Cardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol... Show moreCardiovascular diseases are the leading cause of death worldwide, with atherosclerosis as most common underlying pathology. Atherosclerosis is characterized by arterial narrowing due to cholesterol and lipid accumulation. Despite available effective cholesterol lowering medication, considerable risk for recurrent vascular events remains. This residual risk is at least in part explained by high blood lipid levels. The research described in this thesis revealed novel therapeutic strategies that improve lipid metabolism and reduce atherosclerosis development in mice. Inhibition of the endocannabinoid system was found to be an effective strategy, as well as concomitant activation of two incretin hormone receptors, namely those for GIP and GLP1. For combined GIP/GLP1 receptor agonism we additionally showed strongly attenuated hepatic steatosis. We were also able to identify additional targets to attenuate hyperlipidemia by studying the mechanisms underlying the strong day-night rhythm of brown adipose tissue, which is a lipid combusting tissue. In this thesis, I also stress the importance of the choice in animal model when studying lipid-modifying interventions, and describe the development of the software tool RandoMice which can be used to improve the quality of preclinical studies by creating well-balanced experimental groups. Show less
The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and... Show moreThe research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.Leptin plays an important role during TB infection and has a huge impact on insulin sensitivity in zebrafish larvae. Similarly to what has been observed in the murine model, leptin deficiency in zebrafish increased the bacterial burden and mortality during the infection, leading to hyperglycemia and the development of insulin resistance. In addition, a novel SHP-1/SHP-2 inhibitor, NSC-87877, was shown to represent a promising anti-diabetic drug that can be used for further DM2 research, as it is able to rescue the phenotype of the leptin-deficient zebrafish and to restore glucose transport to the tissues. In contrast to metformin, NSC-87877 can act at very early developmental stages and inhibits the function of SHP-1 and factors that underlay impaired glucose metabolism, whereas metformin is mostly known to improve insulin sensitivity. Additionally, treatment with the glucocorticoid beclomethasone attenuates the metabolic changes associated with the infection, and transcriptional alterations induced by beclomethasone treatment suggest that genes involved in glucose metabolism, insulin and leptin signaling all play an important role in the modulation of the metabolism.Our data show that zebrafish larvae represent an interesting model system to investigate the complex pathology of TB, and the studies described in this thesis in which this model has been used have provided novel insights into the molecular mechanisms underlying wasting syndrome and the possibilities for adjunctive glucocorticoid therapy to alleviate this metabolic state. Show less
This thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome... Show moreThis thesis focuses on two processes involved in fighting infections: metabolism and immune cell motility and navigation.Regarding metabolism, we present ZebraGEM 2.0, an improved whole-genome scale metabolic reconstruction for zebrafish, that we used to study zebrafish metabolism upon infection with Mycobacterium marinum integrating gene expression data from control and infected zebrafish larvae. The chapters focusing on cell motility in response to the environment, revolve around the question of how the environmental inputs of cell-matrix interactions, cell-sized obstacles and cell-signalling upon wounding shape and guide cell motility. Show less
Atherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the... Show moreAtherosclerosis is the main underlying pathology of cardiovascular disease. Atherosclerosis is caused by an immune response which is directed against (modified) lipoproteins which accumulate in the vessel wall. Over time, this accumulation of lipids and immune cells induce morphological abnormalities in the vessel wall which cause the vessel lumen to narrow. This narrowing of the lumen (stenosis) causes ischemia in the downstream tissue. Prolonged ischemia causes myocardial ischemia and/or stroke. The research described in my thesis examines a well-recognized risk factor of atherosclerosis, being dyslipidemia, from an entirely new perspective. More specifically, it describes how dyslipidemia affects intrinsic metabolic processes in T cells, the conductors of the immune response characterizing atherosclerosis, and how this affects their function. My research has contributed to knowledge on the pathophysiology of atherosclerosis and might one day pave the way for the development of novel therapeutic approaches to treat cardiovascular disease. Show less
The work in this thesis describes the fundamental role of Lkb1 as a conductor of metabolism-related processes in zebrafish larvae. We show that Lkb1 is essential for the regulation of glucose... Show moreThe work in this thesis describes the fundamental role of Lkb1 as a conductor of metabolism-related processes in zebrafish larvae. We show that Lkb1 is essential for the regulation of glucose metabolism, the activation of autophagy, and hematopoiesis under conditions of metabolic stress. Furthermore, we also uncovered gene transcription profiles and hematological characteristics that are specific to lkb1 larvae, and independent of metabolic stress. Finally, we illustrate and highlight the potential of lkb1 larvae as screening platform in research related to metabolism, hematopoiesis, and tumors bearing LKB1 mutations. Overall, we have strengthened the value of lkb1 zebrafish larvae as a model to study the effects of Lkb1-inactivation on various metabolism-related processes Show less
Bacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their... Show moreBacteria are highly complex and diverse organisms that have adapted to survive in ecological niches ranging from the most extreme to the most heterogeneous environments. Actinobacteria, with their beautiful morphologies and complex multicellular life cycle, are a striking example. These filamentous bacteria produce many enzymes and natural products, including two-thirds of all known antibiotics, which makes them highly relevant for medical, biotechnological and industrial applications. In Streptomyces, complex and intertwining regulatory networks, consisting of pathway-specific and global regulators, control development and antibiotic production in response to environmental stimuli and stresses. This thesis explores how the model organism Streptomyces coelicolor senses environmental signals, related to oxygen stress and the availability of aminosugars, and how the bacterium translates these into appropriate responses. Show less
In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on... Show more In this thesis, metabolomics is used to study the role of the host-virus interaction on a metabolic level. A special emphasis is directed on the role of inflammation and oxidative stress on the metabolic level, as part of the innate immune response against viral infection. We chose respiratory syncytial virus (RSV) and hepatitis B virus (HBV) as candidate viruses to metabolically study their role in acute respiratory infection and chronic hepatitis B infection. Secondly we also investigated infant metabolic and immunological consequences of in utero exposure to antiretroviral intervention and human immunodeficiency virus (HIV). Collectively, established targeted metabolomics approaches in conjunction with newly developed metabolomics methodologies and complemented with other “omics” techniques, were used to address pertinent questions related to host metabolic functioning and alterations during viral infection. In vitro RSV studies together with in vivo patient based studies relating to chronic HBV infection and in utero exposure too antiretroviral and HIV were used to address these questions. The work is divided into three research parts containing: i. the analytical methodology development work, ii. in vitro based metabolomics and iii. patient based metabolomics. Show less
In today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin... Show moreIn today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin resistance. This thesis focuses on the differences in the energy and fatty acid metabolism that play a role in the susceptibility for metabolic complications. We have investigated certain existing associations between genetic clues and a disturbed energy metabolism, in order to construct a more refined mechanism of action for this genetic association. This knowledge could be used to more precisely target the causal proteins and pathways involved in the development of obesity. We have also investigated the role of fatty acid metabolism in the fat tissue of obese humans and mice. In this way, we have found a direct link in both humans and mice between fatty acids and inflammation, which is relevant for metabolic diseases such as obesity and insulin resistance. Show less
The thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day... Show moreThe thesis contains a large study in which eight male hypocretin deficient narcolepsy with cataplexy patients and eight matched controls were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken 2 times 3g per night for 5 consecutive nights. Both groups underwent 24-h blood sampling and many hormones (prolactin, Growth hormone, melatonin, ghrelin, leptin) were measured and compared before and during SXB treatment. A study using the golden standard on insuline sensitivity is decribed to compare insuline sensitivity between patients and controls, and between patients, before and during satisfactory SXB treatment. ANother study describes body and skintemperature differences between narcolepsy patients and controls. Another chapter describes a rarely described, common feature in narcolepsy, in which patients mistake the memory of a dream for a real experience. In another chapter describes that date of birth is not a risk factor for narcolepsy. Show less
This thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In... Show moreThis thesis aims to describe the role of glucose metabolism in human longevity and to translate the results to an intervention aimed at improving health in older age in the general population. In the first part, we describe evidence for enhanced glucose metabolism in long-lived families. Middle-aged individuals predisposed to longevity were characterized by enhande insulin action at the level of the skeletal muscle, lower accumulation of intramyocellular lipids and lower nocturnal glucose levels. These results have provided the biological basis upon which health-promoting intervention in older age may be funded. In the second part, we have shonw that an internet-based intervention is effective at increasing physical activity and improving health in an older population. Furthermore, increasing total daily physical activity in sedentary elderly was shown to lead to better metabolic health. Show less
The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN... Show moreThe studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated glucose uptake by muscle and insulin-stimulated FA uptake by WAT is in part dependent on insulin action in the brain. These effects of circulating insulin on peripheral organs via the brain are abrogated by high-fat diet. These brain-dependent effects of insulin could reflect a similar situation for other hormones, for instance thyroid hormones. Furthermore, we demonstrate that topiramate improves insulin resistance by restoring insulin sensitivity in the brain, suggesting that therapeutical targets in the brain may offer challenging new approaches to treat insulin resistance of peripheral organs in T2DM. Show less
Obesity and insulin resistance (IR) are multifactorial pathologies, characterized by a complex etiology. In addition to genetics, age and sex, environmental factors such as dietary composition and... Show moreObesity and insulin resistance (IR) are multifactorial pathologies, characterized by a complex etiology. In addition to genetics, age and sex, environmental factors such as dietary composition and lifestyle have profound effects on the development of both pathologies. Excess dietary energy intake (EI) per se has effects on energy homeostasis through physiological systems involved in maintenance of substrate balances. Moreover, the composition of the diet itself may contribute and aggravate the phenotype in time by acting as a second hit. In particular, high levels of saturated long chain fatty acids have been associated with the development of obesity and IR. In this thesis, we have addressed a number of important aspects that play a role in the development of diet-induced obesity and insulin resistance. Show less
Assessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to... Show moreAssessing metabolic risk in dialysis patients, three main aspects are important: a) the pathophysiologic effects of metabolic disturbances as known from the general population are unlikely to completely reverse once patients reach dialysis. b) Specific additional problems related to chronic kidney disease, in particular protein-energy wasting, may act as “competing risk”, overshadow effects and interfere in various hormonal regulations. c) In advanced chronic kidney disease, the pattern and composition of risk is changing. The aim of this thesis is to 1) Detect specific effects of metabolic alterations in dialysis patients 2) Provide explanations for conflicting results in the literature 3) Provide a rationale for novel interventions. In this thesis, the metabolic status of dialysis patients is adressed and its consequences for the decline in residual kidney function, cardiovascular events and survival. The metabolic status includes alterations in nutritional and hormonal status, focussing on: lipid metabolism, diabetes mellitus type 2, obesity, the role of adipokines, specific effects of protein-energy wasting, and Vitamin D status with the clinical consequences. The investigations are performed in two large cohorts of dialysis patients, the 4D and NECOSAD studies (The German Diabetes and Dialysis Study and The Netherlands Cooperative Study on the Adequacy of Dialysis). Show less
The nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include... Show moreThe nuclear symptoms and signs of Huntington__s disease (HD) consist of motor, cognitive and behavioural disturbances. Other less well-known, but prevalent and debilitating features of HD include unintended weight loss, sleep and circadian rhythm disturbances, as well as autonomic nervous system dysfunction. However, the pathogenesis of these less well-known features of HD is poorly understood and currently no effective treatment options are available. It is thus of paramount importance to elucidate the pathological basis of these symptoms and signs in order to design and apply more effective therapeutic interventions. Recently, substantial dysfunction of the hypothalamus was reported in both human studies and various knock-in and transgenic animal models of HD. The hypothalamus consists of groups of interconnected neuronal nuclei located at the base of the brain that regulate a broad array of physiologic, homeostatic and behavioural activities. Therefore, in this thesis we attempt to substantiate the premise that hypothalamic dysfunction per se, as well as secondary (neuro)endocrine and metabolic alterations could contribute to the pathogenesis of several non-motor symptoms and signs of HD. Show less
The first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington... Show moreThe first part deals with the hypothalamic hypocretin system in disorders that are accompanied by narcolepsy-like sleep disturbances, i.e. Prader-Willi Syndrome, Parkinson__s Disease and Huntington__s Disease. To determine whether the hypocretin system is affected in these disorders, the total number of hypocretin neurons was determined using quantitative techniques in post-mortem human hypothalami. The reason why hypocretin neurons disappear in narcolepsy is still a mystery. A putative autoimmune aetiology has been hypothesized, but a screening for autoantibodies and a n=1 trial with intravenous immunoglobulins yielded no unequivocal results in favor of this hypothesis. In the second part, the consequences of hypocretin deficiency in narcoleptic patients are explored, focussing on vigilance, metabolism and the autonomic nervous system and skin temperature regulation. The ability of a specific neuropsychological test to measure vigilance as a severity indicator for narcolepsy is explored. Two possible causes for the obesity commonly seen in narcolepsy are a decreased basal metabolic rate and a changed autonomic tone. To assess the influence of hypocretin deficiency on skin temperature regulation, thermoregulatory profiles of the proximal and distal skin of narcoleptic subjects were compared to profiles of healthy controls during a daytime sleep registration. Show less
There is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid... Show moreThere is a fundamental difference between mammals and fish in how hypoxia affects the lipid metabolism by means of the stress hormone noradrenaline. In mammals, hypoxia induces an increase in lipid metabolism, which can eventually lead to tissue damage due to elevated plasma fatty acid levels, e.g. in case of a heart attack. However, hypoxia is not a normally occurring situation in healthy mammals as opposed to many fish species, because water is a relative poor source of oxygen. In hypoxic fish therefore, noradrenaline mediates a decrease in lipid metabolism, and we believe that this is a general protection mechanism in fish against lipid poisoning. There is a clear difference in the mode of breathing between mammals and fish, namely air- vs. water-breathing. Hence, we hypothesise that this difference is the cause for the opposing effects of noradrenaline. Therefore, we studied the effects of hypoxia on an air-breathing fish, the African catfish. However, physiologically this species reacted the same as other water-breathing fish, namely by means of a reduced lipid metabolism. Additionally, we demonstrated that, despite the opposing effects on the lipid metabolism, the transduction pathways in fish and mammals are very alike, and thus only a minor change has occurred in the course of evolution. This research has aided in a better understanding of the evolutionary changes in lipid metabolism.|Er is een fundamenteel verschil tussen zoogdieren en vissen in hoe het vetmetabolisme onder hypoxie (=zuurstoftekort) wordt veranderd door het stresshormoon noradrenaline. In zoogdieren leidt hypoxie tot een verhoogd vetmetabolisme, wat uiteindelijk zelfs weefselschade kan veroorzaken door te hoge vetzuurgehaltes, b.v. bij een hartaanval. Gezonde zoogdieren komen normaliter niet in zuurstofnood, in tegenstelling tot veel vissoorten, omdat water een relatief arme zuurstofbron is. In hypoxische vissen daalt dan ook het vetmetabolisme door noradrenaline, en wij denken dat dit een beschermingsmechanisme is tegen een vetzuurvergiftiging. Er is een duidelijk verschil in de manier van ademhalen van zoogdieren en vissen, respectievelijk lucht- en waterademhaling, en dit verschil ligt mogelijkerwijs ten grondslag aan deze verschillende effecten van noradrenaline; dit is de centrale hypothese van het onderzoek. Daarom is gekeken naar het effect van zuurstoftekort bij een luchtademhalende vissoort, de Afrikaanse meerval. Deze vis bleek echter fysiologisch hetzelfde te reageren als waterademhalende vissen, namelijk een verlaagd vetmetabolisme. Daarnaast is aangetoond dat, ondanks tegenovergestelde effecten op het vetmetabolisme, de aansturingmechanismen in vissen en zoogdieren vergelijkbaar zijn, en dat er dus maar een minimale verandering in de evolutie heeft plaatsgevonden. Dit onderzoek heeft bijgedragen tot een beter begrip van de evolutionaire veranderingen in het vetmetabolisme. Show less
