Netherlands Nutrigenomics Center

Wageningen, Netherlands

Netherlands Nutrigenomics Center

Wageningen, Netherlands
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Schwarz J.,Wageningen University | Schwarz J.,Netherlands Nutrigenomics Center | Tome D.,Wageningen University | Tome D.,French National Institute for Agricultural Research | And 5 more authors.
PLoS ONE | Year: 2012

Background and Aims: High protein (HP) diets are suggested to positively modulate obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease in humans and rodents. The aim of our study was to detect mechanisms by which a HP diet affects hepatic lipid accumulation. Methods: To investigate the acute and long term effect of high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35 energy%) or low (10 energy%) fat and high (50 energy%) or normal (15 energy%) protein diets for 1 or 12 weeks. Effects on body composition, liver fat, VLDL production rate and the hepatic transcriptome were investigated. Results: Mice fed the HP diets displayed a lower body weight, developed less adiposity and decreased hepatic lipid accumulation, which could be attributed to a combination of several processes. Next to an increased hepatic VLDL production rate, increased energy utilisation due to enhanced protein catabolic processes, such as transamination, TCA cycle and oxidative phosphorylation was found upon high protein ingestion. Conclusion: Feeding a HP diet prevented the development of NAFLD by enhancing lipid secretion into VLDL particles and a less efficient use of ingested calories. © 2012 Schwarz et al.

IJssennagger N.,Top Institute Food and Nutrition | IJssennagger N.,Wageningen University | de Wit N.,Top Institute Food and Nutrition | de Wit N.,Netherlands Nutrigenomics Center | And 5 more authors.
PLoS ONE | Year: 2012

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by luminal cytotoxicity and reactive oxygen species. This surface injury is overcompensated by hyperproliferation and hyperplasia of crypt cells. Transcriptome analysis of mucosa of heme-fed mice showed, besides stress- and proliferation-related genes, many upregulated lipid metabolism-related PPARα target genes. The aim of this study was to investigate the role of PPARα in heme-induced hyperproliferation and hyperplasia. Male PPARα KO and WT mice received a purified diet with or without heme. As PPARα is proposed to protect against oxidative stress and lipid peroxidation, we hypothesized that the absence of PPARα leads to more surface injury and crypt hyperproliferation in the colon upon heme-feeding. Heme induced luminal cytotoxicity and lipid peroxidation and colonic hyperproliferation and hyperplasia to the same extent in WT and KO mice. Transcriptome analysis of colonic mucosa confirmed similar heme-induced hyperproliferation in WT and KO mice. Stainings for alkaline phosphatase activity and expression levels of Vanin-1 and Nrf2-targets indicated a compromised antioxidant defense in heme-fed KO mice. Our results suggest that the protective role of PPARα in antioxidant defense involves the Nrf2-inhibitor Fosl1, which is upregulated by heme in PPARα KO mice. We conclude that PPARα plays a protective role in colon against oxidative stress, but PPARα does not mediate heme-induced hyperproliferation. This implies that oxidative stress of surface cells is not the main determinant of heme-induced hyperproliferation and hyperplasia. © 2012 IJssennagger et al.

van Dijk S.J.,Wageningen University | Mensink M.,Wageningen University | Esser D.,Wageningen University | Feskens E.J.M.,Wageningen University | And 3 more authors.
PLoS ONE | Year: 2012

Background: The ability of subjects to respond to nutritional challenges can reflect the flexibility of their biological system. Nutritional challenge tests could be used as an indicator of health status but more knowledge on metabolic and immune responses of different subjects to nutritional challenges is needed. The aim of this study was to compare the responses to high-fat challenges varying in fat type in subjects with different metabolic risk phenotypes. Methodology/Principal Findings: In a cross-over design 42 men (age 50-70 y) consumed three high-fat shakes containing saturated fat (SFA), monounsaturated fat (MUFA) or n-3 polyunsaturated (PUFA). Men were selected on BMI and health status (lean, obese or obese diabetic) and phenotyped with MRI for adipose tissue distribution. Before and 2 and 4 h after shake consumption blood was drawn for measurement of expression of metabolic and inflammation-related genes in peripheral blood mononuclear cells (PBMCs), plasma triglycerides (TAG), glucose, insulin, cytokines and ex vivo PBMC immune response capacity. The MUFA and n-3 PUFA challenge, compared to the SFA challenge, induced higher changes in expression of inflammation genes MCP1 and IL1β in PBMCs. Obese and obese diabetic subjects had different PBMC gene expression and metabolic responses to high-fat challenges compared to lean subjects. The MUFA challenge induced the most pronounced TAG response, mainly in obese and obese diabetic subjects. Conclusion/Significance: The PBMC gene expression response and metabolic response to high-fat challenges were affected by fat type and metabolic risk phenotype. Based on our results we suggest using a MUFA challenge to reveal differences in response capacity of subjects. Trial Registration: NCT00977262. © 2012 van Dijk et al.

Haenen D.,Wageningen University | Zhang J.,Wageningen University | da Silva C.S.,Wageningen University | Bosch G.,Wageningen University | And 8 more authors.
Journal of Nutrition | Year: 2013

Resistant starch (RS) is highly fermentable by microbiota in the colon, resulting in the production of SCFAs. RS is thought to mediate a large proportion of its health benefits, including increased satiety, through the actions of SCFAs. The aim of this study was to investigate the effects of a diet high in RS on luminal microbiota composition, luminal SCFA concentrations, and the expression of host genes involved in SCFA uptake, SCFA signaling, and satiety regulation in mucosal tissue obtained from small intestine, cecum, and colon. Twenty adult female pigs were either assigned to a digestible starch (DS) diet or a diet high in RS (34%) for a period of 2 wk. After the intervention, luminal content and mucosal scrapings were obtained for detailed molecular analysis. RS was completely degraded in the cecum. In both the cecum and colon, differences in microbiota composition were observed between DS- and RS-fed pigs. In the colon these included the stimulation of the healthy gut-associated butyrate-producing Faecalibacterium prausnitzii, whereas potentially pathogenic members of the Gammaproteobacteria, including Escherichia coli and Pseudomonas spp., were reduced in relative abundance. Cecal and colonic SCFA concentrations were significantly greater in RS-fed pigs, and cecal gene expression of monocarboxylate transporter 1 (SLC16A1) and glucagon (GCG) was induced by RS. In conclusion, our data show that RS modulates microbiota composition, SCFA concentrations, and host gene expression in pig intestine. Combined, our data provide an enhanced understanding of the interaction between diet, microbiota, and host. © 2013 American Society for Nutrition.

van Dijk S.J.,Wageningen University | Feskens E.J.M.,Wageningen University | Bos M.B.,Wageningen University | de Groot L.C.P.G.M.,Wageningen University | And 4 more authors.
Journal of Nutrition | Year: 2012

The Mediterranean (MED) diet is often considered health-promoting due to its high content of MUFA and polyphenols. These bioactive compounds can affect gene expression and accordingly may regulate pathways and proteins related to cardiovascular disease prevention. This study aimed to identify the effects of a MED-type diet, and the replacement of SFA with MUFA in a Western-type diet, on peripheral blood mononuclear cell (PBMC) gene expression and plasma proteins. Abdominally overweight men and women (waist: women ≥80cm, men ≥94cm) were allocated to an 8-wk, completely controlled SFA diet (19% daily energy as SFA), a MUFA diet (20% daily energy MUFA), or a MED diet (21% daily energy MUFA). Concentrations of 124 plasma proteins and PBMC whole-genome transcriptional profiles were assessed. Consumption of the MUFA and MED diets, compared with the SFA diet, decreased the expression of oxidative phosphorylation (OXPHOS) genes, plasma connective tissue growth factor, and apoB concentrations. Compared with the MED and SFA diets, the MUFA diet changed the expression of genes involved in B-cell receptor signaling and endocytosis signaling. Participants who consumed the MED diet had lower concentrations of proinflammatory proteins at 8 wk compared with baseline. We hypothesize that replacement of SFA with MUFA may improve health, thereby reducing metabolic stress and OXPHOS activity in PBMC. The MED diet may have additional antiatherogenic effects by lowering proinflammatory plasma proteins. © 2012 American Society for Nutrition.

IJssennagger N.,Top Institute Food and Nutrition | IJssennagger N.,Wageningen University | Rijnierse A.,Top Institute Food and Nutrition | Rijnierse A.,Wageningen University | And 10 more authors.
Gut | Year: 2012

Objective: Colon cancer is a leading cause of cancer deaths in Western countries and is associated with diets high in red meat. Haem, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents and damages the colon surface epithelium. Compensatory hyperproliferation leads to epithelial hyperplasia which increases the risk of colon cancer. The aim of this study was to identify molecules signalling from the surface epithelium to the crypt to initiate hyperproliferation upon stress induced by haem. Methods: C57Bl6/J mice (n=9/group) received a 'westernised' control diet (40 en% fat) with or without 0.5 mmol/g haem for 14 days. Colon mucosa was used to quantify cell proliferation and for microarray transcriptome analysis. Gene expression profiles of surface and crypt cells were compared using laser capture microdissection. Protein levels of potential signalling molecules were quantified. Results: Haem-fed mice showed epithelial hyperproliferation and decreased apoptosis, resulting in hyperplasia. Microarray analysis of the colon mucosa showed 3710 differentially expressed genes (false discovery rate (q) <0.01), with many involved in the cell cycle. Expression levels of haem- and stress-related genes showed that haem affected surface cells but did not directly affect crypt cells. Injured surface cells should therefore signal to crypt cells to induce compensatory hyperproliferation. Haem downregulated the inhibitors of proliferation, Wnt inhibitory factor 1, Indian Hedgehog and bone morphogenetic protein 2. Interleukin-15 was also downregulated. Haem upregulated amphiregulin, epiregulin and cyclo-oxygenase-2 mRNA in surface cells. Their protein/metabolite levels were, however, not increased as haem induced surface-specific inhibition of translation by increasing 4E-BP1. Conclusions: Haem induces colonic hyperproliferation and hyperplasia by inhibiting the surface to crypt signalling of feedback inhibitors of proliferation.

Afman L.A.,Wageningen University | Afman L.A.,Netherlands Nutrigenomics Center | Muller M.,Wageningen University | Muller M.,Netherlands Nutrigenomics Center
Progress in Lipid Research | Year: 2012

Nutrigenomics employs high-throughput genomics technologies to unravel how nutrients modulate gene and protein expression and ultimately influence cellular and organism metabolism. The most often-applied genomics technique so far is transcriptomics, which allows quantifying genome-wide changes in gene expression of thousands of genes at the same time in one sample. The performance of gene expression quantification requires sufficient high-quality homogenous cellular material, therefore research in healthy volunteers is restricted to biopsies from easy accessible tissues such as subcutaneous adipose tissue, skeletal muscle and intestinal biopsies or even more easily accessible cells such as peripheral blood mononuclear cells from blood. There is now significant evidence that fatty acids, in particular unsaturated fatty acids, exert many of their effects through modulation of gene transcription by regulating the activity of numerous transcription factors, including nuclear receptors such as peroxisome proliferator activated receptors, liver X receptor and sterol regulatory binding proteins. This review evaluates the human nutrigenomics studies performed on dietary fat since the initiation of nutrigenomics research around 10 years ago. Although the number of studies is still limited, all studies clearly suggest that changes in dietary fatty acids intake and composition can have a significant impact on cellular adaptive response capacity by gene transcription changes in humans. This adds important knowledge to our understanding of the strong effects that various fatty acids can have on numerous metabolic and inflammatory pathways, signaling routes and homeostatic control in the cell and ultimately on whole body health. It is important to use and integrate nutrigenomics in all future nutrition studies to build up the necessary framework for evidence-based nutrition in near future. © 2011 Elsevier Ltd. All rights reserved.

Steegenga W.T.,Wageningen University | De Wit N.J.W.,Wageningen University | De Wit N.J.W.,Netherlands Nutrigenomics Center | Boekschoten M.V.,Wageningen University | And 11 more authors.
BMC Medical Genomics | Year: 2012

Background: By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the functional decline associated with aging is still under debate. Methods. Young (4 M) and old (21 M) male C57BL/6J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated and the small intestine was divided in three equal parts. Swiss rolls were prepared of each of the isolated segments for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. Results: Digestible energy intake was similar between the two age groups on both the control and the high-fat diet. Microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a large number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. Conclusion: In 21-month old mice the most pronounced effects of aging were observed in the colon, whereas very few changes were observed in the small intestine. © 2012 Steegenga et al.; licensee BioMed Central Ltd.

Ijssennagger N.,Top Institute Food and Nutrition | Ijssennagger N.,Wageningen University | Rijnierse A.,Top Institute Food and Nutrition | Rijnierse A.,Wageningen University | And 16 more authors.
Carcinogenesis | Year: 2013

Red meat consumption is associated with an increased colon cancer risk. Heme, present in red meat, injures the colon surface epithelium by generating cytotoxic and oxidative stress. Recently, we found that this surface injury is compensated by hyperproliferation and hyperplasia of crypt cells, which was induced by a changed surface to crypt signaling. It is unknown whether this changed signaling is caused by cytotoxic stress and/or oxidative stress, as these processes were never studied separately. The aim of this study was to determine the possible differential effects of dietary heme on these luminal stressors and their impact on the colonic mucosa after 2, 4, 7 and 14 days of heme feeding. Mice received a purified, humanized, control diet or the diet supplemented with 0.2 μmol heme/g. Oxidative and cytotoxic stress were measured in fecal water. Proliferation was determined by Ki67-immunohistochemistry and mucosal responses by whole-genome transcriptomics. After heme ingestion, there was an acute increase in reactive oxygen species (ROS) leading to increased levels of lipid peroxidation products. Mucosal gene expression showed an acute antioxidant response, but no change in cell turnover. After day 4, cytotoxicity of the colonic contents was increased and this coincided with differential signaling and hyperproliferation, indicating that cytotoxicity was the causal factor. Simultaneously, several oncogenes were activated, whereas the tumor suppressor p53 was inhibited. In conclusion, luminal cytotoxicity, but not ROS, caused differential surface to crypt signaling resulting in mucosal hyperproliferation and the differential expression of oncogenes and tumor suppressor genes. © The Author 2013. Published by Oxford University Press. All rights reserved.

Konings E.,Maastricht University | Timmers S.,Maastricht University | Timmers S.,Top Institute Food and Nutrition TIFN | Boekschoten M.V.,Wageningen University | And 11 more authors.
International Journal of Obesity | Year: 2014

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. © 2014 Macmillan Publishers Limited.

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