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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Deletion of hematopoietic Dectin-2 or CARD9 does not protect against atherosclerotic plaque formation in hyperlipidemic mice
Thiem, Kathrin ; Hoeke, Geerte ; Berg, Susan van den; Hijmans, Anneke ; Jacobs, Cor W.M. ; Zhou, Enchen ; Mol, Isabel M. ; Mouktaroudi, Maria ; Bussink, Johan ; Kanneganti, Thirumala D. ; Lutgens, Esther ; Stienstra, Rinke ; Tack, Cees J. ; Netea, Mihai G. ; Rensen, Patrick C.N. ; Berbée, Jimmy F.P. ; Diepen, Janna A. van - \ 2019
Scientific Reports 9 (2019)1. - ISSN 2045-2322

Inflammatory reactions activated by pattern recognition receptors (PRRs) on the membrane of innate immune cells play an important role in atherosclerosis. Whether the PRRs of the C-type lectin receptor (CLR) family including Dectin-2 may be involved in the pathogenesis of atherosclerosis remains largely unknown. Recently, the CLR-adaptor molecule caspase recruitment domain family member 9 (CARD9) has been suggested to play a role in cardiovascular pathologies as it provides the link between CLR activation and transcription of inflammatory cytokines as well as immune cell recruitment. We therefore evaluated whether hematopoietic deletion of Dectin-2 or CARD9 reduces inflammation and atherosclerosis development. Low-density lipoprotein receptor (Ldlr)-knockout mice were transplanted with bone marrow from wild-type, Dectin-2- or Card9-knockout mice and fed a Western-type diet containing 0.1% (w/w) cholesterol. After 10 weeks, lipid and inflammatory parameters were measured and atherosclerosis development was determined. Deletion of hematopoietic Dectin-2 or CARD9 did not influence plasma triglyceride and cholesterol levels. Deletion of hematopoietic Dectin-2 did not affect atherosclerotic lesion area, immune cell composition, ex vivo cytokine secretion by peritoneal cells or bone marrow derived macrophages. Unexpectedly, deletion of hematopoietic CARD9 increased atherosclerotic lesion formation and lesion severity. Deletion of hematopoietic CARD9 did also not influence circulating immune cell composition and peripheral cytokine secretion. Besides a tendency to a reduced macrophage content within these lesions, plasma MCP-1 levels decreased upon WTD feeding. Deletion of hematopoietic Dectin-2 did not influence atherosclerosis development in hyperlipidemic mice. The absence of CARD9 unexpectedly increased atherosclerotic lesion size and severity, suggesting that the presence of CARD9 may protect against initiation of atherosclerosis development.

The impact of dispersal, plant genotype and nematodes on arbuscular mycorrhizal fungal colonization
Rasmussen, Pil U. ; Chareesri, Anupol ; Neilson, Roy ; Bennett, Alison E. ; Tack, Ayco J.M. - \ 2019
Soil Biology and Biochemistry 132 (2019). - ISSN 0038-0717 - p. 28 - 35.
Arbuscular mycorrhizal fungi - Colonization ability - Dispersal - Genotype - Nematodes - Plantago lanceolata

While the majority of parasitic and mutualistic microbes have the potential for long-range dispersal, the high turnover in community composition among nearby hosts has often been interpreted to reflect dispersal constraints. To resolve this apparent contradiction, we need further insights into the relative importance of dispersal limitation, host genotype and the biotic environment on the colonization process. We focused on the important root symbionts, the arbuscular mycorrhizal (AM) fungi. We studied AM fungal colonization ability in a controlled mesocosm setting, where we placed Plantago lanceolata plants belonging to four different genotypes in sterile soil at 10, 30 and 70 cm from a central AM fungal inoculated P. lanceolata plant. In part of the mesocosms, we also inoculated the source plants with nematodes. AM fungi colonized receiver plants <1 m away over the course of ten weeks, with a strong effect of distance from source plant on AM fungal colonization. Plant genotype influenced AM fungal colonization during the early stages of colonization, while nematode inoculation had no effect on AM fungal colonization. Overall, the effect of both dispersal limitation and plant genetic variation may underlie the small-scale heterogeneity found in natural AM fungal communities.

In vitro and in vivo Effects of Lactate on Metabolism and Cytokine Production of Human Primary PBMCs and Monocytes
Ratter, Jacqueline M. ; Rooijackers, Hanne M.M. ; Hooiveld, Guido J. ; Hijmans, Anneke G.M. ; Galan, Bastiaan E. de; Tack, Cees J. ; Stienstra, Rinke - \ 2018
Frontiers in Immunology 9 (2018). - ISSN 1664-3224
cytokines - glycolysis - immunometabolism - innate immune cells - lactate - monocytes

Lactate, the end product of anaerobic glycolysis, is produced in high amounts by innate immune cells during inflammatory activation. Although immunomodulating effects of lactate have been reported, evidence from human studies is scarce. Here we show that expression of genes involved in lactate metabolism and transport is modulated in human immune cells during infection and upon inflammatory activation with TLR ligands in vitro, indicating an important role for lactate metabolism in inflammation. Extracellular lactate induces metabolic reprogramming in innate immune cells, as evidenced by reduced glycolytic and increased oxidative rates of monocytes immediately after exposure to lactate. A short-term infusion of lactate in humans in vivo increased ex vivo glucose consumption of PBMCs, but effects on metabolic rates and cytokine production were limited. Interestingly, long-term treatment with lactate ex vivo, reflecting pathophysiological conditions in local microenvironments such as tumor or adipose tissue, significantly modulated cytokine production with predominantly anti-inflammatory effects. We found time- and stimuli-dependent effects of extracellular lactate on cytokine production, further emphasizing the complex interplay between metabolism and immune cell function. Together, our findings reveal lactate as a modulator of immune cell metabolism which translates to reduced inflammation and may ultimately function as a negative feedback signal to prevent excessive inflammatory responses.

Evaluation of chitotriosidase as a biomarker for adipose tissue inflammation in overweight individuals and type 2 diabetic patients
Tans, Roel ; Diepen, Janna A. van; Bijlsma, Sabina ; Verschuren, Lars ; Suppers, Anouk ; Stienstra, Rinke ; Wevers, Ron A. ; Tack, Cees J. ; Gloerich, Jolein ; Gool, Alain J. van - \ 2018
International Journal of Obesity 43 (2018). - ISSN 0307-0565 - p. 1712 - 1723.

Background: Overweight and obesity can lead to adipose tissue inflammation, which causes insulin resistance and on the long-term type 2 diabetes mellitus (T2D). The inflammatory changes of obese-adipose tissue are characterized by macrophage infiltration and activation, but validated circulating biomarkers for adipose tissue inflammation for clinical use are still lacking. One of the most secreted enzymes by activated macrophages is chitotriosidase (CHIT1). Objective: To test whether circulating CHIT1 enzymatic activity levels reflect adipose tissue inflammation. Methods: Plasma and adipose tissue samples of 105 subjects (35 lean, 37 overweight, and 33 T2D patients) were investigated. CHIT1 mRNA levels were determined in adipose tissue-resident innate immune cells. CHIT1 mRNA levels, protein abundance, and plasma enzymatic activity were subsequently measured in adipose tissue biopsies and plasma of control subjects with varying levels of obesity and adipose tissue inflammation as well as in T2D patients. Results: In adipose tissue, CHIT1 mRNA levels were higher in stromal vascular cells compared to adipocytes, and higher in adipose tissue-residing macrophages compared to circulating monocytes (p < 0.001). CHIT1 mRNA levels in adipose tissue were enhanced in overweightcompared to lean subjects and even more in T2D patients (p < 0.05). In contrast, plasma CHIT1 enzymatic activity did not differ between lean, overweight subjects and T2D patients. A mutation of the CHIT1 gene decreases plasma CHIT1 activity. Conclusions: CHIT1 is expressed by adipose tissue macrophages and expression is higher in overweight subjects and T2D patients, indicating its potential as tissue biomarker for adipose tissue inflammation. However, these differences do not translate into different plasma CHIT1 activity levels. Moreover, a common CHIT1 gene mutation causing loss of plasma CHIT1 activity interferes with its use as a biomarker of adipose tissue inflammation. These results indicate that plasma CHIT1 activity is of limited value as a circulating biomarker for adipose tissue inflammation in human subjects.

Interleukin-37 treatment of mice with metabolic syndrome improves insulin sensitivity and reduces pro-inflammatory cytokine production in adipose tissue
Ballak, Dov B. ; Li, Suzhao ; Cavalli, Giulio ; Stahl, Jonathan L. ; Tengesdal, Isak W. ; Diepen, Janna A. van; Klück, Viola ; Swartzwelter, Benjamin ; Azam, Tania ; Tack, Cees J. ; Stienstra, Rinke ; Mandrup-Poulsen, Thomas ; Seals, Douglas R. ; Dinarello, Charles A. - \ 2018
Journal of Biological Chemistry 293 (2018)37. - ISSN 0021-9258 - p. 14224 - 14236.

Obesity and the metabolic syndrome are characterized by chronic, low-grade inflammation mainly originating from expanding adipose tissue and resulting in inhibition of insulin signaling and disruption of glycemic control.Transgenic mice expressing human interleukin 37 (IL-37),an anti-inflammatory cytokine of the IL-1 family,are protected against metabolic syndrome when fed a high-fat diet (HFD) containing 45% fat. Here, we examined whether treatment with recombinant IL-37 ameliorates established insulin resistance and obesity-induced inflammation. WT mice were fed a HFD for 22 weeks and then treated daily with IL-37 (1 ug/mouse) during the last 2 weeks. Compared with vehicle only-treated mice, IL-37-treated mice exhibited reduced insulin in the plasma and had significant improvements in glucose tolerance and in insulin content of the islets.The IL-37 treatment also increased the levels of circulating IL-1 receptor antagonist. Cultured adipose tissues revealed that IL-37 treatment significantly decreases spontaneous secretions of IL-1β, tumor necrosis factor α (TNFα), and CXC motif chemokine ligand 1 (CXCL-1). We also fed mice a 60% fat diet with concomitant daily IL-37 for 2 weeks and observed decreased secretion of IL-1β, TNFα, and IL-6 and reduced intracellular levels of IL-1β in the liver and adipose tissue, along with improved plasma glucose clearance. Compared with vehicle treatment, these IL-37-treated mice had no apparent weight gain. In human adipose tissue cultures, the presence of 50 pM IL-37 reduced spontaneous release of TNF and 50% of lipopolysaccharide-induced TNFα. These findings indicate that IL-37's anti-inflammatory effects can ameliorate established metabolic disturbances during obesity.

Hypoglycaemia induces recruitment of non-classical monocytes and cytotoxic lymphocyte subsets in type 1 diabetes
Ratter, Jacqueline M. ; Rooijackers, Hanne M.M. ; Jacobs, Cor W.M. ; Galan, Bastiaan E. de; Tack, Cees J. ; Stienstra, Rinke - \ 2018
Diabetologia 61 (2018)9. - ISSN 0012-186X - p. 2069 - 2071.
Hypoglycaemia - Inflammation - Type 1 diabetes
Environmental Signals Influencing Myeloid Cell Metabolism and Function in Diabetes
Ratter, Jacqueline M. ; Tack, Cees J. ; Netea, Mihai G. ; Stienstra, Rinke - \ 2018
Trends in Endocrinology & Metabolism 29 (2018)7. - ISSN 1043-2760 - p. 468 - 480.
diabetes - immunometabolism - inflammation - macrophages

The environment induces metabolic reprogramming of immune cells via specific signaling pathways. Recent studies have revealed that changes in cell metabolism affect key immune cell functions including cytokine production and migration. In diabetes, these functions are either insufficiently or excessively activated, translating into diabetes-associated complications, including increased susceptibility to infection and accelerated cardiovascular disease. Diabetes alters the abundance of environmental signals, including glucose, insulin, and lipids. Subsequently, changes in environmental signals drive metabolic reprogramming, impair immune cell function, and ultimately contribute to diabetes-associated complications. We review here recent studies on changes in innate immune cell metabolism, especially in myeloid cells, that are driven by environmental signals relevant to diabetes, and discuss therapeutic perspectives of targeting metabolism of immune cells in diabetes.

Improvements in fitness are not obligatory for exercise training-induced improvements in CV risk factors
Hartman, Yvonne A.W. ; Hopman, Maria T.E. ; Schreuder, Tim H. ; Verheggen, Rebecca J.H.M. ; Scholten, Ralph R. ; Oudegeest-Sander, Madelijn H. ; Poelkens, Fleur ; Maiorana, Andrew J. ; Naylor, Louise H. ; Willems, Peter H. ; Tack, Cees J. ; Thijssen, Dick H.J. ; Green, Daniel J. - \ 2018
Physiological Reports 6 (2018)4. - ISSN 2051-817X
Cardiovascular diseases - exercise training - physical fitness - risk factors
The purpose of this study was to assess whether changes in physical fitness relate to changes in cardiovascular risk factors following standardized, center-based and supervised exercise training programs in subjects with increased cardiovascular risk. We pooled data from exercise training studies of subjects with increased cardiovascular risk (n = 166) who underwent 8–52 weeks endurance training. We determined fitness (i.e., peak oxygen uptake) and traditional cardiovascular risk factors (body mass index, blood pressure, total cholesterol, high-density lipoprotein cholesterol), before and after training. We divided subjects into quartiles based on improvement in fitness, and examined whether these groups differed in terms of risk factors. Associations between changes in fitness and in cardiovascular risk factors were further tested using Pearson correlations. Significant heterogeneity was apparent in the improvement of fitness and individual risk factors, with nonresponder rates of 17% for fitness, 44% for body mass index, 33% for mean arterial pressure, 49% for total cholesterol, and 49% for high-density lipoprotein cholesterol. Neither the number, nor the magnitude, of change in cardiovascular risk factors differed significantly between quartiles of fitness change. Changes in fitness were not correlated with changes in cardiovascular risk factors (all P > 0.05). Our data suggest that significant heterogeneity exists in changes in peak oxygen uptake after training, while improvement in fitness did not relate to improvement in cardiovascular risk factors. In subjects with increased cardiovascular risk, improvements in fitness are not obligatory for training-induced improvements in cardiovascular risk factors.
Year-to-year variation in the density of Ixodes ricinus ticks and the prevalence of the rodent-associated human pathogens Borrelia afzelii and B. miyamotoi in different forest types
Ruyts, Sanne C. ; Tack, Wesley ; Ampoorter, Evy ; Coipan, Elena C. ; Matthysen, Erik ; Heylen, Dieter ; Sprong, Hein ; Verheyen, Kris - \ 2018
Ticks and Tick-borne Diseases 9 (2018)2. - ISSN 1877-959X - p. 141 - 145.
Host community - Lyme borreliosis - Mast year - Spatiotemporal dynamics - Tick-borne disease risk

The human pathogens Borrelia afzelii, which causes Lyme borreliosis and B. miyamotoi, which causes relapsing fever, both circulate between Ixodes ricinus ticks and rodents. The spatiotemporal dynamics in the prevalence of these pathogens have not yet been fully elucidated, but probably depend on the spatiotemporal population dynamics of small rodents. We aimed to evaluate the effect of different forest types on the density of infected nymphs in different years and to obtain more knowledge about the spatial and temporal patterns of ticks and tick-borne pathogens. We analysed unfed nymphal ticks from 22 stands of four different forest types in Belgium in 2009, 2010, 2013 and 2014 and found that the density of nymphs in general and the density of nymphs infected with B. afzelii and B. miyamotoi varied yearly, but without temporal variation in the infection prevalence. The yearly variation in density of infected nymphs in our study thus seems to be caused most by the variation in the density of nymphs, which makes it a good predictor of disease risk. The risk for rodent-associated tick-borne diseases also varied between forest types. We stress the need to elucidate the contribution of the host community composition to tick-borne disease risk.

Insulin-associated weight gain in type 2 diabetes is associated with increases in sedentary behavior
Hartman, Yvonne A.W. ; Jansen, Henry J. ; Hopman, Maria T.E. ; Tack, Cees J. ; Thijssen, Dick H.J. - \ 2017
Diabetes Care 40 (2017)9. - ISSN 0149-5992 - p. e120 - e121.
Proinflammatory effects of hypoglycemia in humans with or without diabetes
Ratter, Jacqueline M. ; Rooijackers, Hanne M.M. ; Tack, Cees J. ; Hijmans, Anneke G.M. ; Netea, Mihai G. ; Galan, Bastiaan E. de; Stienstra, Rinke - \ 2017
Diabetes 66 (2017)4. - ISSN 0012-1797 - p. 1052 - 1061.

Severe hypoglycemic events have been associated with increased cardiovascular mortality in patients with diabetes, which may be explained by hypoglycemiainduced inflammation. We used ex vivo stimulations of peripheral blood mononuclear cells (PBMCs) and monocytes obtained during hyperinsulinemic-euglycemic (5.0 mmol/L)-hypoglycemic (2.6 mmol/L) clamps in 11 healthy participants, 10 patients with type 1 diabetes and normal awareness of hypoglycemia (NAH), and 10 patients with type 1 diabetes and impaired awareness (IAH) to test whether the composition and inflammatory function of immune cells adapt to a more proinflammatory state after hypoglycemia. Hypoglycemia increased leukocyte numbers in healthy control participants and patients with NAH but not in patients with IAH. Leukocytosis strongly correlated with the adrenaline response to hypoglycemia. Ex vivo, PBMCs and monocytes displayed a more robust cytokine response to microbial stimulation after hypoglycemia compared with euglycemia, although it was less pronounced in patients with IAH. Of note, hypoglycemia increased the expression of markers of demargination and inflammation in PBMCs. We conclude that hypoglycemia promotes mobilization of specific leukocyte subsets from themarginal pool and induces proinflammatory functional changes in immune cells. Inflammatory responses were less pronounced in IAH, indicating that counterregulatory hormone responses are key modulators of hypoglycemia-induced proinflammatory effects. Hypoglycemia-induced proinflammatory changes may promote a sustained inflammatory state.

SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes
Diepen, Janna A. van; Robben, Joris H. ; Hooiveld, Guido J. ; Carmone, Claudia ; Alsady, Mohammad ; Boutens, Lily ; Bekkenkamp-Grovenstein, Melissa ; Hijmans, Anneke ; Engelke, Udo F.H. ; Wevers, Ron A. ; Netea, Mihai G. ; Tack, Cees J. ; Stienstra, Rinke ; Deen, Peter M.T. - \ 2017
Diabetologia 60 (2017)7. - ISSN 0012-186X - p. 1304 - 1313.
Adipose tissue - Chemotaxis - Glucose - Inflammation - Macrophage - Obesity - Succinate - TCA cycle
Aims/hypothesis: Obesity induces macrophages to drive inflammation in adipose tissue, a crucial step towards the development of type 2 diabetes. The tricarboxylic acid (TCA) cycle intermediate succinate is released from cells under metabolic stress and has recently emerged as a metabolic signal induced by proinflammatory stimuli. We therefore investigated whether succinate receptor 1 (SUCNR1) could play a role in the development of adipose tissue inflammation and type 2 diabetes. Methods: Succinate levels were determined in human plasma samples from individuals with type 2 diabetes and non-diabetic participants. Succinate release from adipose tissue explants was studied. Sucnr1−/− and wild-type (WT) littermate mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 16 weeks. Serum metabolic variables, adipose tissue inflammation, macrophage migration and glucose tolerance were determined. Results: We show that hypoxia and hyperglycaemia independently drive the release of succinate from mouse adipose tissue (17-fold and up to 18-fold, respectively) and that plasma levels of succinate were higher in participants with type 2 diabetes compared with non-diabetic individuals (+53%; p < 0.01). Sucnr1−/− mice had significantly reduced numbers of macrophages (0.56 ± 0.07 vs 0.92 ± 0.15 F4/80 cells/adipocytes, p < 0.05) and crown-like structures (0.06 ± 0.02 vs 0.14 ± 0.02, CLS/adipocytes p < 0.01) in adipose tissue and significantly improved glucose tolerance (p < 0.001) compared with WT mice fed an HFD, despite similarly increased body weights. Consistently, macrophages from Sucnr1−/− mice showed reduced chemotaxis towards medium collected from apoptotic and hypoxic adipocytes (−59%; p < 0.05). Conclusions/interpretation: Our results reveal that activation of SUCNR1 in macrophages is important for both infiltration and inflammation of adipose tissue in obesity, and suggest that SUCNR1 is a promising therapeutic target in obesity-induced type 2 diabetes. Data availability: The dataset generated and analysed during the current study is available in GEO with the accession number GSE64104, www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE64104.
Activation of proteinase 3 contributes to nonalcoholic fatty liver disease and insulin resistance
Toonen, Erik J.M. ; Mirea, Andreea Manuela ; Tack, Cees J. ; Stienstra, Rinke ; Ballak, Dov B. ; Diepen, Janna A. van; Hijmans, Anneke ; Chavakis, Triantafyllos ; Dokter, Wim H. ; Pham, Christine Tn ; Netea, Mihai G. ; Dinarello, Charles A. ; Joosten, Leo A.B. - \ 2016
Molecular Medicine 22 (2016). - ISSN 1076-1551 - p. 202 - 214.

Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

Diabetes propels the risk for cardiovascular disease : sweet monocytes becoming aggressive?
Diepen, Janna A. van; Thiem, Kathrin ; Stienstra, Rinke ; Riksen, Niels P. ; Tack, Cees J. ; Netea, Mihai G. - \ 2016
Cellular and Molecular Life Sciences 73 (2016)24. - ISSN 1420-682X - p. 4675 - 4684.
Atherosclerosis - Diabetes - Epigenetics - Hyperglycemia - Inflammation - Metabolism - Trained immunity

Diabetes strongly predisposes to cardiovascular disease (CVD), the leading cause of mortality in these patients, as well as in the entire population. Hyperglycemia is an important cardiovascular risk factor as shown by the observation that even transient periods of hyperglycemia, despite return to normoglycemia during follow-up, increase the risk for CVD, a phenomenon termed ‘hyperglycemic memory’. The molecular mechanisms underlying this phenomenon remain largely unknown. As inflammation plays an important role in the pathogenesis of atherosclerosis, we propose that long-term functional reprogramming of monocytes and macrophages, induced by hyperglycemia, plays an important role in the phenomenon of hyperglycemic memory leading to cardiovascular complications in patients with diabetes. In this review, we discuss recent insights showing that innate immune cells possess the capacity to reprogram their function through epigenetically mediated rewiring of gene transcription, a process termed ‘trained immunity’. The long-term reprogramming of monocytes can be induced by microbial as well as metabolic products, and involves a shift in cellular metabolism from oxidative phosphorylation to aerobic glycolysis. We hypothesize that hyperglycemia in diabetes patients induces long-term activation of monocytes and macrophages through similar mechanisms, thereby contributing to plaque development and subsequent macrovascular complications.

Genetic and pharmacological inhibition of vanin-1 activity in animal models of type 2 diabetes
Diepen, Janna A. Van; Jansen, Patrick A. ; Ballak, Dov B. ; Hijmans, Anneke ; Rutjes, Floris P.J.T. ; Tack, Cees J. ; Netea, Mihai G. ; Schalkwijk, Joost ; Stienstra, Rinke - \ 2016
Scientific Reports 6 (2016). - ISSN 2045-2322

Vanins are enzymes that convert pantetheine to pantothenic acid (vitamin B5). Insights into the function of vanins have evolved lately, indicating vanin-1 to play a role in inflammation, oxidative stress and cell migration. Moreover, vanin-1 has recently gained attention as a novel modulator of hepatic glucose and lipid metabolism. In the present study, we investigated the role of vanin-1 in the development of hepatic steatosis and insulin resistance in animal models of obesity and diabetes. In addition, we evaluated the potency of RR6, a novel pharmacological vanin-1 inhibitor, as an anti-diabetic drug. Increased vanin activity was observed in plasma and liver of high fat diet (HFD)-induced obese mice, as well as ZDF-diabetic rats. Ablation of vanin-1 (Vnn1-/- mice) mildly improved glucose tolerance and insulin sensitivity in HFD-fed mice, but had no effects on body weight, hepatic steatosis or circulating lipid levels. Oral administration of RR6 for 8 days completely inhibited plasma vanin activity, but did not affect hepatic glucose production, insulin sensitivity or hepatic steatosis in ZDF-diabetes rats. In conclusion, absence of vanin-1 activity improves insulin sensitivity in HFD-fed animals, yet short-term inhibition of vanin activity may have limited value as an anti-diabetic strategy.

Beyond metacommunity paradigms : Habitat configuration, life history, and movement shape an herbivore community on oak
Zheng, Chaozhi ; Ovaskainen, Otso ; Roslin, Tomas ; Tack, Ayco J.M. - \ 2015
Ecology 96 (2015)12. - ISSN 0012-9658 - p. 3175 - 3185.
Bayesian community model - Dispersal ability - Habitat configuration - Metacommunity - Movement - Oak herbivore communities - Plant-insect interactions - Quercus robur - Southern Finland

Many empirical studies of metacommunities have focused on the classification of observational patterns into four contrasting paradigms characterized by different levels of movement and habitat heterogeneity. However, deeper insight into the underlying local and regional processes may be derived from a combination of long-term observational data and experimental studies. With the aim of exploring forces structuring the insect metacommunity on oak, we fit a hierarchical Bayesian state-space model to data from observations and experiments. The fitted model reveals large variation in species-specific dispersal abilities and basic reproduction numbers, R0. The residuals from the model show only weak correlations among species, suggesting a lack of strong interspecific interactions. Simulations with modelderived parameter estimates indicate that habitat configuration and species attributes both contribute substantially to structuring insect communities. Overall, our findings demonstrate that community-level variation in movement and life history are key drivers of metacommunity dynamics.

TLR-3 is present in human adipocytes, but its signalling is not required for obesity- Induced inflammation in adipose tissue in vivo
Ballak, Dov B. ; Asseldonk, Edwin J.P. Van; Diepen, Janna A. Van; Jansen, Henry ; Hijmans, Anneke ; Joosten, Leo A.B. ; Tack, Cees J. ; Netea, Mihai G. ; Stienstra, Rinke - \ 2015
PLoS ONE 10 (2015)4. - ISSN 1932-6203

Innate immunity plays a pivotal role in obesity-induced low-grade inflammation originating from adipose tissue. Key receptors of the innate immune system including Toll-like receptors- 2 and -4 (TLRs) are triggered by nutrient excess to promote inflammation. The role of other TLRs in this process is largely unknown. In addition to double-stranded viral mRNA, TLR-3 can also recognize mRNA from dying endogenous cells, a process that is frequently observed within obese adipose tissue. Here, we identified profound expression of TLR-3 in adipocytes and investigated its role during diet-induced obesity. Human adipose tissue biopsies (n=80) and an adipocyte cell-line were used to study TLR-3 expression and function. TLR-3-/- and WT animals were exposed to a high-fat diet (HFD) for 16 weeks to induce obesity. Expression of TLR-3 was significantly higher in human adipocytes compared to the non-adipocyte cells part of the adipose tissue. In vitro, TLR-3 expression was induced during differentiation of adipocytes and stimulation of the receptor led to elevated expression of pro-inflammatory cytokines. In vivo, TLR-3 deficiency did not significantly influence HFDinduced obesity, insulin sensitivity or inflammation. In humans, TLR-3 expression in adipose tissue did not correlate with BMI or insulin sensitivity (HOMA-IR). Together, our results demonstrate that TLR-3 is highly expressed in adipocytes and functionally active. However, TLR-3 appears to play a redundant role in obesity-induced inflammation and insulin resistance.

IL-1 family members in the pathogenesis and treatment of metabolic disease : Focus on adipose tissue inflammation and insulin resistance
Ballak, D.B. ; Stienstra, Rinke ; Tack, C.J. ; Dinarello, C.A. ; Diepen, J.A. van - \ 2015
Cytokine 75 (2015)2. - ISSN 1043-4666 - p. 280 - 290.
Adipose tissue - Inflammation - Insulin resistance - Interleukin-1 family - Obesity

Obesity is characterized by a chronic, low-grade inflammation that contributes to the development of insulin resistance and type 2 diabetes. Cytokines and chemokines produced by immunocompetent cells influence local as well as systemic inflammation and are therefore critical contributors to the pathogenesis of type 2 diabetes. Hence, cytokines that modulate inflammatory responses are emerging as potential targets for intervention and treatment of the metabolic consequences of obesity. The interleukin-1 (IL-1) family of cytokines and receptors are key mediators of innate inflammatory responses and exhibit both pro- and anti-inflammatory functions. During the last decades, mechanistic insights into how the IL-1 family affects the initiation and progression of obesity-induced insulin resistance have increased significantly. Here, we review the current knowledge and understanding, with emphasis on the therapeutic potential of individual members of the IL-1 family of cytokines for improving insulin sensitivity in patients with diabetes.

One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus
Asseldonk, E.J.P. van; Poppel, P.C.M. van; Ballak, D.B. ; Stienstra, Rinke ; Netea, M.G. ; Tack, C.J. - \ 2015
Clinical Immunology 160 (2015)2. - ISSN 1521-6616 - p. 155 - 162.
Adipose tissue - Anakinra - Inflammation - Insulin sensitivity - Interleukin 1 - Type 1 diabetes

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity.In an open label proof-of-concept study, we included overweight patients diagnosed with type 1 diabetes with an HbA1c level over 7.5%. Selecting insulin resistant patients with longstanding type 1 diabetes allowed us to study the effects of anakinra on insulin sensitivity. Patients were treated with 100. mg anakinra daily for one week. Insulin sensitivity, insulin need and blood glucose profiles were measured before, after one week and after four weeks of follow-up.Fourteen patients completed the study. One week of anakinra treatment led to an improvement of insulin sensitivity, an effect that was sustained for four weeks. Similarly, glucose profiles, HbA1c levels and insulin needs improved.In conclusion, one week of treatment with anakinra improves insulin sensitivity in patients with type 1 diabetes.

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.
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