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.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Correcting palindromes in long reads after whole-genome amplification
Warris, S. ; Schijlen, E.G.W.M. ; Geest, H.C. van de; Vegesna, R. ; Hesselink, T. ; Lintel Hekkert, B. te; Sanchez Perez, G.F. ; Medvedev, P. ; Makova, K.D. ; Ridder, D. de - \ 2018
BMC Genomics 19 (2018). - ISSN 1471-2164
Background: Next-generation sequencing requires sufficient DNA to be available. If limited, whole-genome amplification is applied to generate additional amounts of DNA. Such amplification often results in many chimeric DNA fragments, in particular artificial palindromic sequences, which limit the usefulness of long sequencing reads. Results: Here, we present Pacasus, a tool for correcting such errors. Two datasets show that it markedly improves read mapping and de novo assembly, yielding results similar to these that would be obtained with non-amplified DNA. Conclusions: With Pacasus long-read technologies become available for sequencing targets with very small amounts of DNA, such as single cells or even single chromosomes.
Circadian misalignment induces fatty acid metabolism gene profiles and compromises insulin sensitivity in human skeletal muscle
Wefers, Jakob ; Moorsel, Dirk van; Hansen, Jan ; Connell, Niels J. ; Havekes, Bas ; Hoeks, Joris ; Marken Lichtenbelt, Wouter D. van; Duez, Hélène ; Phielix, Esther ; Kalsbeek, Andries ; Boekschoten, Mark V. ; Hooiveld, Guido J. ; Hesselink, Matthijs K.C. ; Kersten, Sander ; Staels, Bart ; Scheer, Frank A.J.L. ; Schrauwen, Patrick - \ 2018
Proceedings of the National Academy of Sciences of the United States of America 115 (2018)30. - ISSN 0027-8424 - p. 7789 - 7794.
Circadian misalignment, such as in shift work, has been associated with obesity and type 2 diabetes. However, direct effects of circadian misalignment on skeletal muscle insulin sensitivity and the muscle molecular circadian clock have never been studied in humans. Here, we investigated insulin sensitivity and muscle metabolism in 14 healthy young lean men [age 22.4 ± 2.8 years; body mass index (BMI) 22.3 ± 2.1 kg/m2 (mean ± SD)] after a 3-d control protocol and a 3.5-d misalignment protocol induced by a 12-h rapid shift of the behavioral cycle. We show that short-term circadian misalignment results in a significant decrease in muscle insulin sensitivity due to a reduced skeletal muscle nonoxidative glucose disposal (rate of disappearance: 23.7 ± 2.4 vs. 18.4 ± 1.4 mg/kg per minute; control vs. misalignment; P = 0.024). Fasting glucose and free fatty acid levels as well as sleeping metabolic rate were higher during circadian misalignment. Molecular analysis of skeletal muscle biopsies revealed that the molecular circadian clock was not aligned to the inverted behavioral cycle, and transcriptome analysis revealed the human PPAR pathway as a key player in the disturbed energy metabolism upon circadian misalignment. Our findings may provide a mechanism underlying the increased risk of type 2 diabetes among shift workers.
A high-quality genome sequence of Rosa chinensis to elucidate ornamental traits
Hibrand Saint-Oyant, L. ; Ruttink, T. ; Hamama, L. ; Kirov, I. ; Lakhwani, D. ; Zhou, N.N. ; Bourke, P.M. ; Daccord, N. ; Leus, L. ; Schulz, D. ; Geest, H. van de; Hesselink, T. ; Laere, K. Van; Debray, K. ; Balzergue, S. ; Thouroude, T. ; Chastellier, A. ; Jeauffre, J. ; Voisine, L. ; Gaillard, S. ; Borm, T.J.A. ; Arens, P. ; Voorrips, R.E. ; Maliepaard, C. ; Neu, E. ; Linde, M. ; Paslier, M.C. Le; Bérard, A. ; Bounon, R. ; Clotault, J. ; Choisne, N. ; Quesneville, H. ; Kawamura, K. ; Aubourg, S. ; Sakr, S. ; Smulders, M.J.M. ; Schijlen, E. ; Bucher, E. ; Debener, T. ; Riek, J. De; Foucher, F. - \ 2018
Nature Plants 4 (2018). - ISSN 2055-026X - p. 473 - 484.

Rose is the world’s most important ornamental plant, with economic, cultural and symbolic value. Roses are cultivated worldwide and sold as garden roses, cut flowers and potted plants. Roses are outbred and can have various ploidy levels. Our objectives were to develop a high-quality reference genome sequence for the genus Rosa by sequencing a doubled haploid, combining long and short reads, and anchoring to a high-density genetic map, and to study the genome structure and genetic basis of major ornamental traits. We produced a doubled haploid rose line (‘HapOB’) from Rosa chinensis ‘Old Blush’ and generated a rose genome assembly anchored to seven pseudo-chromosomes (512 Mb with N50 of 3.4 Mb and 564 contigs). The length of 512 Mb represents 90.1–96.1% of the estimated haploid genome size of rose. Of the assembly, 95% is contained in only 196 contigs. The anchoring was validated using high-density diploid and tetraploid genetic maps. We delineated hallmark chromosomal features, including the pericentromeric regions, through annotation of transposable element families and positioned centromeric repeats using fluorescent in situ hybridization. The rose genome displays extensive synteny with the Fragaria vesca genome, and we delineated only two major rearrangements. Genetic diversity was analysed using resequencing data of seven diploid and one tetraploid Rosa species selected from various sections of the genus. Combining genetic and genomic approaches, we identified potential genetic regulators of key ornamental traits, including prickle density and the number of flower petals. A rose APETALA2/TOE homologue is proposed to be the major regulator of petal number in rose. This reference sequence is an important resource for studying polyploidization, meiosis and developmental processes, as we demonstrated for flower and prickle development. It will also accelerate breeding through the development of molecular markers linked to traits, the identification of the genes underlying them and the exploitation of synteny across Rosaceae.

Whole-genome amplification (WGA) create specific chimeric fragments, which consist mainly of palindrome sequences. We developed the tool Pacasus to detect and correct these palindromic sequences in long reads, for example from PacBio and Nanopore
Warris, S. ; Schijlen, E.G.W.M. ; Geest, H.C. van de; Vegesna, R. ; Hesselink, T. ; Lintel Hekkert, B. te; Sanchez Perez, G.F. ; Medvedev, P. ; Makova, K.D. ; Ridder, D. de - \ 2017
PRJEB21791 - GCA_900199665 - ERP024083 - Arabidopsis thaliana
Next-generation sequencing requires sufficient DNA to be available. If limited, whole-genome amplification is applied to generate additional amounts of DNA. Such amplification often results in many chimeric DNA fragments, in particular artificial palindromic sequences, which limit the usefulness long reads from technologies such as PacBio and Oxford Nanopore unusable for further analysis. We developed Pacasus, a tool for correcting such errors in long reads. With Pacasus long-read technologies become readily available for sequencing targets with very small amounts of DNA.
Regulation of lipid droplet-associated proteins by peroxisome proliferator-activated receptors
Rosa Rodriguez, Montserrat A. de la; Kersten, Sander - \ 2017
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1862 (2017)10. - ISSN 1388-1981 - p. 1212 - 1220.
Lipid droplet - Lipid droplet-associated proteins - Perilipins - PPARs
Excess fatty acids are stored in cells as triglycerides in specialized organelles called lipid droplets (LD). LD can be found in nearly all cell types and may expand during certain (patho)physiological conditions. The synthesis and breakdown of triglycerides and their deposition in LD is governed by a diverse set of enzymes and LD-associated proteins. These proteins serve structural roles in and around LD and regulate the activity of key lipogenic and lipolytic enzymes. The LD-associated proteins are subject to multiple regulatory mechanisms at the protein and gene expression level. A group of transcription factors that govern the expression of many LD-associated proteins are the Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are lipid-activated transcription factors that play a key role in the regulation of lipid metabolism in liver (PPARα), adipose tissue (PPARγ), and skeletal muscle (PPARδ). This review provides an overview of the regulation of LD-associated proteins by PPARα, PPARδ, and PPARγ in adipose tissue, liver, macrophages, and skeletal muscle. It is concluded that many LD-associated proteins, including members of the PLIN family, CIDEC, CIDEA, HILPDA, FITM1, FITM2, and G0S2 are under direct transcriptional control of PPARs. Upregulation of LD-associated proteins by PPARs provides a mechanism to link uptake of lipids to regulation of lipid storage capacity. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink.
Habitual diet and diet quality in Irritable Bowel Syndrome: A case-control study
Tigchelaar, Ettje F. ; Mujagic, Zlatan ; Zhernakova, Alexandra ; Hesselink, M. ; Meijboom, S. ; Perenboom, C.W.M. ; Masclee, A.A.M. ; Wijmenga, Cisca ; Feskens, E.J.M. ; Jonkers, D. - \ 2017
Neurogastroenterology & Motility 29 (2017)12. - ISSN 1365-2982
Background Diet is considered to be a key factor in symptom generation in Irritable Bowel Syndrome (IBS) and patients tend to exclude food products from their diet in pursue of symptom relief, which may impair diet quality. Methods We evaluated habitual dietary intake in IBS patients with regard to nutrients and food products using an extensive food frequency questionnaire. One hundred ninety-four IBS patients were compared to 186 healthy controls using multiple logistic regression analysis. An overall diet quality score was calculated for each participant based on the criteria of the Dutch Healthy Diet (DHD) index. Key Results A lower DHD-score was found for IBS (mean [SD]: 52.9 [9.6]) vs controls (55.1 [9.2], P=.02). The diet of patients was lower in fibers (21 g vs 25 g per day, P=.002) and fructose (14 g vs 16 g, P=.033), while higher in total fat (37% vs 36% of total energy intake, P=.010) and added sugars (46 g vs 44 g, P=.029). Differences in daily intake of food products included lower consumption of apples (40 g vs 69 g, P<.001), pasta (28 vs 37 g, P=.029) and alcoholic beverages (130 g vs 193 g, P=.024) and higher consumption of processed meat (38 g vs 29 g, P<.001). Some of these findings correlated with gastrointestinal symptoms, showing differences between IBS subtypes. Conclusions and Inferences Differences in habitual diet were described, showing lower diet quality in IBS patients compared to controls, with increased consumption of fat and lower intake of fibers and fructose. Our data support the importance of personalized and professional nutritional guidance of IBS patients.
Botryococcus braunii strains compared for biomass productivity, hydrocarbon and carbohydrate content
Gouveia, J.D.G. ; Ruiz, Jesus ; Broek, Ben van den; Hesselink, T. ; Peters, S.A. ; Kleinegris, D.M.M. ; Smith, Alison G. ; Veen, Douwe van der; Barbosa, M.J. ; Wijffels, R.H. - \ 2017
Journal of Biotechnology 248 (2017). - ISSN 0168-1656 - p. 77 - 86.
Botryococcus braunii can produce both long-chain hydrocarbons as well as carbohydrates in large quantities, and is therefore a promising industrial organism for the production of biopolymer building blocks. Many studies describe the use of different strains of Botryococcus braunii but differences in handling and cultivation conditions make the comparison between strains difficult. In this study, 16 B. braunii strains obtained from six culture collections were compared for their biomass productivity and hydrocarbon and carbohydrate content. Biomass productivity was highest for AC768 strain with 1.8 g L−1 day−1, while hydrocarbon production ranged from none to up to 42% per gram biomass dry weight, with Showa showing the highest hydrocarbon content followed by AC761. The total carbohydrate content varied from 20% to 76% per gram of the biomass dry weight, with CCALA777 as the highest producer. Glucose and galactose are the main monosaccharides in most strains and fucose content reached 463 mg L−1 in CCALA778.
A footprint of desiccation tolerance in the genome of Xerophyta viscosa
Dias Costa, M.C. ; Silva Artur, M.A. ; Maia de Oliveira, Julio ; Jonkheer, Eef ; Derks, Martijn ; Nijveen, H. ; Williams, B. ; Mundree, Sagadevan ; Jiménez-Gómez, José M. ; Hesselink, T. ; Schijlen, E.G.W.M. ; Ligterink, W. ; Oliver, Melvin J. ; Farrant, Jill M. ; Hilhorst, H.W.M. - \ 2017
Nature Plants 3 (2017). - ISSN 2055-026X - 10 p.
Desiccation tolerance is common in seeds and various other organisms, but only a few angiosperm species possess vegetative desiccation tolerance. These ‘resurrection species’ may serve as ideal models for the ultimate design of crops with enhanced drought tolerance. To understand the molecular and genetic mechanisms enabling vegetative desiccation tolerance, we produced a high-quality whole-genome sequence for the resurrection plant Xerophyta viscosa and assessed transcriptome changes during its dehydration. Data revealed induction of transcripts typically associated with desiccation
tolerance in seeds and involvement of orthologues of ABI3 and ABI5, both key regulators of seed maturation. Dehydration resulted in both increased, but predominantly reduced, transcript abundance of genomic ‘clusters of desiccation-associated genes’ (CoDAGs), reflecting the cessation of growth that allows for the expression of desiccation tolerance. Vegetative
desiccation tolerance in X. viscosa was found to be uncoupled from drought-induced senescence. We provide strong support for the hypothesis that vegetative desiccation tolerance arose by redirection of genetic information from
desiccation-tolerant seeds.
ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure
Dijk, Wieneke ; Heine, Markus ; Vergnes, Laurent ; Boon, Mariëtte R. ; Schaart, Gert ; Hesselink, Matthijs K.C. ; Reue, Karen ; Marken Lichtenbelt, Wouter D. van; Olivecrona, Gunilla ; Rensen, Patrick C.N. ; Heeren, Joerg ; Kersten, Sander - \ 2015
eLife 4 (2015). - ISSN 2050-084X - 23 p.

Brown adipose tissue (BAT) activation via cold exposure is increasingly scrutinized as a potential approach to ameliorate cardio-metabolic risk. Transition to cold temperatures requires changes in the partitioning of energy substrates, re-routing fatty acids to BAT to fuel non-shivering thermogenesis. However, the mechanisms behind the redistribution of energy substrates to BAT remain largely unknown. Angiopoietin-like 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL) activity, is highly expressed in BAT. Here, we demonstrate that ANGPTL4 is part of a shuttling mechanism that directs fatty acids derived from circulating triglyceride-rich lipoproteins to BAT during cold. Specifically, we show that cold markedly down-regulates ANGPTL4 in BAT, likely via activation of AMPK, enhancing LPL activity and uptake of plasma triglyceride-derived fatty acids. In contrast, cold up-regulates ANGPTL4 in WAT, abolishing a cold-induced increase in LPL activity. Together, our data indicate that ANGPTL4 is an important regulator of plasma lipid partitioning during sustained cold.

Effects of high-fat feeding on ectopic fat storage and postprandial lipid metabolism in mouse offspring
Ewijk, Petronella A. Van; Paglialunga, Sabina ; Kooi, M.E. ; Nunes, Patricia M. ; Gemmink, Anne ; Slenter, Jos ; Kornips, Esther ; Jörgensen, Johanna A. ; Hoeks, Joris ; Wildberger, Joachim E. ; Hesselink, Matthijs K.C. ; Glatz, Jan F.C. ; Heerschap, Arend ; Kersten, Sander ; Schrauwen, Patrick ; Schrauwen-Hinderling, Vera B. - \ 2015
Obesity 23 (2015)11. - ISSN 1930-7381 - p. 2242 - 2250.

Objective Parental high-fat feeding was proposed to negatively impact metabolic health in offspring. Here, the ectopic fat storage in heart and liver in offspring was investigated, and the effects on mitochondrial function, de novo lipogenesis, and postprandial lipid metabolism were explored in detail. Methods Male and female mice received either a high-fat (HF) or standard chow (LF) diet during mating, gestation and lactation. All offspring animals received the HF diet. Results Abdominal visceral adipose tissue tended to be higher in HF/HF mice. Cardiac lipid content was also higher in the HF/HF mice (LF/HF vs. HF/HF: 1.03% ± 0.08% vs. 1.33% ± 0.07% of water signal, P = 0.01). In contrast, hepatic lipid content tended to be lower in HF/HF mice compared to LF/HF mice. A severely disturbed postprandial lipid clearance was revealed in HF/HF mice by the results from the triglyceride (TG) tolerance tests (LF/HF vs. HF/HF: 6,753 ± 2,213 vs. 14,367 ± 1,978 mmol l-1 min-1, P = 0.01) and 13C-fatty acid retention test (LF/HF vs. HF/HF: 2.73% ± 0.85% vs. 0.89% ± 0.26% retention from bolus, P = 0.04), which may underlie the lower hepatic lipid content. Conclusions Here it is shown that HF diet negatively impacts postprandial TG clearance in offspring and results in an overall metabolic unfavorable phenotype and ectopic lipid deposition in the heart and in visceral storage sites.

Perilipin 5 mediated lipid droplet remodelling revealed by coherent Raman imaging
Billecke, Nils ; Bosma, Madeleen ; Rock, William ; Fleissner, Frederik ; Best, Gerrit ; Schrauwen, Patrick ; Kersten, Sander ; Bonn, Mischa ; Hesselink, M.K.C. ; Parekh, S.H. - \ 2015
Integrative Biology (United Kingdom) 7 (2015)4. - ISSN 1757-9694 - p. 467 - 476.

Accumulation of fat in muscle tissue as intramyocellular lipids (IMCLs) is closely related to the development of insulin resistance and subsequent type 2 diabetes. Most IMCLs organize into lipid droplets (LDs), the fates of which are regulated by lipid droplet coat proteins. Perilipin 5 (PLIN5) is an LD coating protein, which is strongly linked to lipid storage in muscle tissue. Here we employ a tandem in vitro/ex vivo approach and use chemical imaging by label-free, hyperspectral coherent Raman microscopy to quantify compositional changes in individual LDs upon PLIN5 overexpression. Our results directly show that PLIN5 overexpression in muscle alters individual LD composition and physiology, resulting in larger LDs with higher esterified acyl chain concentration, increased methylene content, and more saturated lipid species. These results suggest that lipotoxic protection afforded by natural PLIN5 upregulation in muscle involves molecular changes in lipid composition within LDs. This journal is

Expression of natural human b1,4-GalT1 variants and of non-mammalian homologues in plants leads to differences in galactosylation of N-glycans
Hesselink, T. ; Rouwendal, G.J.A. ; Henquet, M.G.L. ; Florack, D.E.A. ; Helsper, J.P.F.G. ; Bosch, H.J. - \ 2014
Transgenic Research 23 (2014)5. - ISSN 0962-8819 - p. 717 - 728.
golgi-apparatus - murine beta-1,4-galactosyltransferase - beta 1,4-galactosyltransferase - transgenic plants - gene - cells - localization - antibodies - oligosaccharides - glycoproteins
b1,4-Galactosylation of plant N-glycans is a prerequisite for commercial production of certain biopharmaceuticals in plants. Two different types of galactosylated N-glycans have initially been reported in plants as the result of expression of human b1,4-galactosyltransferase 1 (GalT). Here we show that these differences are associated with differences at its N-terminus: the natural short variant of human GalT results in hybrid type N-glycans, whereas the long form generates bi-antennary complex type N-glycans. Furthermore, expression of non-mammalian, chicken and zebrafish GalT homologues with N-termini resembling the short human GalT N-terminus also induce hybrid type N-glycans. Providing both non-mammalian GalTs with a 13 amino acid N-terminal extension that distinguishes the two naturally occurring forms of human GalT, acted to increase the levels of biantennary galactosylated N-glycans when expressed in tobacco leaves. Replacement of the cytosolic tail and transmembrane domain of chicken and zebrafish GalTs with the corresponding region of rat a2,6-sialyltransferase yielded a gene whose expression enhanced the level of bi-antennary galactosylation even further.
Palmitoylethanolamide (PEA)—‘Promiscuous’ anti-inflammatory and analgesic molecule at the interface between nutrition and pharma
Keppel Hesselink, J.M. ; Kopsky, D.J. ; Witkamp, R.F. - \ 2014
PharmaNutrition 2 (2014)1. - ISSN 2213-4344 - p. 19 - 25.
Palmitoylethanolamide (N-palmitoylethanolamine or PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamine (NAE) class of signalling molecules. Earliest reports on the anti-inflammatory and immune modulating properties of PEA date back to 1957 when its isolation from soy lecithin, peanut meal, and egg yolk was reported. PEA is structurally related to anandamide and other endocannabinoids and possesses similar pathways for synthesis and breakdown. However, instead of being an endocannabinoid per se, PEA may be called a ‘promiscuous’ compound. It does not bind to cannabinoid receptors but interacts with several other receptors and non-receptor targets. This rather complex biology has indisputably contributed to the initially slow development of PEA, which witnessed a revival around 1993 with the seminal work of the late Rita Levi-Montalcini. Presently the compound is receiving increasing attention as a drug or nutraceutical against chronic pain, inflammation and degenerative diseases of the central nervous system. In this paper we review the development and pharmacology of this remarkable lipid mediator with its pleiotropic and ‘promiscuous’ character. The history of PEA exemplifies an evolving paradigm shift in pharma and nutrition from ‘single-target’ to ‘multiple-target’ approaches and provides new perspectives for future development in these fields.
Orientation of llama antibodies strongly increases sensitivity of biosensors
Trilling, A.K. ; Hesselink, T. ; Houwelingen, A. van; Cordewener, J.H.G. ; Jongsma, M.A. ; Schoffelen, S. ; Hest, J.C.M. van; Zuilhof, J.T. ; Beekwilder, J. - \ 2014
Biosensors and Bioelectronics 60 (2014). - ISSN 0956-5663 - p. 130 - 136.
autodisplayed z-domains - click chemistry - immobilization - coli
Sensitivity of biosensors depends on theorientation of bio-receptors on the sensor surface.The objective of this study was to organize bio-receptors on surfaces in a way that their analyte binding site is exposed to the analyte solution. VHH proteins recognizing foot-and-mouth disease virus (FMDV) were used for making biosensors, and azides were introduced in the VHH to function as bioorthogonal reactive groups. The importance of the orientation of bio-receptors was addressed by comparing sensors with randomly oriented VHH (with multiple exposed azide groups)to sensors with uniformly oriented VHH (with only a single azide group). A surface plasmon resonance (SPR) chip exposing cyclooctyne was reacted to azide functionalized VHH domains, using click chemistry. Comparison between randomly and uniformly oriented bio-receptors showed up to 800-fold increase in biosensor sensitivity. This technique may increase the containment of infectious diseases such as FMDV as its strongly enhanced sensitivity may facilitate early diagnostics.
Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity
Bosma, Madeleen ; Sparks, Lauren ; Hooiveld, Guido ; Jorgensen, Johanna ; Houten, Sander ; Schrauwen, Patrick ; Kersten, Sander ; Hesselink, Matthijs - \ 2013
GSE43832 - Rattus norvegicus - PRJNA187510
Aims/hypothesis: While lipid deposition in skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like skeletal muscle. Here we investigated the effects of PLIN5 overexpression – in comparison with effects of PLIN2 – on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in skeletal muscle promoted expression of a cluster of genes under control of PPARα and PGC1α involved in FA catabolism and mitochondrial oxidation.
Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold
Keppel Hesselink, J.M. ; Boer, T. de; Witkamp, R.F. - \ 2013
International Journal of Inflammation 2013 (2013). - ISSN 2090-8040 - 8 p.
Palmitoylethanolamide (PEA) is a food component known since 1957. PEA is synthesized and metabolized in animal cells via a number of enzymes and exerts a multitude of physiological functions related to metabolic homeostasis. Research on PEA has been conducted for more than 50 years, and over 350 papers are referenced in PubMed describing the physiological properties of this endogenous modulator and its pharmacological and therapeutical profile. The major focus of PEA research, since the work of the Nobel laureate Levi-Montalcini in 1993, has been neuropathic pain states and mast cell related disorders. However, it is less known that 6 clinical trials in a total of nearly 4000 people were performed and published last century, specifically studying PEA as a therapy for influenza and the common cold. This was done before Levi-Montalcini’s clarification of PEA’s mechanism of action, analyzing the role of PEA as an anti-inflammatory agent. We will review in depth these studies, as the results support the effectiveness and safety of PEA in flu and respiratory infections.
Overexpression of PLIN5 in skeletal muscle promotes oxidative gene expression and intramyocellular lipid content without compromising insulin sensitivity
Bosma, M. ; Sparks, L.M. ; Hooiveld, G.J.E.J. ; Jorgensen, J.A. ; Houten, S.M. ; Schrauwen, P. ; Kersten, A.H. ; Hesselink, M.K.C. - \ 2013
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1831 (2013)4. - ISSN 1388-1981 - p. 844 - 852.
fatty-acid oxidation - perilipin 5 - weight-loss - ppar-alpha - in-vivo - resistance - protein - mitochondria - carnitine - phosphorylation
Aims/hypothesis: While lipid deposition in the skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like the skeletal muscle. Here we investigated the effects of PLIN5 overexpression - in comparison with the effects of PLIN2 - on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet Eight days after electroporation, insulin-mediated glucose uptake in the skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PUNS in the skeletal muscle promoted expression of a cluster of genes under control of PPAR alpha and PGC1 alpha involved in FA catabolism and mitochondrial oxidation. (C) 2013 Elsevier B.V. All rights reserved.
Identification of alg3 in the mushroom-forming fungus Schizophyllum commune and analysis of the ¿alg3 knockout mutant
Berends, E. ; Lehle, L. ; Henquet, M. ; Hesselink, T. ; Wösten, H.A.B. ; Lugones, L.G. ; Bosch, H.J. - \ 2013
Glycobiology 23 (2013)2. - ISSN 0959-6658 - p. 147 - 154.
saccharomyces-cerevisiae - n-glycan - gene - glycoproteins - enzyme - mannosyltransferase - glucocerebrosidase - oligosaccharides - glycosylation - therapy
Alg3 of Saccharomyces cerevisiae catalyzes the mannosyl transfer from Man-P-Dol to Man(5)GlcNAc(2)-PP-Dol resulting in the formation of Man(6)GlcNAc(2)-PP-Dol, which is then further processed to the final precursor oligosaccharide Glc(3)Man(9)GlcNAc(2) for N-glycosylation of proteins. Here, we identified the alg3 gene of the mushroom-forming fungus Schizophyllum commune by homology search. Its function was confirmed by the complementation of the Delta alg3 strain of S. cerevisiae. Inactivation of alg3 in S. commune resulted in the production of predominantly Man(3)GlcNAc(2) protein-linked N-glycans. No impact on growth nor a developmental phenotype due to the deletion was observed. This provides a first step toward engineering of a homogeneous, humanized N-glycosylation pattern for the production of therapeutic glycoproteins in mushrooms.
Perilipin 2 improves insulin sensitivity in skeletal muscle despite elevated intramuscular lipid levels
Bosma, Madeleen ; Hesselink, Matthijs ; Sparks, Lauren ; Timmers, Silvie ; Ferraz, Maria ; Mattijssen, Frits ; Beurden, Denis van; Schaart, Gert ; DeBaets, Marc ; Verheyen, Fons ; Kersten, Sander ; Schrauwen, Patrick - \ 2012
Mus musculus - GSE38590 - PRJNA168236
Type 2 diabetes is characterized by excessive lipid storage in skeletal muscle. Excessive intramyocellular lipid storage exceeds intracellular needs and induces lipotoxic events ultimately contributing to the development of insulin resistance. Lipid droplet (LD)-coating proteins may control proper lipid storage in skeletal muscle. Perilipin 2 (PLIN2/ADRP) is one of the most abundantly expressed LD-coating proteins in skeletal muscle. Here we examined the role of PLIN2 in myocellular lipid handling and insulin sensitivity by investigating the effects of in vitro PLIN2 knockdown and in vitro and in vivo overexpression. PLIN2 knockdown decreased LD formation and triacylglycerol storage, marginally increased FA oxidation, and increased incorporation of palmitate into diacylglycerols and phospholipids. PLIN2 overexpression in vitro increased intramyocellular TAG storage paralleled with improved insulin sensitivity. In vivo muscle-specific PLIN2 overexpression resulted in increased LD accumulation and blunted the high-fat diet-induced increase of OXPHOS protein content. Diacylglycerol levels were unchanged, while ceramide levels were increased. Despite the increased intramyocellular lipid accumulation, PLIN2 overexpression improved skeletal muscle insulin sensitivity. We conclude that PLIN2 is essential for lipid storage in skeletal muscle by enhancing the partitioning of excess FAs towards triacylglycerol storage in LDs thereby blunting lipotoxicity-associated insulin resistance.
Long- and Medium-Chain Fatty Acids Induce Insulin Resistance to a Similar Extent in Humans Despite Marked Differences in Muscle Fat Accumulation
Hoeks, J. ; Mensink, M.R. ; Hesselink, M.K.C. ; Ekroos, K. ; Schrauwen, P. - \ 2012
Journal of Clinical Endocrinology and Metabolism 97 (2012)1. - ISSN 0021-972X - p. 208 - 216.
human skeletal-muscle - intramyocellular lipid-content - prolonged exercise - ceramide content - obese subjects - oxidation - mechanism - men - diacylglycerol - sensitivity
Context: Animal studies revealed that medium-chain fatty acids (MCFA), due to their metabolic characteristics, are not stored in skeletal muscle and may therefore not give rise to potentially hazardous lipid species impeding insulin signaling. Objective: We here hypothesized that infusion of medium-chain triacylglycerols (MCT) in healthy lean subjects does not lead to ectopic fat accumulation and hence does not result in lipid-induced insulin resistance. Design and Methods: Nine healthy lean male subjects underwent a 6-h hyperinsulinemic-euglycemic clamp with simultaneous infusion of 1) a 100% long-chain triacylglycerols (LCT) emulsion, 2) a 50/50% MCT/LCT emulsion, or 3) glycerol in a randomized crossover design. Muscle biopsies were taken before and after each clamp. Results: MCT/LCT infusion raised plasma free fatty acid levels to a similar level compared with LCT infusion alone. Despite elevated free fatty acid levels, intramyocellular triacylglycerol (IMTG) levels were not affected by the MCT/LCT emulsion, whereas LCT infusion resulted in an approximately 1.6-fold increase in IMTG. These differences in muscle fat accumulation did not result in significant differences in lipid-induced insulin resistance between LCT (- 28%, P = 0.003) andMCT/LCT (-20%, P <0.001). Total skeletal muscle ceramide content as well as lactosyl-and glucosylceramide levels were not affected by any of the interventions. In addition, the distribution pattern of all ceramide species remained unaltered. Conclusions: Although we confirm that MCFA do not lead to ceramide and IMTG accumulation in skeletal muscle tissue in humans, they do induce insulin resistance. These results indicate that, in humans, MCFA may not be beneficial in preventing peripheral insulin resistance. (J Clin Endocrinol Metab 97: 208-216, 2012)
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