With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
De uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische... Show moreDe uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische onderbouwing, overwogen dient te worden. Inmiddels wordt adipositas in de dagelijkse praktijk op meer dan alleen het BMI beoordeeld, namelijk ook de tailleomtrek en het lipidenprofiel. Echter, dergelijke aandacht bestaat nog niet voor de heterogeniteit van depressie. Een grotere bewustwording van de verschillende manifestaties van depressie-symptomatologie, die het gevolg kunnen zijn van uiteenlopende pathofysiologische mechanismen, is van essentieel belang. Wanneer een patiënt met depressie een atypisch energie-gerelateerd symptoomprofiel heeft, kan het nuttig zijn om diens metabole biomarkers te controleren om mogelijke ontwikkeling van cardiometabole ziekten te voorkomen. In de klinische praktijk moeten wij ons bij de behandeling van patiënten met depressie ook meer bewust worden van de correlatie tussen symptoomprofielen van depressie en afzonderlijke biologische en klinische manifestaties. Het is cruciaal om goed te kijken naar de symptomen die bij elke patiënt tot uiting komen. De resultaten van dit proefschrift tonen aan dat patiënten met een depressie die atypische energie-gerelateerde depressieve symptomen vertonen, genetisch en klinisch kwetsbaar zijn voor aan insulineresistentie gerelateerde ziekten (namelijk adipositas, metabole ontregelingen en diabetes mellitus type 2). Een gepersonaliseerde aanpak kan behulpzaam zijn in preventie van deze chronische en complexe ziekten. Hierbij dient er rekening gehouden worden met de heterogeniteit van depressie en de associatie tussen atypische energie-gerelateerde symptomen van depressie en deze ziekten. Show less
Rapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate... Show moreRapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate the impacts of urbanization on human health, especially metabolic health and allergic disease, by incorporating many aspects of scientific investigation. Our cluster-randomized-controlled trial showed that, helminth infection, a characteristic feature of rural areas, and anthelmintic treatment, could significantly affect metabolic profiles and hormones. Thus, the ongoing deworming program in Indonesia require in parallel, monitoring of the metabolic health. Additionally, based on our prospective cohort study and analysis on a large scale nationally representative data, although Indonesian rural populations have relatively better metabolic profiles compared to urban, lifelong residence in rural areas does not protect their community members from adverse metabolic changes due to urbanization. Next, we observed that majority of individuals with diabetes in Indonesia were undiagnosed and untreated, especially in rural populations, which warrants extensive action plan from all related stakeholders. Lastly, high-dimensional data analyses on the systemic and nasal mucosal immune profiles revealed a stronger inflammatory immune responses in the nasal mucosal of Indonesian urban young adults with allergic rhinitis compared to their rural counterparts. Show less
Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic... Show moreGlucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic control. In this thesis, the effects of treatment on the different adipose tissue depots and on cardiac function are described. In a randomised controlled trial, we treated patients with type 2 diabetes from South Asian descent, a population with increased risk to develop type 2 diabetes and cardiovascular disease compared to Western Europeans, with liraglutide, a GLP-1 receptor agonist, or placebo, and studied these subjects with MRI. We concluded that liraglutide and possibly other GLP-1 receptor agonists can be a good strategy to reduce the volume of visceral adipose tissue. This reduction was accompanied by a significant improvement of glycemic control. Lastly, we provided evidence that liraglutide does not improve cardiac function and myocardial tissue characteristics and thus does not improve diabetic cardiomyopathy. In addition, in another study, we studied the mechanism behind GLP-1 receptor agonism induced weight loss and concluded that liraglutide induces weight loss in humans by decreasing energy intake rather than by activating brown adipose tissue or increasing energy expenditure. Show less
Cardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases... Show moreCardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases, indicating inter-organ cross-talk as a therapeutic target. Herein, I explored the therapeutic potential of targeting inter-organ communication in cardiometabolic diseases, including obesity, atherosclerotic cardiovascular disease and non-alcoholic steatohepatitis, based on which I proposed novel therapies to tackle these diseases. On one hand, strategies can focus on regulating the gut microbiota-centered inter-organ cross-talk. We demonstrated that dietary interventions are efficient to modulate the gut microbiota composition and function, thereby regulating the gut microbial metabolite production. In particularly, we showed that dietary supplementation of butyrate, a gut microbial metabolite, and choline, a nutrient enriched in red meat, can beneficially modulate the gut microbiota to alleviate adiposity. On the other hand, therapies can also focus on liver-centered inter-organ cross-talk. We showed that improving hepatocyte mitochondrial function by γ hydroxybutyric acid not only improves liver metabolic function, but also reverses obesity and its associated metabolic diseases. Besides, cardiometabolic health can be improved by regulating systemic levels of hepatokines (e.g. FGF21). We showed that FGF21-based pharmacotherapies can regulate the cross-talk between the liver and adipose tissue to improve cardiometabolic diseases, especially fibrotic non-alcoholic steatohepatitis and atherosclerotic cardiovascular disease. Thus, the findings described in this thesis emphasize the importance of inter-organ cross-talk for cardiometabolic diseases, and have improved our knowledge on the mechanisms that underlie the risk in the ever-increasing population of individuals who suffer from cardiometabolic diseases. Show less
In this thesis, we have addressed two key objectives: 1) to gain more insight in various pathophysiological aspects of cardiometabolic diseases including in the disease proneSouth Asian population,... Show moreIn this thesis, we have addressed two key objectives: 1) to gain more insight in various pathophysiological aspects of cardiometabolic diseases including in the disease proneSouth Asian population, and 2) to study the physiological effects of cold exposure and identify a novel pharmacological approach to directly target BAT. Show less
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
Osteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for... Show moreOsteoarthritis is one of the most common musculoskeletal disorders. Despite its high prevalence, the pathogenesis of osteoarthritis is incompletely understood. A major risk factor for osteoarthritis is obesity. Not only due to increased mechanical stress, but also due to systemic factors such as lipids. Our knowledge on how lipids are involved in osteoarthritis is limited. Therefore, this thesis focusses on the association of lipids with hand and knee osteoarthritis. Firstly, we investigated the reproducibility of lipid measurements to guide future lipidomic research. Subsequently, comparison of the lipid profile of osteoarthritis patients in different disease stages showed that the lipid profile explained disease severity to a limited extent. We observed the strongest association of the lipid profile with hand pain, and no association with knee osteoarthritis. This suggests that lipotoxicity may play a larger role in the hand, while in the knee mechanical stress is more relevant. In addition, treatment with anti-inflammatory medication resulted in a change in lipid concentrations in patients with hand osteoarthritis, suggesting that lipids are involved in inflammation and/or pain processes. These insights may increase our understanding of osteoarthritis pathophysiology and lead to new targets for future development of disease modifying osteoarthritis medication. Show less
The aim of this thesis was to study the cardiometabolic consequences of obesity and weight gain during the life course. We investigated the association between body mass index (BMI) and... Show moreThe aim of this thesis was to study the cardiometabolic consequences of obesity and weight gain during the life course. We investigated the association between body mass index (BMI) and cardiometabolic disease using Mendelian randomization. We observed that all BMI-associated gene sets, grouped based on tissue expression, were similarly associated with increased risks of cardiometabolic disease. We observed that abdominal adiposity in adolescence was associated with early changes in metabolomic measures indicative of an atherogenic profile already present in young men. Weight gain during adulthood was specifically related to an atherogenic metabolic profile, in addition to increased adipocyte size. Adult weight gain between age 20 years and middle age was associated with increased visceral and liver fat at middle age. Additionally, the association between adult weight gain and insulin resistance at middle age was partly mediated by increased levels of visceral and liver fat at middle age. Lastly, we observed that a favourable body fat distribution as well as metabolic profile are associated with a decreased risk of incident cardiometabolic disease in a population with obesity. Overall, the results of this thesis emphasize the importance of maintaining a stable body weight during young adulthood throughout middle age. Show less
Overweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI)... Show moreOverweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI) classification, which is a measure of a person’s weight in kilograms (kg) divided by the square of height in meters (m2). Overweight is defined as a BMI of 25 kg/m2 or higher, whereas obesity is defined as a BMI of 30 kg/m2 or higher. It is estimated that one of every three individuals in the global population has overweight. The prevalence of obesity is increased threefold from 1975 to 2016, with a faster-growing pace in low- and middle-income countries than high-income countries. One common complication of obesity is the metabolic syndrome, which is defined as the co-occurrence of at least three out of five cardiometabolic abnormalities (abdominal obesity, hypertension, hyperglycaemia, hypertriglyceridemia, and low HDL-cholesterol). The metabolic syndrome is a strong risk factor for type 2 diabetes and cardiovascular diseases, and is considered a pathway from obesity to the cardiometabolic diseases occurrence. Thus, if metabolic syndrome or its components are identified and treated early, type 2 diabetes and cardiovascular diseases may be prevented. In this multi-ethnic global population, it is well-established that different ethnic populations have different cardiometabolic risks. Studies have shown that Asian populations develop cardiometabolic complications earlier at the same amount of adiposity as the Western populations. Show less
The overall aim of this thesis was to gain a clearer picture of the prevalence of food insecurity in the Netherlands and its consequences for dietary quality and health. The studies included in... Show moreThe overall aim of this thesis was to gain a clearer picture of the prevalence of food insecurity in the Netherlands and its consequences for dietary quality and health. The studies included in this thesis provide potential targets for interventions aimed at reducing food insecurity among affected people and families in the Netherlands.Based on this thesis, we can conclude that a considerable number of people in the Netherlands experience food insecurity. The findings described in this thesis provide insight into the consequences: food insecurity is associated with obesity, poor physical and mental health, and poor dietary quality. Our results also illuminate the role of sociodemographic and lifestyle factors, psychosocial factors and the food environment in these associations. In addition, our findings offer a clearer understanding of the perceived needs, perceptions and barriers regarding healthy eating among people at risk of experiencing food insecurity, as well as suggesting potential interventions. This thesis has shown that the issue of food insecurity needs to be better recognized and addressed in the Netherlands, for example through the development and implementation of population-based and risk group-based interventions for which appropriate screening and targeted interventions should be further explored. 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
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
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
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
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
In this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss... Show moreIn this thesis, we focussed on the management of obese patients with asthma. Based on the available knowledge about the obesity and asthma relationship, and the effects of different weight loss interventions in obese asthmatics, we defined the following aimsfor this thesis:1. To gain insight in the effects of exercise training in obese asthmatics and to determine the feasibility and effects of high intensity training in obese subjects2. To design a pulmonary rehabilitation program for obese patients with suboptimalcontrolled asthma and to determine the effectiveness of this program in a randomized controlled trial3. To improve our knowledge on the pathophysiology of obesity related asthma4. To gain insight in the risks and long-term effects of bariatric surgery in morbidlyobese subjects with asthma. Show less
Over the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart... Show moreOver the past decades, the number of individuals with type 2 diabetes has been growing worldwide. Type 2 diabetes is a major health concern, as it is related to several conditions, including heart failure and coronary artery disease. Despite remarkable advances in cardiovascular prevention and treatment, heart disease remains a common cause of death and an important contributor to health loss. The aim of this thesis was to characterize cardiovascular remodeling associated with metabolic disturbances, using a variety of magnetic resonance techniques. This thesis demonstrates that reduced diastolic function is a common characteristic of myocardial remodeling in type 2 diabetes and obesity, but also a potential marker for the detection of patients at increased cardiovascular risk after hematopoietic stem cell transplantation and possibly a contributing factor in the pathogenesis of ventricular arrhythmia after myocardial infarction. Also, in this thesis, it was shown that the evaluation of visceral adiposity and myocardial triglyceride content may help to identify distinct cardiometabolic phenotypes and to better understand the cardiometabolic actions of the glucagon-like peptide 1 receptor agonist liraglutide. With the emergence of non-contrast cardiovascular protocols, magnetic resonance techniques may be increasingly used for cardiometabolic phenotyping in population-based cohorts as well as clinical studies. Show less
The aim of this thesis was to evaluate quantitative MRI techniques in reno-cardiovascular health, and to study the links between obesity and reno-cardiovascular health using quantitative MRI... Show moreThe aim of this thesis was to evaluate quantitative MRI techniques in reno-cardiovascular health, and to study the links between obesity and reno-cardiovascular health using quantitative MRI metrics. Furthermore, we aimed to address novel insights on the safety of contrast media with regard to the use of gadolinium. The general introduction (Chapter 1) of this thesis introduces the concept of quantitative MRI, its application in epidemiological research, reno-cardiovascular health, and in obesity. In addition, the general introduction addresses the safety of gadolinium as an MRI contrast agent. Following the general introduction a review of the clinical application and technical considerations of quantitative MRI using T1 and T2(*) mapping in cardiac and renal imaging was provided in Chapter 2. Part 1 of this thesis focused on the reproducibility and clinical validity of T1 mapping and proton magnetic resonance spectroscopy (1H-MRS) in renal imaging. Part 2, described different studies evaluating the association between obesity and reno-cardiovascular function which was analyzed in population-based imaging studies using different quantitative MRI metrics. Part 3, provides an overview of the safety profile of gadolinium containing contrast agents, and reflection on the recent EMA recommendations. Show less
