Metabolism and Genomics Group

Wageningen, Netherlands

Metabolism and Genomics Group

Wageningen, Netherlands
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Steegenga W.T.,Metabolism and Genomics Group | Mischke M.,Metabolism and Genomics Group | Lute C.,Metabolism and Genomics Group | Boekschoten M.V.,Metabolism and Genomics Group | And 8 more authors.
Biology of Sex Differences | Year: 2014

Background: There is increasing appreciation for sexually dimorphic effects, but the molecular mechanisms underlying these effects are only partially understood. In the present study, we explored transcriptomics and epigenetic differences in the small intestine and colon of prepubescent male and female mice. In addition, the microbiota composition of the colonic luminal content has been examined. Methods: At postnatal day 14, male and female C57BL/6 mice were sacrificed and the small intestine, colon and content of luminal colon were isolated. Gene expression of both segments of the intestine was analysed by microarray analysis. DNA methylation of the promoter regions of selected sexually dimorphic genes was examined by pyrosequencing. Composition of the microbiota was explored by deep sequencing. Results: Sexually dimorphic genes were observed in both segments of the intestine of 2-week-old mouse pups, with a stronger effect in the small intestine. Amongst the total of 349 genes displaying a sexually dimorphic effect in the small intestine and/or colon, several candidates exhibited a previously established function in the intestine (i.e. Nts, Nucb2, Alox5ap and Retnlγ). In addition, differential expression of genes linked to intestinal bowel disease (i.e. Ccr3, Ccl11 and Tnfr) and colorectal cancer development (i.e. Wt1 and Mmp25) was observed between males and females. Amongst the genes displaying significant sexually dimorphic expression, nine genes were histone-modifying enzymes, suggesting that epigenetic mechanisms might be a potential underlying regulatory mechanism. However, our results reveal no significant changes in DNA methylation of analysed CpGs within the selected differentially expressed genes. With respect to the bacterial community composition in the colon, a dominant effect of litter origin was found but no significant sex effect was detected. However, a sex effect on the dominance of specific taxa was observed. Conclusions: This study reveals molecular dissimilarities between males and females in the small intestine and colon of prepubescent mice, which might underlie differences in physiological functioning and in disease predisposition in the two sexes. © 2014 Steegenga et al.; licensee BioMed Central Ltd.

Baumgartner J.,ETH Zurich | Baumgartner J.,North West University South Africa | Smuts C.M.,North West University South Africa | Malan L.,North West University South Africa | And 10 more authors.
Journal of Nutrition | Year: 2012

Deficiencies of iron (Fe) (ID) and (n-3) fatty acids (FA) [(n-3)FAD] may impair brain development and function through shared mechanisms. However, little is known about the potential interactions between these 2 common deficiencies. We studied the effects of ID and (n-3)FAD, alone and in combination, on brain monoamine pathways (bymeasuring monoamines and related gene expression) and spatial working and referencememory (by Morris watermaze testing). Using a 23 2 design, male rats were fed an ID, (n-3)FAD, ID+(n-3)FAD, or control diet for 5 wk postweaning (postnatal d 21-56) after (n-3)FAD had been induced over 2 generations. The (n-3)FAD and ID diets decreased brain (n-3) FA by 70-76% and Fe by 20-32%, respectively. ID and (n-3)FAD significantly increased dopamine (DA) concentrations in the olfactory bulb (OB) and striatum, with an additive 1- to 2-fold increase in ID+(n-3)FAD rats compared with controls (P < 0.05). ID decreased serotonin (5-HT) levels in OB, with a significant decrease in ID+(n-3)FAD rats. Furthermore, norepinephrine concentrations were increased 2-fold in the frontal cortex (FC) of (n-3)FAD rats (P < 0.05). Dopa decarboxylase was downregulated in the hippocampus of ID and ID+(n-3)FAD rats (fold-change =21.33; P < 0.05). ID and (n-3)FAD significantly impairedworking memory performance and the impairment positively correlatedwith DA concentrations in FC (r = 0.39; P = 0.026). Referencememorywas impaired in the ID+(n-3)FAD rats (P < 0.05) and was negatively associated with 5-HT in FC (r =20.42; P = 0.018). These results suggest that the combined deficiencies of Fe and (n-3) FA disrupt brainmonoamine metabolism and produce greater deficits in reference memory than ID or (n-3)FAD alone. © 2012 American Society for Nutrition.

De Vogel-Van Den Bosch J.,Top Institute Food and Nutrition | De Vogel-Van Den Bosch J.,Maastricht University | Hoeks J.,Maastricht University | Timmers S.,Top Institute Food and Nutrition | And 14 more authors.
Obesity | Year: 2011

Accumulation of triacylglycerols (TAGs) and acylcarnitines in skeletal muscle upon high-fat (HF) feeding is the resultant of fatty acid uptake and oxidation and is associated with insulin resistance. As medium-chain fatty acids (MCFAs) are preferentially Β-oxidized over long-chain fatty acids, we examined the effects of medium-chain TAGs (MCTs) and long-chain TAGs (LCTs) on muscle lipid storage and whole-body glucose tolerance. Rats fed a low-fat (LF), HFLCT, or an isocaloric HFMCT diet displayed a similar body weight gain over 8 weeks of treatment. Only HFLCT increased myocellular TAG (42.3 4.9, 71.9 6.7, and 48.5 6.5 νmol/g for LF, HFLCT, and HFMCT, respectively, P 0.05) and long-chain acylcarnitine content (P 0.05). Neither HF diet increased myocellular diacylglycerol (DAG) content. Intraperitoneal (IP) glucose tolerance tests (1.5 g/kg) revealed a significantly decreased glucose tolerance in the HFMCT compared to the HFLCT-fed rats (802 40, 772 18, and 886 18 area under the curve for LF, HFLCT, and HFMCT, respectively, P 0.05). Finally, no differences in myocellular insulin signaling after bolus insulin injection (10 U/kg) were observed between LF, HFLCT, or HFMCT-fed rats. These results show that accumulation of TAGs and acylcarnitines in skeletal muscle in the absence of body weight gain do not impede myocellular insulin signaling or whole-body glucose intolerance. © 2010 The Obesity Society.

Lichtenstein L.,Nutrigenomics Consortium | Lichtenstein L.,Metabolism and Genomics Group | Kersten S.,Nutrigenomics Consortium | Kersten S.,Metabolism and Genomics Group
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

There is evidence that elevated plasma triglycerides (TG) serve as an independent risk factor for coronary heart disease. Plasma TG levels are determined by the balance between the rate of production of chylomicrons and VLDL in intestine and liver, respectively, and their rate of clearance in peripheral tissues. Lipolytic processing of TG-rich lipoproteins is mediated by the enzyme lipoprotein lipase (LPL), which is tethered to the capillary endothelium via heparin sulphate proteoglycans. In recent years the Angiopoietin-like proteins ANGPTL3 and ANGPTL4 have emerged as novel modulators of LPL activity. Studies in transgenic animals supported by in vitro experiments have demonstrated that ANGPTL3 and ANGPTL4 impair plasma TG clearance by inhibiting LPL activity. In humans, genetic variation within the ANGPTL3 and ANGPTL4 genes contributes to variation in plasma TG and HDL levels, thereby validating the importance of ANGPTLs in the regulation of lipoprotein metabolism in humans. Combined with the discovery of GPIHBP1 as a likely LPL anchor, these findings have led to a readjustment of the mechanism of LPL function. This review provides an overview of our current understanding of the role and regulation of ANGPTL3, ANGPTL4 and GPIHBP1, and places the newly acquired knowledge in the context of the established function and mechanism of LPL-mediated lipolysis. © 2010 Elsevier B.V. All rights reserved.

Kersten S.,Metabolism and Genomics Group
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2014

The enzyme lipoprotein lipase (LPL), originally identified as the clearing factor lipase, hydrolyzes triglycerides present in the triglyceride-rich lipoproteins VLDL and chylomicrons. LPL is primarily expressed in tissues that oxidize or store fatty acids in large quantities such as the heart, skeletal muscle, brown adipose tissue and white adipose tissue. Upon production by the underlying parenchymal cells, LPL is transported and attached to the capillary endothelium by the protein GPIHBP1. Because LPL is rate limiting for plasma triglyceride clearance and tissue uptake of fatty acids, the activity of LPL is carefully controlled to adjust fatty acid uptake to the requirements of the underlying tissue via multiple mechanisms at the transcriptional and post-translational level. Although various stimuli influence LPL gene transcription, it is now evident that most of the physiological variation in LPL activity, such as during fasting and exercise, appears to be driven via post-translational mechanisms by extracellular proteins. These proteins can be divided into two main groups: the liver-derived apolipoproteins APOC1, APOC2, APOC3, APOA5, and APOE, and the angiopoietin-like proteins ANGPTL3, ANGPTL4 and ANGPTL8, which have a broader expression profile. This review will summarize the available literature on the regulation of LPL activity in various tissues, with an emphasis on the response to diverse physiological stimuli. © 2014 Elsevier B.V. All rights reserved.

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