Patrick Schrauwen

Maastricht Universitair Medisch Centrum, Maestricht, Limburg, Netherlands

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Publications (216)1250.22 Total impact

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    ABSTRACT: Fat accumulation in nonadipose tissue is linked to insulin resistance and metabolic diseases. Earlier studies have shown that hepatic lipid accumulation can occur after 4 d of a high-fat diet in humans, and this fat accumulation can be blunted by the ingestion of additional proteins. In this study, we explored whether a single high-fat meal increased the lipid content in liver and skeletal muscle as measured by using in vivo proton magnetic resonance spectroscopy ((1)H-MRS) and whether the addition of protein can modulate the postprandial ectopic lipid storage. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) concentrations were determined by using (1)H-MRS before and 3 and 5 h after a high-fat with added protein meal (61.5% of energy from fat) or a high-fat without added protein meal (mean ± SEM: 51.1 ± 7.9 g of protein; 191.9 ± 9.9 kcal added) in a randomized crossover study. IHL and IMCL concentrations were converted to absolute concentrations (g/kg wet weight) by using water as an internal reference. Nine lean, healthy subjects [6 men and 3 women; mean (±SD) age: 22.7 ± 3.0 y; mean body mass index (in kg/m(2)): 21.8 ± 1.8] were included in this study. IHL concentrations increased ∼20% (P < 0.01) at 3 h after the meal and did not further increase after 5 h. In contrast, IMCL concentrations were not altered during the postprandial period (P = 0.74). The addition of protein to a single high-fat meal did not change the postprandial accumulation of fat in the liver (P = 0.93) or skeletal muscle (P = 0.84). In this study, we showed that a single energy-dense, high-fat meal induced net lipid accumulation in the liver, which was detected by using in vivo (1)H-MRS. This noninvasive approach might bring new opportunities to study postprandial hepatic lipid dynamics. The addition of protein did not change the ectopic lipid retention after a single high-fat meal. This trial was registered at as NCT01709643. © 2015 American Society for Nutrition.
    American Journal of Clinical Nutrition 01/2015; 101(1):65-71. · 6.50 Impact Factor
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    ABSTRACT: Aims/hypothesis Human brown adipose tissue (BAT) has recently emerged as a potential target in the treatment of type 2 diabetes, owing to its capacity to actively clear glucose from the circulation—at least upon cold exposure. The effects of insulin resistance on the capacity of human BAT to take up glucose are unknown. Prolonged fasting is known to induce insulin resistance in peripheral tissues in order to spare glucose for the brain. Methods We studied the effect of fasting-induced insulin resistance on the capacity of BAT to take up glucose during cold exposure as well as on cold-stimulated thermogenesis. BAT glucose uptake was assessed by means of cold-stimulated dynamic 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) imaging. Results We show that a 54 h fasting period markedly decreases both cold-induced BAT glucose uptake and nonshivering thermogenesis (NST) during cold stimulation. In vivo molecular imaging and modelling revealed that the reduction of glucose uptake in BAT was due to impaired cellular glucose uptake and not due to decreased supply. Interestingly, decreased BAT glucose uptake upon fasting was related to a decrease in core temperature during cold exposure, pointing towards a role for BAT in maintaining normothermia in humans. Conclusions/interpretation Cold-stimulated glucose uptake in BAT is strongly reduced upon prolonged fasting. When cold-stimulated glucose uptake in BAT is also reduced under other insulin-resistant states, such as diabetes, cold-induced activation of BAT may not be a valid way to improve glucose clearance by BAT under such conditions. Trial registration: NTR3523 Funding: This work was supported by the EU FP7 project DIABAT (HEALTH-F2-2011-278373 to WDvML) and by the Netherlands Organization for Scientific Research (TOP 91209037 to WDvML).
    Diabetologia 12/2014; · 6.88 Impact Factor
  • Marlies de Ligt, Silvie Timmers, Patrick Schrauwen
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    ABSTRACT: There is an increasing need for novel preventive and therapeutic strategies to combat obesity and related metabolic disorders. In this respect, the natural polyphenol resveratrol has attracted significant interest. Animal studies indicate that resveratrol mimics the effects of calorie restriction via activation of sirtuin 1 (SIRT1). SIRT1 is an important player in the regulation of cellular energy homeostasis and mitochondrial biogenesis. Rodent studies have shown beneficial effects of resveratrol supplementation on mitochondrial function, glucose metabolism, body composition and liver fat accumulation. However, confirmation of these beneficial effects in humans by placebo-controlled clinical trials remains relatively limited. This review will give an overview of pre-clinical and clinical studies examining the effects of resveratrol on obesity-induced negative health outcomes. This article is part of a Special Issue entitled: Resveratol: Challenges in translating pre-clinical findings to improve patient outcomes, guest edited by J. Dyck and P. Schrauwen. Copyright © 2014 Elsevier B.V. All rights reserved.
    Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 11/2014; · 5.09 Impact Factor
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    ABSTRACT: UCP3's exact physiological function in lipid handling in skeletal and cardiac muscle remains unknown. Interestingly, etomoxir, a fat oxidation inhibitor and strong inducer of UCP3, is proposed for treating both diabetes and heart failure. We hypothesize that the upregulation of UCP3 upon etomoxir serves to protect mitochondria against lipotoxicity. To evaluate UCP3's role in skeletal muscle (skm) and heart under lipid-challenged conditions, the effect of UCP3 ablation was examined in a state of dysbalance between fat availability and oxidative capacity. Wild type (WT) and UCP3(-/-) mice were subjected to high-fat feeding for 14 days. From day 6 onwards, they were given either saline or etomoxir. Etomoxir treatment induced an increase in markers of lipotoxicity in skm compared to saline. This increase upon etomoxir was similar for both, WT and UCP3(-/-) mice, suggesting that UCP3 does not play a role in protection against lipotoxicity. Interestingly, we observed 25 % mortality in UCP3(-/-)s upon etomoxir administration vs. 11 % in WTs. This increased mortality in UCP3(-/-) compared to WT mice could not be explained by differences in cardiac lipotoxicity, apoptosis, fibrosis (histology, immunohistochemistry), oxidative capacity (respirometry) or function (echocardiography). Electrophysiology demonstrated, however, prolonged QRS and QTc intervals and greater susceptibility to ventricular tachycardia upon programmed electrical stimulation in etomoxir-treated UCP3(-/-)s versus WTs. Isoproterenol administration after pacing resulted in 75 % mortality in UCP3(-/-)s vs. 14 % in WTs. Our results argue against a protective role for UCP3 on skm metabolism under lipid overload, but suggest UCP3 to be crucial in prevention of arrhythmias upon lipid-challenged conditions.
    Archiv für Kreislaufforschung 11/2014; 109(6):447. · 5.96 Impact Factor
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    ABSTRACT: Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide : NAD+ : precursors to increase oxidative phosphorylation and improve metabolic health, but human data is lacking. Here, we hypothesized that the nicotinic acid derivative Acipimox, a NAD(+) precursor, would directly affect mitochondrial function, independent of reductions in non-esterified fatty acid (NEFA) concentrations. In a multi-center randomized cross-over trial, 21 patients with type 2 diabetes (age 57.7±1.1 years, BMI, 33.4±0.8 kg/m(2)) received either placebo or 250 mg Acipimox thrice daily for 2 weeks. Acipimox treatment increased plasma NEFA (759±44 vs. 1135±97 µmol/L, p<0.01 for placebo vs. Acipimox), due to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that Acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene-sets and by presence of a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response (UPR(mt)). Further studies in C2C12 myotubes confirmed a direct effect of Acipimox on NAD+ levels, mitonuclear protein imbalance and mitochondrial oxidative capacity. To the best of our knowledge, this is the first demonstration that NAD+ boosters can also directly impact skeletal muscle mitochondrial function in humans.
    Diabetes 10/2014; · 7.90 Impact Factor
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    ABSTRACT: Animal models suggest that acetylcarnitine production is essential for maintaining metabolic flexibility and insulin sensitivity. Because current methods to detect acetylcarnitine involve biopsy of the tissue of interest, noninvasive alternatives to measure acetylcarnitine concentrations could facilitate our understanding of its physiological relevance in humans. Here, we investigated the use of long-echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) to measure skeletal muscle acetylcarnitine concentrations on a clinical 3T scanner. We applied long-TE 1H-MRS to measure acetylcarnitine in endurance-trained athletes, lean and obese sedentary subjects, and type 2 diabetes mellitus (T2DM) patients to cover a wide spectrum in insulin sensitivity. A long-TE 1H-MRS protocol was implemented for successful detection of skeletal muscle acetylcarnitine in these individuals. There were pronounced differences in insulin sensitivity, as measured by hyperinsulinemic-euglycemic clamp, and skeletal muscle mitochondrial function, as measured by phosphorus-MRS (31P-MRS), across groups. Insulin sensitivity and mitochondrial function were highest in trained athletes and lowest in T2DM patients. Skeletal muscle acetylcarnitine concentration showed a reciprocal distribution, with mean acetylcarnitine concentration correlating with mean insulin sensitivity in each group. These results demonstrate that measuring acetylcarnitine concentrations with 1H-MRS is feasible on clinical MR scanners and support the hypothesis that T2DM patients are characterized by a decreased formation of acetylcarnitine, possibly underlying decreased insulin sensitivity.
    Journal of Clinical Investigation 10/2014; · 13.77 Impact Factor
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    ABSTRACT: The relevance of functional brown adipose tissue (BAT) depots in human adults was undisputedly proven approximately seven years ago. Here we give an overview of all dedicated studies that were published on cold-induced BAT activity in adult humans that appeared since then. Different cooling protocols and imaging techniques to determine BAT activity are reviewed. BAT activation can be achieved by means of air- or water-cooling protocols. The most promising approach is individualized cooling, during which subjects are studied at the lowest temperature for nonshivering condition, probably revealing maximal nonshivering thermogenesis. The highest BAT prevalence (i.e. close to 100%) is observed using the individualized cooling protocol. Currently, the most widely used technique to study the metabolic activity of BAT is [(18)F]FDG-PET/CT-imaging. Dynamic imaging provides quantitative information about glucose uptake rates, while static imaging reflects overall BAT glucose uptake, localization and distribution. In general, standardized uptake values (SUV) are used to quantify BAT activity. An accurate determination of total BAT volume is hampered by the limited spatial resolution of the PET-image, leading to spill over. Different research groups use different SUV threshold values, which make it difficult to directly compare BAT activity levels between studies. Another issue is the comparison of [(18)F]FDG uptake in BAT with respect to other tissues or upon with baseline values. This comparison can be performed by using the 'fixed volume' methodology. Finally, the potential use of other relatively noninvasive methods to quantify BAT, like MRI or thermography, is discussed.
    American journal of physiology. Regulatory, integrative and comparative physiology. 05/2014;
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    ABSTRACT: We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.
    Cell metabolism 05/2014; · 17.35 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of hepatic fat oxidation that serves as an energy source during starvation. Vanin-1 has been described as a putative PPARα target gene in liver, but its function in hepatic lipid metabolism is unknown. We investigated the regulation of vanin-1, and total vanin activity, by PPARα in mice and humans. Furthermore, the function of vanin-1 in the development of hepatic steatosis in response to starvation was examined in Vnn1 deficient mice, and in rats treated with an inhibitor of vanin activity. Liver microarray analyses reveals that Vnn1 is the most prominently regulated gene after modulation of PPARα activity. In addition, activation of mouse PPARα regulates hepatic- and plasma vanin activity. In humans, consistent with regulation by PPARα, plasma vanin activity increases in all subjects after prolonged fasting, as well as after treatment with the PPARα agonist fenofibrate. In mice, absence of vanin-1 exacerbates the fasting-induced increase in hepatic triglyceride levels. Similarly, inhibition of vanin activity in rats induces accumulation of hepatic triglycerides upon fasting. Microarray analysis reveal that the absence of vanin-1 associates with gene sets involved in liver steatosis, and reduces pathways involved in oxidative stress and inflammation. We show that hepatic vanin-1 is under extremely sensitive regulation by PPARα and that plasma vanin activity could serve as a readout of changes in PPARα activity in human subjects. In addition, our data propose a role for vanin-1 in regulation of hepatic TG levels during fasting.
    Journal of Hepatology 04/2014; · 9.86 Impact Factor
  • Marlies de Ligt, Patrick Schrauwen, Silvie Timmers
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    ABSTRACT: Resveratrol is een polyfenol dat van nature voorkomt in onder andere druiven, bramen en pinda’s. Resveratrol staat tegenwoordig veel in de belangstelling vanwege zijn potentiele gezondheidsbevorderende effecten bij mensen met een verstoorde stofwisseling, zoals mensen met obesitas of diabetes type 2. Zo zou resveratrol insuline en glucose in het bloed kunnen verlagen, vervetting van de lever verminderen en de mitochondriële functie verbeteren. Helaas zijn er nog maar weinig klinische studies verricht met resveratrol die deze bevindingen kunnen bevestigen of ontkrachten. Dit artikel zal ingaan op humaan onderzoek verricht binnen ons onderzoeksteam naar de effecten van resveratrol in obesitas en diabetes mellitus type 2.
    Nederlands tijdschrift voor fytotherapie. 04/2014; 27(2):10-12.
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    ABSTRACT: Physical activity increases energy metabolism in exercising muscle. Whether acute exercise elicits metabolic changes in nonexercising muscles remains unclear. We show that one of the few genes that is more highly induced in nonexercising muscle than in exercising human muscle during acute exercise encodes angiopoietin-like 4 (ANGPTL4), an inhibitor of lipoprotein lipase-mediated plasma triglyceride clearance. Using a combination of human, animal, and in vitro data, we show that induction of ANGPTL4 in nonexercising muscle is mediated by elevated plasma free fatty acids via peroxisome proliferator-activated receptor-δ, presumably leading to reduced local uptake of plasma triglyceride-derived fatty acids and their sparing for use by exercising muscle. In contrast, the induction of ANGPTL4 in exercising muscle likely is counteracted via AMP-activated protein kinase (AMPK)-mediated down-regulation, promoting the use of plasma triglycerides as fuel for active muscles. Our data suggest that nonexercising muscle and the local regulation of ANGPTL4 via AMPK and free fatty acids have key roles in governing lipid homeostasis during exercise.
    Proceedings of the National Academy of Sciences 03/2014; · 9.81 Impact Factor
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    ABSTRACT: Endurance exercise is associated with significant improvements in cardio-metabolic risk parameters. A role for myokines has been hypothesized, yet limited information is available about myokines induced by acute endurance exercise in humans. Therefore the aim of the study was to identify novel exercise-induced myokines in humans. To this end, we carried out a one hour one-legged acute endurance exercise intervention in 12 male subjects and a 12 week exercise training intervention in 18 male subjects. Muscle biopsies were taken before and after acute exercise or exercise training, and were subjected to microarray-based analysis of secreted proteins (secretome). For acute exercise, secretome analysis resulted in a list of 86 putative myokines, which was reduced to 29 by applying a fold-change cut-off of 1.5. Based on that shortlist, a selection of putative myokines was measured in the plasma using ELISA or multiplex assay. From that selection, CX3CL1 (fractalkine) and CCL2 (MCP-1) increased at both mRNA and plasma level. From the known myokines, only IL-6 and FGF21 changed at the mRNA level, whereas none of the known myokines changed at the plasma level. Secretome analysis of exercise training intervention resulted in a list of 69 putative myokines. Comparing putative myokines altered by acute exercise and exercise training revealed a very limited overlap of only 13 genes. In conclusion, this study identified CX3CL1 and CCL2 as myokines that were induced by acute exercise at the gene expression and plasma level and that may be involved in communication between skeletal muscle and other organs.
    Physiological Genomics 02/2014; · 2.81 Impact Factor
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    ABSTRACT: Calcium/calmodulin dependent protein kinase (CaMK) activation induces mitochondrial biogenesis in response to increasing cytosolic calcium concentrations. Calcium leak from the ryanodine receptor is regulated by reactive oxygen species (ROS), which are increased with high-fat feeding. Therefore, we examined whether ROS-induced CaMKII-mediated signalling induced skeletal muscle mitochondrial biogenesis in selected models of lipid oversupply. In obese Zucker rats and in high fat-fed rodents, in which muscle mitochondrial content was upregulated, CaMKII phosphorylation was increased independent of changes in calcium uptake, as sarco(endo)plasmic (SR) reticulum Ca(2+)-ATPase (SERCA) protein expression or activity were not altered, implicating altered SR calcium leak in the activation of CaMKII. In support of this, we found that high-fat feeding increased mitochondrial ROS emission and S-nitrosylation of the ryanodine receptor while hydrogen peroxide induced SR calcium leak from the ryanodine receptor and activation of CaMKII. Moreover, administration of a mitochondrial-specific antioxidant (SkQ) prevented high-fat diet-induced phosphorylation of CaMKII as well as the induction of mitochondrial biogenesis. Altogether these data suggest that increased mitochondrial ROS emission is required for the induction of SR-calcium leak, activation of CaMKII and the induction of mitochondrial biogenesis in response to excess lipid availability.
    Diabetes 02/2014; · 7.90 Impact Factor
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    ABSTRACT: Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). Here we investigated muscle lipid turnover in T2D versus BMI-matched controls and examined if putative in vivo differences would be preserved in the myotubes.Male obese T2D individuals (T2D) (n=6) and their BMI-matched controls (C) (n=6) underwent a hyperinsulinemic-euglycemic clamp, VO2max test, DXA scan, underwater weighing and muscle biopsy of v. lateralis. (14)C-palmitate and (14)C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue, as well as in primary myotubes.Palmitate oxidation (C: 0.99 ± 0.17, T2D: 0.53 ± 0.07nmol/mg protein; P=0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (C: 0.45 ± 0.13, T2D: 0.11 ± 0.02nmol/mg protein; P=0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P=0.38); however, incorporation of FAs into TAG was lower in T2D (P=0.03 for oleate and P=0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r=0.848, P=0.008).Our data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D.
    Diabetes 01/2014; · 7.90 Impact Factor
  • Patrick Schrauwen, Silvie Timmers
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    ABSTRACT: The number of people suffering from metabolic diseases is dramatically increasing worldwide. This stresses the need for new therapeutic strategies to combat this growing epidemic of metabolic diseases. A reduced mitochondrial function is one of the characteristics of metabolic diseases and therefore a target for intervention. Here we review the evidence that mitochondrial function may act as a target to treat and prevent type 2 diabetes mellitus, and, if so, whether these effects are due to reduction in skeletal muscle fat accumulation. We describe how exercise may affect these parameters and can be beneficial for type 2 diabetes. We next focus on alternative ways to improve mitochondrial function in a non-exercise manner. Thus, in 2003, resveratrol (3,5,4'-trihydroxystilbene) was discovered to be a small molecule activator of sirtuin 1, an important molecular target regulating cellular energy metabolism and mitochondrial homoeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. Here we review data in human subjects that is available on the effects of resveratrol on metabolism and mitochondrial function and discuss how resveratrol may serve as a new therapeutic strategy to preserve metabolic health. We also discuss whether the effects of resveratrol are similar to the effects of exercise training and therefore if resveratrol can be considered as an exercise mimetic.
    Proceedings of The Nutrition Society 01/2014; · 3.67 Impact Factor
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    ABSTRACT: PURPOSE Brown adipose tissue (BAT) is involved in non-shivering thermogenesis (NST). Novel non-invasive imaging methods are required to monitor the pharmaceutical targeting of BAT as a potential treatment of obesity. FDG-PET combined with CT is so far the only non-invasive method to detect active BAT. The aim of this work was to investigate the use of MRI to determine the presence of active BAT. METHOD AND MATERIALS Eleven healthy young adults were included. The subjects underwent MRI and FDG-PET/CT imaging of the supra-clavicular/cervical fat depots containing BAT. Cooling was performed by wrapping the subjects in a water-perfused suit connected to temperature controlled water baths. Prior to the PET/CT, subjects were exposed to mild cold conditions during which maximum NST occurs. Subjects were injected with 74 MBq FDG as a tracer of metabolic activity. BAT activity was quantified by auto-contouring BAT with a set threshold. In the MRI water-fat (Dixon) imaging was performed under normal ambient conditions followed by dynamic T2* weighted imaging during which subjects were exposed to a repeated boxcar cooling paradigm to activate the BAT. RESULTS Water-fat MRI showed that supra-clavicular/cervical fat depots had an average fat content of 65.2 ± 7.0 %. For the regions identified as active BAT on PET/CT, the fat content was 66.0 ± 9.3 %. The volume fraction of activated voxels in the depots as measured by fMRI correlated with the activity concentration of FDG uptake on the PET/CT (R=0.63, P<0.05). CONCLUSION Our results suggest (active) BAT cannot be identified based on the fat fraction of the supra-clavicular/cervical depots. The use of fMRI to measure the presence of active BAT is promising as the fraction of activating voxels correlated with FDG uptake on PET/CT. CLINICAL RELEVANCE/APPLICATION Pharmaceutical targeting of BAT may be a potential strategy in the treatment of obesity and imaging methods are needed to monitor its response.
    Radiological Society of North America 2013 Scientific Assembly and Annual Meeting; 12/2013
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    ABSTRACT: The accumulation of lipids in non-adipose tissues is attracting increasing attention due to its correlation with obesity. In muscle tissue, ectopic deposition of specific lipids is further correlated with pathogenic development of insulin resistance and type 2 diabetes. Most intramyocellular lipids are organized into lipid droplets (LDs), which are metabolically active organelles. In order to better understand the putative role of LDs in pathogenesis, insight into both the location of LDs and nearby chemistry of muscle tissue is very useful. Here, we demonstrate the use of label-free coherent anti-Stokes Raman scattering (CARS) microscopy in combination with multivariate, chemometric analysis to visualize intracellular lipid accumulations in ex vivo muscle tissue. Consistent with our previous results, hyperspectral CARS microscopy showed an increase in LDs in tissues where LD proteins were overexpressed, and further chemometric analysis showed additional features morphologically (and chemically) similar to mitochondria that colocalized with LDs. CARS imaging is shown to be a very useful method for label-free stratification of ectopic fat deposition and cellular organelles in fresh tissue sections with virtually no sample preparation.
    Histochemie 11/2013; · 2.93 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptor δ (PPARδ) is a critical regulator of energy metabolism in the heart. Here, we propose a mechanism that integrates two deleterious characteristics of heart failure, hypoxia and a metabolic shift toward glycolysis, involving the microRNA cluster miR-199a∼214 and PPARδ. We demonstrate that under hemodynamic stress, cardiac hypoxia activates DNM3os, a noncoding transcript that harbors the microRNA cluster miR-199a∼214, which shares PPARδ as common target. To address the significance of miR-199a∼214 induction and concomitant PPARδ repression, we performed antagomir-based silencing of both microRNAs and subjected mice to biomechanical stress to induce heart failure. Remarkably, antagomir-treated animals displayed improved cardiac function and restored mitochondrial fatty acid oxidation. Taken together, our data suggest a mechanism whereby miR-199a∼214 actively represses cardiac PPARδ expression, facilitating a metabolic shift from predominant reliance on fatty acid utilization in the healthy myocardium toward increased reliance on glucose metabolism at the onset of heart failure.
    Cell metabolism 09/2013; 18(3):341-54. · 17.35 Impact Factor
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    ABSTRACT: Polyphenolic compounds, such as resveratrol have recently received widespread interest due to 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/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 towards 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 (TFEB) were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function.International Journal of Obesity accepted article preview online, 20 August 2013. doi:10.1038/ijo.2013.155.
    International journal of obesity (2005) 08/2013; · 5.22 Impact Factor
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    ABSTRACT: In recent years, it has been shown that humans have active brown adipose tissue (BAT) depots, raising the question of whether activation and recruitment of BAT can be a target to counterbalance the current obesity pandemic. Here, we show that a 10-day cold acclimation protocol in humans increases BAT activity in parallel with an increase in nonshivering thermogenesis (NST). No sex differences in BAT presence and activity were found either before or after cold acclimation. Respiration measurements in permeabilized fibers and isolated mitochondria revealed no significant contribution of skeletal muscle mitochondrial uncoupling to the increased NST. Based on cell-specific markers and on uncoupling protein-1 (characteristic of both BAT and beige/brite cells), this study did not show "browning" of abdominal subcutaneous white adipose tissue upon cold acclimation. The observed physiological acclimation is in line with the subjective changes in temperature sensation; upon cold acclimation, the subjects judged the environment warmer, felt more comfortable in the cold, and reported less shivering. The combined results suggest that a variable indoor environment with frequent cold exposures might be an acceptable and economic manner to increase energy expenditure and may contribute to counteracting the current obesity epidemic.
    The Journal of clinical investigation 07/2013; · 15.39 Impact Factor

Publication Stats

6k Citations
1,250.22 Total Impact Points


  • 2009–2014
    • Maastricht Universitair Medisch Centrum
      Maestricht, Limburg, Netherlands
  • 1995–2014
    • Maastricht University
      • • Humane Biologie
      • • Radiologie
      • • Department of Respiratory Medicine
      • • Bewegingswetenschappen
      Maestricht, Limburg, Netherlands
  • 2013
    • IT University of Copenhagen
      København, Capital Region, Denmark
    • Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval)
      Québec, Quebec, Canada
  • 2012
    • Wageningen University
      • Division of Human Nutrition
      Wageningen, Provincie Gelderland, Netherlands
  • 2011
    • Leiden University Medical Centre
      • Department of Human Genetics
      Leiden, South Holland, Netherlands
  • 2005
    • Pennington Biomedical Research Center
      Baton Rouge, Louisiana, United States
    • Clinique romande de réadaptation
      Sitten, Valais, Switzerland
  • 2003
    • University of Geneva
      • Department of Biochemistry
      Genève, GE, Switzerland
  • 1998–1999
    • National Institutes of Health
      • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
      Bethesda, MD, United States