrolled in a randomized, double-blind, placebo-controlled, crossover trial. CVD risk factors were measured before and after 4 wk of daily flavonoid supplementation. Participants received (-)-epicatechin (100 mg/d), quercetin-3-glucoside (160 mg/d), or placebo capsules for 4 wk in random order. The primary outcome was the change in flow-mediated dilation from pre- to postintervention. Secondary outcomes included other markers of CVD risk and vascular function. RESULTS: Epicatechin supplementation did not change flow-mediated dilation significantly (1.1% absolute; 95% CI: -0.1%, 2.3%; P = 0.07). Epicatechin supplementation improved fasting plasma insulin (¿ insulin: -1.46 mU/L; 95% CI: -2.74, -0.18 mU/L; P = 0.03) and insulin resistance (¿ homeostasis model assessment of insulin resistance: -0.38; 95% CI: -0.74, -0.01; P = 0.04) and had no effect on fasting plasma glucose. Epicatechin did not change BP (office BP and 24-h ambulatory BP), arterial stiffness, nitric oxide, endothelin 1, or blood lipid profile. Quercetin-3-glucoside supplementation had no effect on flow-mediated dilation, insulin resistance, or other CVD risk factors. CONCLUSIONS: Our results suggest that epicatechin may in part contribute to the cardioprotective effects of cocoa and tea by improving insulin resistance. It is unlikely that quercetin plays an important role in the cardioprotective effects of tea. This study was registered at as NCT01691404.
Peripheral blood mononuclear cells as a source to detect markers of homeostatic alterations caused by the intake of diets with an unbalanced macronutrient composition
Diaz-Rua, R. ; Keijer, J. ; Caimari, A. ; Schothorst, E.M. van; Oliver, P. ; Palou, A. - \ 2015
Journal of Nutritional Biochemistry 26 (2015)4. - ISSN 0955-2863 - p. 398 - 407.
high-fat-diet - high-protein diet - gene-expression profiles - preadipocyte factor-i - beta-casein 1-28 - insulin-resistance - oxidative stress - adipose-tissue - antigen presentation - energy homeostasis
Peripheral blood mononuclear cells (PBMC) are accessible in humans and their gene expression pattern was shown to reflect overall physiological response of the body to a specific stimulus, such as diet. We aimed to study the impact of sustained intake (4 months) of diets with an unbalanced macronutrient proportion (rich in fat or protein) administered isocalorically to a balanced control diet, as physiological stressors on PBMC whole genome gene expression in rats, to better understand the effects of these diets on metabolism and health and to identify biomarkers of nutritional imbalance. Dietary macronutrient composition (mainly increased protein content) altered PBMC gene expression, with genes involved in immune response being the most affected. Intake of a high-fat (HF) diet decreased the expression of genes related to antigen recognition/presentation, whereas the high-protein (HP) diet increased the expression of these genes and of genes involved in cytokine signaling and immune system maturation/activation. Key energy homeostasis genes (mainly related to lipid metabolism) were also affected, reflecting an adaptive response to the diets. Moreover, HF diet feeding impaired expression of genes involved in redox balance regulation. Finally, we identified a common gene expression signature of 7 genes whose expression changed in the same direction in response to the intake of both diets. These genes, individually or together, constitute a potential risk marker of diet macronutrient imbalance. In conclusion, we newly show that gene expression analysis in PBMC allows detection of diet-induced physiological deviations that distinguish from a diet with a proper and equilibrated macronutrient composition.
A weekly alternating diet between caloric restriction and medium-fat protects the liver from fatty liver development in middle-aged C57BL/6J mice
Rusli, F. ; Boekschoten, M.V. ; Zubia, A.A. ; Lute, C. ; Müller, M.R. ; Steegenga, W.T. - \ 2015
Molecular Nutrition & Food Research 59 (2015)3. - ISSN 1613-4125 - p. 533 - 543.
metabolic syndrome - insulin-resistance - small-intestine - induced obesity - adipose-tissue - life-span - disease - prevalence - population - expression
Scope : We aimed to investigate whether a novel dietary intervention consisting of an every-other-week calorie restricted diet could prevent non-alcoholic fatty liver disease (NAFLD) development induced by a medium-fat diet. Methods and results : Nine week-old male C57BL/6J mice received either a 1) control (C), 2) 30E% calorie restricted (CR), 3) medium-fat (MF; 25E% fat) or 4) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight. Conclusions : Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevent the development of NAFLD in 12-month-old male C57BL/6J mice.
Probabilistic networks of blood metabolites in healthy subjects as indicators of latent cardiovascular risk
Saccenti, E. ; Suarez Diez, M. ; Luchinat, C. ; Santucci, C. ; Tenori, L. - \ 2015
Journal of Proteome Research 14 (2015)2. - ISSN 1535-3893 - p. 1101 - 1111.
l-arginine supplementation - gene-coexpression network - insulin-resistance - metabolomic networks - disease - obesity - expression - cholesterol - association - validation
The complex nature of the mechanisms behind cardiovascular diseases prevents the detection of latent early risk conditions. Network representations are ideally suited to investigate the complex interconnections between the individual components of a biological system underlying complex diseases. Here we investigate the patterns of correlations of an array of 29 metabolites identified and quantified in the plasma of 864 healthy blood donors and use a systems biology approach to define metabolite probabilistic networks specific for low and high latent cardiovascular risk. We adapted methods based on the likelihood of correlation and methods from information theory and combined them with resampling techniques. Our results show that plasma metabolite networks can be defined that associate with latent cardiovascular disease risk. The analysis of the networks supports our previous finding of a possible association between cardiovascular risk and impaired mitochondrial activity and highlights post-translational modifications (glycosilation and oxidation) of lipoproteins as a possible target-mechanism for early detection of latent cardiovascular risk.
Oxygen restriction as challenge test reveals early high-fat-diet-induced changes in glucose and lipid metabolism
Duivenvoorde, L.P.M. ; Schothorst, E.M. van; Derous, D. ; Stelt, I. van der; Masania, J. ; Rabbani, N. ; Thornalley, P.J. ; Keijer, J. - \ 2015
Pflugers Archiv-European Journal of Physiology 467 (2015)6. - ISSN 0031-6768 - p. 1179 - 1193.
adipose-tissue - gene-expression - intermittent hypoxia - energy-expenditure - insulin-resistance - transcriptional regulation - mass-spectrometry - mice - obesity - oxidation
Challenge tests stress homeostasis and may reveal deviations in health that remain masked under unchallenged conditions. Ideally, challenge tests are non-invasive and applicable in an early phase of an animal experiment. Oxygen restriction (OxR; based on ambient, mild normobaric hypoxia) is a non-invasive challenge test that measures the flexibility to adapt metabolism. Metabolic inflexibility is one of the hallmarks of the metabolic syndrome. To test whether OxR can be used to reveal early diet-induced health effects, we exposed mice to a low-fat (LF) or high-fat (HF) diet for only 5 days. The response to OxR was assessed by calorimetric measurements, followed by analysis of gene expression in liver and epididymal white adipose tissue (eWAT) and serum markers for e.g. protein glycation and oxidation. Although HF feeding increased body weight, HF and LF mice did not differ in indirect calorimetric values under normoxic conditions and in a fasting state. Exposure to OxR; however, increased oxygen consumption and lipid oxidation in HF mice versus LF mice. Furthermore, OxR induced gluconeogenesis and an antioxidant response in the liver of HF mice, whereas it induced de novo lipogenesis and an antioxidant response in eWAT of LF mice, indicating that HF and LF mice differed in their adaptation to OxR. OxR also increased serum markers of protein glycation and oxidation in HF mice, whereas these changes were absent in LF mice. Cumulatively, OxR is a promising new method to test food products on potential beneficial effects for human health.
Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity
Bosma, M. ; Dapito, D.H. ; Drosatos-Tampakaki, Z. ; Huiping-Son, N. ; Huang, L.S. ; Kersten, A.H. ; Drosatos, K. ; Goldberg, I.J. - \ 2014
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1841 (2014)12. - ISSN 1388-1981 - p. 1648 - 1655.
hormone-sensitive lipase - activated receptor-gamma - skeletal-muscle - insulin-resistance - cardiac myocytes - transgenic mice - cell-death - lipid-metabolism - heart-failure - ppar-alpha
We used human cardiomyocyte-derived cells to create an in vitro model to study lipid metabolism and explored the effects of PPAR gamma, ACSL1 and ATGL on fatty acid-induced ER stress. Compared to oleate, palmitate treatment resulted in less intracellular accumulation of lipid droplets and more ER stress, as measured by upregulation of CHOP, ATF6 and GRP78 gene expression and phosphorylation of eukaryotic initiation factor 2a (ElF2a). Both ACSL1 and PPAR gamma adenovirus-mediated expression augmented neutral lipid accumulation and reduced palmitate-induced upregulation of ER stress markers to levels similar to those in the oleate and control treatment groups. This suggests that increased channeling of non-esterffied free fatty acids (NEFA) towards storage in the form of neutral lipids in lipid droplets protects against palmitate-induced ER stress. Overexpression of ATGL in cells incubated with oleate-containing medium increased NEFA release and stimulated expression of ER stress markers. Thus, inefficient creation of lipid droplets as well greater release of stored lipids induces ER stress. (C) 2014 Elsevier B.V. All rights reserved.
Molecular mechanisms underlying the potential antiobesity-related diseases effect of cocoa polyphenols
Ali, F. ; Ismail, A. ; Kersten, A.H. - \ 2014
Molecular Nutrition & Food Research 58 (2014)1. - ISSN 1613-4125 - p. 33 - 48.
low-density-lipoprotein - diet-induced obesity - flavanol-rich cocoa - high-fat diet - nf-kappa-b - ldl oxidative susceptibility - alpha-mediated inflammation - insulin-resistance - dark chocolate - in-vitro
Obesity and related metabolic diseases (e.g., type 2 diabetes, cardiovascular diseases, and hypertension) are the most prevailing nutrition-related issues in the world. An emerging feature of obesity is their relationship with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential dietary strategy to reduce glucose intolerance and inflammation is consumption of polyphenol-rich cocoa-like cocoa or their by-products. In vitro as well as in vivo data indicate that cocoa polyphenols (CPs) may exhibit antioxidant and anti-inflammatory properties. Polyphenols commonly found in cocoa have been reported to regulate lipid metabolism via inducing metabolic gene expression or activating transcription factors that regulate the expression of numerous genes, many of which play an important role in energy metabolism. Currently, several molecular targets (e.g., nuclear factor Kappa B, activated protein-1, peroxisome proliferator-activated receptors, liver X receptors, and adiponectin gene) have been identified, which may explain potential beneficial obesity-associated diseases effects of CPs. Further studies have been performed regarding the protective effects of CPs against metabolic diseases by suppressing transcription factors that antagonize lipid accumulation. Thus, polyphenols-rich cocoa products may diminish obesity-mediated metabolic diseases by multiple mechanisms, thereby attenuating chronic inflammation.
Transcriptomic signatures of peroxisome proliferator-activated receptor a (PPARa) in different mouse liver models identify novel aspects of its biology
Szalowska, E. ; Tesfay, H.A. ; Hijum, S.A.F.T. van; Kersten, A.H. - \ 2014
BMC Genomics 15 (2014). - ISSN 1471-2164 - 14 p.
fatty-acid transport - kupffer cells - gene-expression - microarray experiments - primary hepatocytes - insulin-resistance - rat-liver - inflammation - secretion - agonists
Background The peroxisome proliferator-activated receptor alpha (PPARa) is a ligand-activated transcription factor that regulates lipid catabolism and inflammation and is hepatocarcinogenic in rodents. It is presumed that the functions of PPARa in liver depend on cross-talk between parenchymal (hepatocytes) and non-parenchymal (Kupffer and endothelial cells) fractions as well as inter-organ interactions. In order to determine how cellular composition and inter-organ interactions influence gene expression upon pharmacological activation of PPARa, we performed a meta-analysis of transcriptomics data obtained from mouse hepatocytes (containing only the parenchymal fraction), mouse liver slices (containing both fractions), and mouse livers exposed to a PPARa agonist. The aim was to obtain a comprehensive view of common and model-specific PPARa-dependent genes and biological processes to understand the impact of cross-talk between parenchymal and non-parenchymal fractions as well as the effect of inter-organ interactions on the hepatic PPARa transcriptome. To this end we analyzed microarray data of experiments performed in mouse primary hepatocytes treated with the PPARa agonist Wy14643 for 6 or 24 h (in vitro), mouse precision cut liver slices treated with Wy14643 for 24 h (ex vivo), and livers of wild type and Ppara knockout mice treated with Wy14643 for 6 h or 5 days (in vivo). Results In all models, activation of PPARa significantly altered processes related to various aspects of lipid metabolism. In ex vivo and in vivo models, PPARa activation significantly regulated processes involved in inflammation; these processes were unaffected in hepatocytes. Only in vivo models showed significant regulation of genes involved in coagulation, carcinogenesis, as well as vesicular trafficking and extracellular matrix. Conclusions PPARa-dependent regulation of genes/processes involved in lipid metabolism is mostly independent of the presence of non-parenchymal cells or systemic factors, as it was observed in all liver models. PPARa-dependent regulation of inflammatory genes requires the presence of non-parenchymal cells, as it was observed only ex vivo and in vivo. However, the full spectrum of PPARa biology at the level of lipid metabolism, immunity, carcinogenesis, as well as novel aspects of PPARa signaling such as coagulation, vesicular trafficking and the extracellular matrix, seems to require systemic factors, as it was observed exclusively in vivo.
MAP3K8 (TPL2/COT) Affects Obesity-Induced Adipose Tissue Inflammation without Systemic Effects in Humans and in Mice
Ballak, D.B. ; Essen, P. van; Diepen, J.A. van; Jansen, H. ; Hijmans, A. ; Matsuguchi, T. ; Sparrer, H. ; Tack, C.J. ; Netea, M.G. ; Joosten, L.A. ; Stienstra, R. - \ 2014
PLoS One 9 (2014)2. - ISSN 1932-6203 - 8 p.
insulin-resistance - kinase - oncoprotein - disease - tpl-2
Chronic low-grade inflammation in adipose tissue often accompanies obesity, leading to insulin resistance and increasing the risk for metabolic diseases. MAP3K8 (TPL2/COT) is an important signal transductor and activator of pro-inflammatory pathways that has been linked to obesity-induced adipose tissue inflammation. We used human adipose tissue biopsies to study the relationship of MAP3K8 expression with markers of obesity and expression of pro-inflammatory cytokines (IL-1ß, IL-6 and IL-8). Moreover, we evaluated obesity-induced adipose tissue inflammation and insulin resistance in mice lacking MAP3K8 and WT mice on a high-fat diet (HFD) for 16 weeks. Individuals with a BMI >30 displayed a higher mRNA expression of MAP3K8 in adipose tissue compared to individuals with a normal BMI. Additionally, high mRNA expression levels of IL-1ß, IL-6 and IL-8, but not TNF -a, in human adipose tissue were associated with higher expression of MAP3K8. Moreover, high plasma SAA and CRP did not associate with increased MAP3K8 expression in adipose tissue. Similarly, no association was found for MAP3K8 expression with plasma insulin or glucose levels. Mice lacking MAP3K8 had similar bodyweight gain as WT mice, yet displayed lower mRNA expression levels of IL-1ß, IL-6 and CXCL1 in adipose tissue in response to the HFD as compared to WT animals. However, MAP3K8 deficient mice were not protected against HFD-induced adipose tissue macrophage infiltration or the development of insulin resistance. Together, the data in both human and mouse show that MAP3K8 is involved in local adipose tissue inflammation, specifically for IL-1ß and its responsive cytokines IL-6 and IL-8, but does not seem to have systemic effects on insulin resistance.
Mannose-Binding Lectin Is Required for the Effective Clearance of Apoptotic Cells by Adipose Tissue Macrophages During Obesity
Stienstra, R. ; Dijk, W. ; Beek, L. van; Jansen, H. ; Heemskerk, M. ; Houtkooper, R.H. ; Denis, S. ; Harmelen, V. van; Willems van Dijk, K. ; Tack, C.J. ; Kersten, A.H. - \ 2014
Diabetes 63 (2014)12. - ISSN 0012-1797 - p. 4143 - 4153.
insulin-resistance - cytokine secretion - hepatic steatosis - dendritic cells - deficient mice - tnf-alpha - innate - protein - inflammation - adipocytes
Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL-/- mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL-/- mice. In parallel with increased adipocyte size, MBL-/- mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity.
Differential regulation of pancreatic digestive enzymes during chronic high-fat diet-induced obesity in C57BL/6J mice
Birk, R.Z. ; Rubio-Aliaga, I. ; Boekschoten, M.V. ; Danino, H. ; Müller, M.R. ; Daniel, H. - \ 2014
British Journal of Nutrition 112 (2014)2. - ISSN 0007-1145 - p. 154 - 161.
lipase messenger-rna - 2 related proteins - exocrine pancreas - cholesterol absorption - insulin-resistance - rats - adaptation - cholecystokinin - expression - colipase
Exocrine pancreatic digestive enzymes are essential for the digestion of dietary components and are regulated by them. Chronic excess dietary high fat (HF) consumption is a contributing factor of diet-induced obesity (DIO) and associated chronic diseases and requires adaptation by the pancreas. The aim of the present study was to investigate the effects of chronic HF diet feeding on exocrine pancreatic digestive enzyme transcript levels in DIO C57BL/6J mice. C57BL/6J mice were fed diets containing either 10 or 45 % energy (E%) derived from fat for 12 weeks (n 10 mice per diet group). Pancreatic tissue and blood samples were collected at 0, 4 and 12 weeks. The expression of a panel of exocrine pancreatic digestive enzymes was analysed using quantitative RT-PCR and Western blot analysis. The HF (45 E%) diet-fed C57BL/6J mice developed obesity, hyperleptinaemia, hyperglycaemia and hyperinsulinaemia. The transcript levels of pancreatic lipase (PL), pancreatic lipase-related protein 2 (PLRP2) and pancreatic phospholipase A2 (PLA2) were initially elevated; however, they were down-regulated to basal control levels at week 12. The transcript levels of colipase were significantly affected by diet and time. The protein levels of PL and PLRP2 responded to HF diet feeding. The transcript levels of amylase and proteases were not significantly affected by diet and time. The transcript levels of specific lipases in hyperinsulinaemic, hyperleptinaemic and hyperglycaemic DIO C57BL/6J mice are down-regulated. However, these mice compensate for this by the post-transcriptional regulation of the levels of proteins that respond to dietary fat. This suggests a complex regulatory mechanism involved in the modulation of fat digestion.
Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)
Aleksandrova, K. ; Jenab, M. ; Bueno-de-Mesquita, H.B. ; Fedirko, V. ; Kaaks, R. ; Lukanova, A. ; Duijnhoven, F.J.B. van - \ 2014
European Journal of Epidemiology 29 (2014)4. - ISSN 0393-2990 - p. 261 - 275.
soluble leptin receptor - density-lipoprotein cholesterol - c-reactive protein - insulin-resistance - oxidative stress - hdl-cholesterol - multiple imputation - plasma adiponectin - binding-proteins - adipose-tissue
A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development.
The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men
Konings, E. ; Timmers, S. ; Boekschoten, M.V. ; Goossens, G.H. ; Jocken, J.W. ; Afman, L.A. ; Müller, M.R. ; Schrauwen, P. ; Mariman, E.C. ; Blaak, E.E. - \ 2014
International Journal of Obesity 38 (2014)3. - ISSN 0307-0565 - p. 470 - 473.
insulin-resistance - glucose-tolerance - adipogenesis - metabolism - health - women - mice
Polyphenolic compounds, such as resveratrol, have recently received widespread interest because of their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days (150¿mg per day), separated by a 4-week washout period in a double-blind randomized crossover design. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function.
Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet
Hoevenaars, F.P.M. ; Keijer, J. ; Herreman, L. ; Palm, I.F. ; Hegeman, M.A. ; Swarts, J.J.M. ; Schothorst, E.M. van - \ 2014
Genes & Nutrition 9 (2014). - ISSN 1555-8932 - 11 p.
nicotinamide nucleotide transhydrogenase - c57bl/6j mice - mitochondrial biogenesis - energy restriction - insulin-resistance - glucose - acid - expression - health - gene
Restriction of a high-fat diet (HFD) and a change to a low-fat diet (LFD) are two interventions that were shown to promote weight loss and improve parameters of metabolic health in obesity. Examination of the biochemical and molecular responses of white adipose tissue (WAT) to these interventions has not been performed so far. Here, male C57BL/6JOlaHsd mice, harboring an intact nicotinamide nucleotide transhydrogenase gene, were fed a purified 40 energy% HFD for 14 weeks to induce obesity. Afterward, mice were divided into three dietary groups: HFD (maintained on HFD), LFD (changed to LFD with identical ingredients), and HFD-CR (restricted to 70 % of the HFD). The effects of the interventions were examined after 5 weeks. Beneficial effects were seen for both HFD-CR and LFD (compared to HFD) regarding physiological parameters (body weight and fat mass) and metabolic parameters, including circulating insulin and leptin levels. Macrophage infiltration in WAT was reduced by both interventions, although more effectively by HFDCR. Strikingly, molecular parameters in WAT differed between HFD-CR and LFD, with increased activation of mitochondrial carbohydrate and fat metabolism in HFDCR mice. Our results confirm that restriction of the amount of dietary intake and reduction in the dietary energy content are both effective in inducing weight loss. The larger decrease in WAT inflammation and increase in mitochondrial carbohydrate metabolism may be due to a larger degree of energy restriction in HFD-CR, but could also be due to superior effectiveness of dietary restriction in weight loss strategies.
Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise
Catoire, M. ; Alex, S. ; Paraskevopulos, N. ; Mattijssen, F.B.J. ; Mensink, M.R. ; Kersten, A.H. - \ 2014
Proceedings of the National Academy of Sciences of the United States of America 111 (2014)11. - ISSN 0027-8424 - p. E1043 - E1052.
human skeletal-muscle - angiopoietin-like protein-4 - lipoprotein-lipase - adipose-tissue - insulin-resistance - postprandial triacylglycerol - endurance exercise - in-vivo - expression - receptor
Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-d, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
PPAR-alpha dependent regulation of vanin-1 mediates hepatic lipid metabolism
Diepen, J.A. van; Jansen, P.A. ; Ballak, D.B. ; Hijmans, A. ; Hooiveld, G.J.E.J. ; Rommelaere, S. ; Kersten, A.H. ; Stienstra, R. - \ 2014
Journal of Hepatology 61 (2014)2. - ISSN 0168-8278 - p. 366 - 372.
high-fat diet - gene-expression - insulin-resistance - null mice - liver - cysteamine - tissue - acids - hepatocytes - fenofibrate
Background & Aims Peroxisome proliferator-activated receptor alpha (PPARa) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARa target gene in liver, but its function in hepatic lipid metabolism is unknown. Methods We investigated the regulation of vanin-1, and total vanin activity, by PPARa in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Results Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARa activity. In addition, activation of mouse PPARa regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARa, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARa agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. Conclusions We show that hepatic vanin-1 is under extremely sensitive regulation by PPARa and that plasma vanin activity could serve as a readout of changes in PPARa activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting. Abbreviations PPAR, Peroxisome proliferator-activated receptor; RXR, Retinoid X Receptor; VNN1, vanin-1; VNN2, vanin-2; VNN3, vanin-3; WT, wild-type; BMI, body mass index; Pan-AMC, pantothenate-7-amino-4-methylcoumarin; TG, Triglycerides; TC, total cholesterol; FFA, free fatty acids; KLF15, Kruppel-like factor 15; STAT3, signal transducer and activator of transcription 3; SP1, trans-acting transcription factor 1; CBFB, core binding factor beta; XBP1, x-box binding protein 1; NAFLD, non-alcoholic fatty liver disease; Pan-PNa, pantothenate-4-nitroanilide; Abcd2, chemokine (C-C motif) ligand 17; Acadm, acyl-CoA dehydrogenase, medium chain; Acot1, acyl-CoA thioesterase 1; Acot2, acyl-CoA thioesterase 2; Acsl5, acyl-CoA synthetase long-chain family member 5; Ehhadh, enoyl-CoA hydratase/3-hydroxylacyl CoA dehydrogenase; NASH, non-alcoholic steatohepatitis (NASH)
Smoking and long-term risk of type 2 Diabetes: The EPIC-InterAct Study in European populations
The InterAct Consortium, A. ; Spijkerman, A.M.W. ; A, D.L. van der; Nilsson, P. ; Balkau, B. ; Beulens, J.W.J. ; Boeing, H. ; Feskens, E.J.M. ; Kaaks, R. - \ 2014
Diabetes Care 37 (2014)12. - ISSN 0149-5992 - p. 3164 - 3171.
kora s4/f4 cohort - middle-aged men - cigarette-smoking - insulin-resistance - physical-activity - fat distribution - active smoking - mellitus - women - glucose
OBJECTIVE The aims of this study were to investigate the association between smoking and incident type 2 diabetes, accounting for a large number of potential confounding factors, and to explore potential effect modifiers and intermediate factors. RESEARCH DESIGN AND METHODS The European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct is a prospective case-cohort study within eight European countries, including 12,403 cases of incident type 2 diabetes and a random subcohort of 16,835 individuals. After exclusion of individuals with missing data, the analyses included 10,327 cases and 13,863 subcohort individuals. Smoking status was used (never, former, current), with never smokers as the reference. Country-specific Prentice-weighted Cox regression models and random-effects meta-analysis were used to estimate hazard ratios (HRs) for type 2 diabetes. RESULTS In men, the HRs (95% CI) of type 2 diabetes were 1.40 (1.26, 1.55) for former smokers and 1.43 (1.27, 1.61) for current smokers, independent of age, education, center, physical activity, and alcohol, coffee, and meat consumption. In women, associations were weaker, with HRs (95% CI) of 1.18 (1.07, 1.30) and 1.13 (1.03, 1.25) for former and current smokers, respectively. There was some evidence of effect modification by BMI. The association tended to be slightly stronger in normal weight men compared with those with overall adiposity. CONCLUSIONS Former and current smoking was associated with a higher risk of incident type 2 diabetes compared with never smoking in men and women, independent of educational level, physical activity, alcohol consumption, and diet. Smoking may be regarded as a modifiable risk factor for type 2 diabetes, and smoking cessation should be encouraged for diabetes prevention.
Identification of the human exercise-induced myokines using secretome analysis
Catoire, M. ; Mensink, M.R. ; Kalkhoven, E. ; Schrauwen, P. ; Kersten, A.H. - \ 2014
Physiological genomics 46 (2014)2014. - ISSN 1094-8341 - p. 256 - 267.
human skeletal-muscle - kappa-b activity - plasma interleukin-6 - insulin-resistance - endocrine organ - macrophages - expression - release - cells - mice
Endurance exercise is associated with significant improvements in cardio-metabolic risk parameters. A role for myokines has been hypothesized, yet limited information is available about myokines induced by acute endurance exercise in humans. Therefore, the aim of the study was to identify novel exercise-induced myokines in humans. To this end, we carried out a 1 h one-legged acute endurance exercise intervention in 12 male subjects and a 12 wk exercise training intervention in 18 male subjects. Muscle biopsies were taken before and after acute exercise or exercise training and were subjected to microarray-based analysis of secreted proteins (secretome). For acute exercise, secretome analysis resulted in a list of 86 putative myokines, which was reduced to 29 by applying a fold-change cut-off of 1.5. Based on that shortlist, a selection of putative myokines was measured in the plasma by ELISA or multiplex assay. From that selection, CX3CL1 (fractalkine) and CCL2 (MCP-1) increased at both mRNA and plasma levels. From the known myokines, only IL-6 and FGF 21 changed at the mRNA level, whereas none of the known myokines changed at the plasma level. Secretome analysis of exercise training intervention resulted in a list of 69 putative myokines. Comparing putative myokines altered by acute exercise and exercise training revealed a limited overlap of only 13 genes. In conclusion, this study identified CX3CL1 and CCL2 as myokines that were induced by acute exercise at the gene expression and plasma level and that may be involved in communication between skeletal muscle and other organs.
Effect of moderate alcohol consumption on fetuin-A levels in men and women: post-hoc analyses of three open-label randomized crossover trials
Joosten, M.M. ; Schrieks, I.C. ; Hendriks, H.F.J. - \ 2014
Diabetes & Metabolic Syndrome: Clinical Research & Reviews 6 (2014). - ISSN 1871-4021 - 5 p.
community-dwelling adults - insulin-resistance - cardiovascular-disease - rancho bernardo - older-adults - risk - association - metaanalysis - expression - biomarkers
Background Fetuin-A, a liver-derived glycoprotein that impairs insulin-signalling, has emerged as a biomarker for diabetes risk. Although moderate alcohol consumption has been inversely associated with fetuin-A, data from clinical trials are lacking. Thus, we evaluated whether moderate alcohol consumption decreases circulating levels of fetuin-A. Methods We analyzed data of three separate open-label, randomized, crossover trials: 1) 36 postmenopausal women consuming 250 ml white wine (25 g alcohol) or white grape juice daily for 6 weeks, 2) 24 premenopausal women consuming 660 ml beer (26 g alcohol) or alcohol-free beer daily for 3 weeks, and 3) 24 young men consuming 100 ml vodka (30 g alcohol) orange juice or only orange juice daily for 4 weeks. After each treatment period fasting blood samples were collected. Results Circulating fetuin-A concentrations decreased in men after vodka consumption (Mean¿±¿SEM: 441¿±¿11 to 426¿±¿11 µg/ml, p¿=¿0.02), but not in women after wine (448¿±¿17 to 437¿±¿17 µg/ml, p¿=¿0.16) or beer consumption (498¿±¿15 to 492¿±¿15 µg/ml, p¿=¿0.48) compared to levels after each corresponding alcohol-free treatment. Post-hoc power analyses indicated that the statistical power to detect a similar effect as observed in men was 30% among the postmenopausal women and 31% among the premenopausal women. Conclusions In these randomized crossover trials, moderate alcohol consumption decreased fetuin-A in men but not in women. This sex-specific effect may be explained by the relatively short intervention periods or the low statistical power in the trials among women.
Adherence to predefined dietary patterns and incident type 2 diabetes in European populations: EPIC-InterAct Study
Kröger, J. ; Schulze, M.B. ; Romaguera, D. ; Feskens, E.J.M. - \ 2014
Diabetologia 57 (2014)2. - ISSN 0012-186X - p. 321 - 333.
chronic disease - fatty-acids - mediterranean diet - insulin-resistance - physical-activity - quality index - risk-factors - dash diet - nutrition - cancer
Aims/hypothesis - Few studies have investigated the relationship between predefined dietary patterns and type 2 diabetes incidence; little is known about the generalisability of these associations. We aimed to assess the association between predefined dietary patterns and type 2 diabetes risk in European populations. Methods - From among a case-cohort of 12,403 incident diabetes cases and 16,154 subcohort members nested within the prospective European Prospective Investigation into Cancer and Nutrition study, we used data on 9,682 cases and 12,595 subcohort participants from seven countries. Habitual dietary intake was assessed at baseline with country-specific dietary questionnaires. Two diet-quality scores (alternative Healthy Eating Index [aHEI], Dietary Approaches to Stop Hypertension [DASH] score) and three reduced rank regression (RRR)-derived dietary-pattern scores were constructed. Country-specific HRs were calculated and combined using a random-effects meta-analysis. Results - After multivariable adjustment, including body size, the aHEI and DASH scores were not significantly associated with diabetes, although for the aHEI there was a tendency towards an inverse association in countries with higher mean age. We observed inverse associations of the three RRR-derived dietary-pattern scores with diabetes: HRs (95% CIs) for a 1-SD difference were 0.91 (0.86, 0.96), 0.92 (0.84, 1.01) and 0.87 (0.82, 0.92). Random-effects meta-analyses revealed heterogeneity between countries that was explainable by differences in the age of participants or the distribution of dietary intake. Conclusions/interpretation - Adherence to specific RRR-derived dietary patterns, commonly characterised by high intake of fruits or vegetables and low intake of processed meat, sugar-sweetened beverages and refined grains, may lower type 2 diabetes risk.
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