Atherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional... Show moreAtherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional coactivator to modulate inflammatory and metabolic processes. Here we investigated the potential anti-atherogenic effect of PRMT4 inhibitor TP-064 in vivo.\nMale apolipoprotein E knockout mice fed a high cholesterol/high fat Western-type diet were intraperitoneally injected three times a week with 2.5 mg/kg (low dose) or 10 mg/kg (high dose) TP-064 or with DMSO control.\nTP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p < 0.05 for trend) in the context of unchanged blood monocyte concentrations and neutrophilia induction (p < 0.01 for trend). A dose-dependent decrease in gonadal white adipose tissue expression levels of PPARγ target genes was detected, which translated into a reduced body weight gain after high dose TP-064 treatment (p < 0.05). TP-064 treatment also dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). In addition, a trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (-55%; p < 0.001) and Gck (-47%; p < 0.001) in high dose-treated mice. Plasma triglyceride levels were reduced by high dose TP-064 treatment (-30%; p < 0.05). However, no change was observed in the size or composition of aortic root atherosclerotic lesions.\nThe PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice. Show less
Stress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger... Show moreStress, obesity and (stress-related) mood disorders such as depression and anxiety disorders are highly prevalent in modern society. These diseases often coincide. This may be because they trigger and reinforce each other, creating a vicious cycle. Social and psychological factors play a role in this cycle, but in this thesis we focused on the underlying biological mechanisms. We identified new obesity-related factors that likely affect fear and discovered new sites of action in the brain for factors that are already known to regulate fear. We also applied three novel drug treatment strategies. Each of these target (different) components of the stress system and were shown to alleviate stress- or diet-induced metabolic disease in mice. Certain strategies reduced obesity, while others seemed to prevent or even cure fatty liver disease in mice. This thesis thus represents a step towards breaking the vicious cycle between stress, obesity and (stress-related) mood disorders. Show less
Background Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic... Show moreBackground Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown.MethodsCross-sectional study in 100 (65% women) individuals aged 18-25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample.ResultsIndividuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+42.5%), triglycerides (+63.9%), C-reactive protein (+124.2%), diastolic blood pressure (+5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity.ConclusionsPlasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults. Show less
Meulmeester, F.L.; Luo, J.; Martens, L.G.; Ashrafi, N.; Mutsert, R. de; Mook-Kanamori, D.O.; ... ; Noordam, R. 2021
Background and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations... Show moreBackground and aims: The accumulation of fat increases the formation of lipid perox-ides, which are partly scavenged by alpha-tocopherol (a-TOH). Here, we aimed to investigate the associations between different measures of (abdominal) fat and levels of urinary a-TOH metab-olites in middle-aged individuals. Methods and results: In this cross-sectional analysis in the Netherlands Epidemiology of Obesity study (N Z 511, 53% women; mean [SD] age of 55 [6.1] years), serum a-TOH and a-TOH metab-olites from 24-h urine were measured as alpha-tocopheronolactone hydroquinone (a-TLHQ, oxidized) and alpha-carboxymethyl-hydroxychroman (a-CEHC, enzymatically converted) using liquid-chromatography-tandem mass spectrometry. Body mass index and total body fat were measured, and abdominal subcutaneous and visceral adipose tissue (aSAT and VAT) were as-sessed using magnetic resonance imaging. Using multivariable-adjusted linear regression ana -lyses, we analysed the associations of BMI, TBF, aSAT and VAT with levels of urinary a-TOH metabolites, adjusted for confounders. We observed no evidence for associations between body fat measures and serum a-TOH. Higher BMI and TBF were associated with lower urinary levels of TLHQ (0.95 [95%CI: 0.90, 1.00] and 0.94 [0.88, 1.01] times per SD, respectively) and with lower TLHQ relative to CEHC (0.93 [0.90, 0.98] and 0.93 [0.87, 0.98] times per SD, respectively). We observed similar associations for VAT (TLHQ: 0.94 [0.89, 0.99] times per SD), but not for aSAT. Conclusions: Opposite to our research hypothesis, higher abdominal adiposity was moderately associated with lower levels of oxidized a-TOH metabolites, which might reflect lower vitamin E antioxidative activity in individuals with higher abdominal fat instead. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background: Hand osteoarthritis (HOA) is a highly prevalent rheumatic disease that predominates in females and causes pain and loss of functional capacity. Obesity and metabolic syndrome have been... Show moreBackground: Hand osteoarthritis (HOA) is a highly prevalent rheumatic disease that predominates in females and causes pain and loss of functional capacity. Obesity and metabolic syndrome have been previously suggested to associate with the severity of HOA, but clarity on these associations is yet to be achieved.Objective: Test the association between obesity and other components of the metabolic syndrome and disability in women with hand osteoarthritis (HOA).Design: Individuals from EpiReumaPt epidemiological community-based study (2011-2013) are representative of the Portuguese population. Women with diagnosis of primary HOA were included.Primary outcome: hand functional status, assessed by Cochin questionnaire.Secondary outcomes: hand pain, assessed by visual analogue scale and tender hand joint count (THJ).Explanatory variables: obesity, diabetes mellitus, arterial hypertension and hypercholesterolemia. Possible associations between obesity and the other components of metabolic syndrome with Cochin score, hand pain and THJ were tested in a multivariable linear regression model.Potential confounders considered: age, education level and countrywide distribution.Results: 473 women with primary HOA were included. Forty percent were overweight and 29% obese. Ninety-three (19.8%) participants had diabetes, 261 (55.8%) reported hypertension and 261 (55.9%) hypercholesterolemia. Mean Cochin score was 15.5 +/- 14.8, mean pain VAS was 4.7 +/- 2.6 and mean THJ 1.4 +/- 3. In the multivariable analysis, obesity (beta 4.6 CI 0.7;8.5) and diabetes (beta 4.0 CI 0.4;7.6) were found to significantly associate with HOA functional disability. In addition, diabetes, but not obesity, associated with hand pain. There was no association between obesity or diabetes with THJ.Conclusion: In a Portuguese female population with primary HOA, obesity and diabetes mellitus independently associated with a worse hand functional status. These data add to evidence suggesting a role of metabolic factors in the severity of HOA. Show less
Objective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 2013dihydrocorticosterone (2013-DHB), is upregulated in... Show moreObjective: Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 2013dihydrocorticosterone (2013-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states. Methods: The actions of 2013-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding. Results: 2013-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 2013-DHB and absent in female mice with higher baseline adipose 2013-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding. Conclusions: Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice. (c) 2021 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Our increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher... Show moreOur increasing obesogenic and aging society has resulted in a steeply increasing prevalence of cardiometabolic diseases. The main underlying reason is our modern lifestyle with respect to higher availability and intake of food, which often appears unhealthy, and lower energy expenditure related to a sedentary lifestyle. Although the most efficient ways to slow this high prevalence of obesity are just eating less and more healthy, and moving more, to reduce energy intake and increase energy expenditure, respectively, current strategies to achieve this in the long-term are still both insufficient and ineffective, and novel strategies are still eagerly warranted.This thesis emphasizes dietary butyrate as a promising and feasible therapeutic strategy to combat obesity and related cardiometabolic diseases with respect to not only reducing appetite but also activating brown adipose tissue. In a series of subsequent mechanistic studies, we elucidated the mechanisms underlying these metabolic properties systematically from gut to the brain, showing the involvement of gut microbiota, intestinal GLP-1 secretion, vagal nerve activation, and finally central GLP-1 receptor signaling to inhibit NPY neuronal activation. The findings of this thesis provide valuable information on the development of novel therapeutic strategies for combating obesity and associated cardiometabolic diseases. Show less
Akpinar, E.O.; Marang- Van de Mheen, P.J.; Nienhuijs, S.W.; Greve, J.W.M.; Liem, R.S.L. 2021
Introduction Pooling population-based data from all national bariatric registries may provide international real-world evidence for outcomes that will help establish a universal standard of care,... Show moreIntroduction Pooling population-based data from all national bariatric registries may provide international real-world evidence for outcomes that will help establish a universal standard of care, provided that the same variables and definitions are used. Therefore, this study aims to assess the concordance of variables across national registries to identify which outcomes can be used for international collaborations. Methods All 18 countries with a national bariatric registry who contributed to The International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) Global Registry report 2019 were requested to share their data dictionary by email. The primary outcome was the percentage of perfect agreement for variables by domain: patient, prior bariatric history, screening, operation, complication, and follow-up. Perfect agreement was defined as 100% concordance, meaning that the variable was registered with the same definition across all registries. Secondary outcomes were defined as variables having "substantial agreement" (75-99.9%) and "moderate agreement" (50-74.9%) across registries. Results Eleven registries responded and had a total of 2585 recorded variables that were grouped into 250 variables measuring the same concept. A total of 25 (10%) variables have a perfect agreement across all domains: 3 (18.75%) for the patient domain, 0 (0.0%) for prior bariatric history, 5 (8.2%) for screening, 6 (11.8%) for operation, 5 (8.8%) for complications, and 6 (11.8%) for follow-up. Furthermore, 28 (11.2%) variables have substantial agreement and 59 (23.6%) variables have moderate agreement across registries. Conclusion There is limited uniform agreement in variables across national bariatric registries. Further alignment and uniformity in collected variables are required to enable future international collaborations and comparison. Show less
The objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long... Show moreThe objectives of this thesis were to elucidate the pathogenesis of metabolic heart disease, evaluate the associated changes in myocardial structure and contractile function, and determine the long-term prognostic implications of subclinical myocardial dysfunction on all-cause mortality. Show less
The research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in... Show moreThe research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in depth characterization of lysosome function in health and disease. An integrative approach was used to study the physiological role of the lysosome, characterizing the function of lysosomal hydrolases and signalling on a cellular level as well as within the context of tissue. Show less
Hoogenboom, S.A.; Bolan, C.W.; Chuprin, A.; Raimondo, M.T.; Hooft, J.E. van; Wallace, M.B.; Raimondo, M. 2021
Background: The prevalence of pancreatic ductal adenocarcinoma (PDAC) is on the rise, driven by factors such as aging and an increasing prevalence of obesity and diabetes mellitus. To improve the... Show moreBackground: The prevalence of pancreatic ductal adenocarcinoma (PDAC) is on the rise, driven by factors such as aging and an increasing prevalence of obesity and diabetes mellitus. To improve the poor survival rate of PDAC, early detection is vital. Recently, pancreatic steatosis has gained novel interest as a risk factor for PDAC. This study aimed to investigate if pancreatic steatosis on computed tomography (CT) is an early imaging feature in patients with pre-diagnostic PDAC.Methods: A retrospective case-control study was performed. Patients diagnosed with PDAC (2010-2016) were reviewed for abdominal non-contrast CT-imaging 1 month-3 years prior to their diagnosis. Cases were matched 1:4 with controls based on age, gender and imaging date. Unenhanced CT-images were evaluated for pancreatic steatosis (pancreas-to-spleen ratio in Hounsfield Units <0.70) by a blinded radiologist and results were compared between cases and controls.Results: In total, 32 cases and 117 controls were included in the study with a comparable BMI (29.6 and 29.2 respectively, p = 0.723). Pancreatic steatosis was present in 71.9% of cases compared to 45.3% of controls (Odds ratio (OR) 3.09(1.32-7.24), p = 0.009). Adjusted for BMI and diabetes mellitus, pancreatic steatosis on CT remained a significant independent risk factor for PDAC (Adjusted OR 2.70(1.14-6.58), p = 0.037).Conclusion: Pancreatic steatosis measured on CT is independently associated with PDAC up to three years before the clinical diagnosis in overweight patients. If these data are confirmed, this novel imaging feature may be used to identify high-risk individuals and to stratify the risk of PDAC in individuals that already undergo PDAC screening. (C) 2021 IAP and EPC. Published by Elsevier B.V. Show less
Type 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op... Show moreType 2 diabetes en hart- en vaatziekten (‘cardiometabole ziekten’) leiden wereldwijd tot veel sterfte. Vergeleken met mensen van West-Europese afkomst hebben Zuid-Aziaten een verhoogd risico op deze ziekten. Dit komt gedeeltelijk door hun ongunstige lichaamssamenstelling met veel buikvet en vetopslag in organen zoals spieren en lever, wat hun werking verstoort. Het verminderen van overgewicht verlaagt het risico op type 2 diabetes en hart- en vaatziekten. Verminderen van voedselinname en verhogen van het energieverbruik kan hieraan bijdragen. Een veelbelovende aanpak om het energieverbruik te verhogen, is het stimuleren van vet- en suikerverbranding door lichaamseigen bruin vetweefsel. In dit proefschrift onderzochten wij eerst mechanismen die bijdragen aan cardiometabole ziekten in Zuid-Aziaten. Wij observeerden verminderde Wnt signaaltransductie in wit vet van Zuid-Aziaten, wat samenhing met minder insulinegevoeligheid in dit weefsel. Ook vonden wij een andere samenstelling van LDL-deeltjes in Zuid-Aziaten, wat samenhing met een verhoogde neiging van deze deeltjes om samen te klonteren. Daarna onderzochten wij de effectiviteit van geneesmiddelen om bruin vet activiteit te verhogen en de cardiometabole gezondheid te verbeteren. Wij lieten zien dat stimuleren van de beta-adrenerge receptor de stofwisseling verhoogt en vetverbranding door bruin vet stimuleert, echter niet méer dan koudeblootstelling. Ook vonden wij dat GLP-1 receptoragonisme de suikeropname door bruin vet stimuleert, wat mogelijk bijdraagt aan een gunstig effect op het lichaamsgewicht en suiker- en vetstofwisseling. Deze studies hebben bijgedragen aan kennis over risicofactoren voor cardiometabole ziekten en de ontwikkeling van nieuwe therapeutische strategieën om deze ziekten tegen te gaan, vooral in Zuid-Aziaten. Show less
