In this thesis we examined several effects of fasting in lean and obese individuals. As expected, both the hormonal response as well as the metabolic shift from glucose towards lipid oxidation was... Show moreIn this thesis we examined several effects of fasting in lean and obese individuals. As expected, both the hormonal response as well as the metabolic shift from glucose towards lipid oxidation was impaired in obese individuals. At baseline, mitochondrial protein content in skeletal muscle of obese subjects was significantly reduced compared to lean individuals. We assessed the neuronal response to fasting by fMRI scanning. We found a different neuronal response to fasting between lean and obese individuals in terms of functional connectivity between the hypothalamus and respectively the dACC and insula. Since these regions are part of the saliency network, these differences may reflect distinct perception of calorie imbalance between lean and obese subjects. The effects of fasting on sympathetic tone (estimated by heart rate variability) were studied. Our data suggests that fasting decreases sympathetic tone in lean subjects, whereas it increases sympathetic activity in obese individuals. Weight loss in obese individuals increased HRV parameters that reflect the postprandial sympathetic tone. Finally, we studied the effects of fasting in the presence and absence of food-odors since this has been shown to reduce the fasting-induced increase in life span in fruit flies __ no differences were found in our human subjects. Show less
In this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic... Show moreIn this thesis, we evaluated the acute and more long-term effects of different weight loss strategies; pure calorie restriction by very low calorie diet and gastric banding, versus the drastic surgical procedure Roux-en-Y gastric bypass. Moreover, we found differences between NGT and T2DM subjects at baseline, which enable us to better be able to dissect the subsequent effects of the procedures. To our surprise, and in contrast to previous studies, we observed no additional effect of the RYGB as compared to calorie restriction, on our main outcome parameters: postprandial glucose, insulin and the gut peptide levels three weeks after surgery. Furthermore, both restrictive and RYGB induced weight loss resulted in comparable effects on the lipidome, circulating thyroid hormone levels and the autonomic nervous system. For these outcome parameters, it seems that calorie restriction is the common denominator of the effect of the different weight loss strategies on the short term. Clearly distinct effects of RYGB, however, were seen on bile salt, FGF21 and glucagon levels in response to food intake. Although neither the exact mechanisms, nor the eventual metabolic effect are as yet clear, the gut-liver-pancreas axis may be an important mediator of the effect of the RYGB Show less
This thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of... Show moreThis thesis investigates the role of adipose tissue inflammation in joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA) . In the first part, we show that baseline levels of circulating adiponectin can predict radiographic progression in patients with early RA. In contrast, in patients with hand OA, this association appears protective. Therefore, to obtain insight into the mechanisms underlying these associations, we investigated the high-molecular-weight isoform of adiponectin (hmwAPN), which is one of the most biologically active isoforms of adiponectin. We show that the associations of total adiponectin with radiographic progression are not mediated by hmwAPN, in either RA or HOA. In the second part, we present the immunological characterization of the infrapatellar fat pad (IFP), a joint associated adipose tissue, in patients with advanced knee OA. We observed profound differences in secreted inflammatory factors and immune cell composition between the IFP and paired subcutaneous adipose tissue samples. Interestingly, we observed obesity-related changes in the IFP phenotype, and in macrophages and adipocytes, Therefore, we investigated the modulatory effects of adipocytes on the phenotype of human macrophages in vitro and we observed that adipocyte-derived lipids can mediate the obesity-related changes in the phenotype of adipose tissue macrophages in humans Show less
In 1551, the Swiss naturalist Konrad Gessner first described brown adipose tissue (BAT) as being __neither fat, nor flesh (nec pinguitudo, nec caro), but something in between__. Now, some 460 years... Show moreIn 1551, the Swiss naturalist Konrad Gessner first described brown adipose tissue (BAT) as being __neither fat, nor flesh (nec pinguitudo, nec caro), but something in between__. Now, some 460 years later, we know that Gessner had guessed the origin of brown adipocytes correctly. A unique property of the brown adipocyte is its capacity to dissipate energy stored in triglycerides (TG) as heat, which is mediated via the uncoupling protein UCP1. The recent discovery that active BAT is present in human adults meant the beginning of an exciting new area in metabolic research. BAT is currently regarded as a potential target to combat obesity and related diseases by inducing a sustained increase in energy expenditure. Interestingly, South Asians have lower energy expenditure, which may thus theoretically be caused by a reduction in BAT activity. The studies of which the results are described in this thesis were aimed at 1) gaining more insight into the physiology of BAT, 2) identifying novel tools and targets that may activate BAT, and 3) investigating the involvement of BAT in metabolism in humans with a focus on potential differences between South Asians and white Caucasians. Show less
This thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients.... Show moreThis thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients. Because of the increasing number of patients with obesity and T2DM, more research is needed to identify patients at risk of developing T2DM and to elucidate specific therapeutic targets to improve insulin resistance. For now, the prevention of overweight and obesity is the most essential step in the fight against the worldwide obesity and T2DM epidemic Show less
Osteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular... Show moreOsteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular cartilage as main outcome. Despite extensive research on the pathogenesis of OA, there is until now no cure and treatments are primarily aimed at reducing pain. Evidence starts to appear that mild inflammation and obesity-related biochemical changes are involved in OA pathology. It is uncertain what the relative contribution of these processes is and if they characterize a certain type of OA patients. We identified obesity, high cholesterol and systemic inflammation associated with these conditions as major players in OA development, which may activate joint tissues to secrete inflammatory mediators and contribute to the initiation and progression of OA. Our work suggests that a stratification of OA patients with (features of) the metabolic syndrome as underlying mechanism is recommendable, to optimize the efficacy of clinical trials. Approaching OA as a disease induced by whole body metabolism, and integrating knowledge about different potentially active tissues in the OA process, will provide new insights for possible pharmacological interventions. Show less
For most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on... Show moreFor most commonly used drugs in morbidly obese patients evidence based dosing guidelines are not available. Therefore, current dosing is based on experience of the prescriber rather than on clinical evidence. Pharmacokinetic and pharmacodynamics data in non-obese patients are extrapolated without proper exploration of influence of overweight on the dose-exposure-effect relationship. The research described in this thesis focused on two commonly used drugs, propofol and the low-molecular-weight heparin (LMWH) nadroparin with the aim to develop weight appropriate dosing algorithms for these drugs in morbidly obese patients based on population pharmacokinetic and pharmacodynamics analysis. A non-linear relationship was found between propofol clearance and total body weight in both morbidly obese and non-obese adults, adolescents and children. Furthermore, the influence of age on propofol clearance was described using a bilinear function. A model based dosing algorithm using an adjusted dosing weight for propofol maintenance infusion was successfully evaluated in a prospective study in morbidly obese adults and can therefore be implemented in daily practice. For nadroparin in both morbidly obese and non-obese patients, total body clearance increased linearly with total body weight whereas the central of volume distribution increased linearly with lean body weight, suggesting that lean body weight is clinically useful for nadroparin dosing. The developed pharmacodynamic model for nadroparin in non-obese and morbidly obese patients can be used as a starting point to further identify the appropriate anti-Xa targets in morbidly obese patients. Show less
Obesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live... Show moreObesity is a major risk factor of osteoarthritis development and progression. Theoretically, obesity is a factor that can be modified. While obesity epidemic is difficult to reverse because we live in lipogenic environment, personal approach in modify obesity may avail. Therefore, understanding how obesity leads to osteoarthritis is needed. The first three chapters of this thesis investigate several aspects of osteoarthritis: what structures are damaged, what factors are associated with worsening of osteoarthritis and how to measure worsening of osteoarthritis. The other four chapters investigate the link between obesity and osteoarthritis. We show that obesity is associated with hand osteoarthritis. Since we do not walk on our hand, there must be another factor than mechanical that cause joint damage in osteoarthritis. One of the factors is adipokines, protein produced mainly by fat tissue. We showed that adiponectin, one of the adipokines, prevents worsening of hand osteoarthritis. We concluded that obesity plays role in osteoarthritis not only due to added mechanical force but also due to added metabolic force (adipokines). These adipokines might be used as target in modifying the effect of obesity on osteoarthritis. However, we still need more studies on how obesity links with osteoarthritis Show less
Aardoom, J.J.; Dingemans, A.E.; Landt, M.C.T.S.O.; Furth, E.F. van 2012
The first aim of this study was to provide norms for the Eating Disorder Examination Questionnaire (EDE-Q) in a diverse and large clinical sample of individuals with an eating disorder (ED), and a... Show moreThe first aim of this study was to provide norms for the Eating Disorder Examination Questionnaire (EDE-Q) in a diverse and large clinical sample of individuals with an eating disorder (ED), and a general population sample without an ED. Norms for individuals with obesity without an ED were also provided, as a more relevant comparison group for individuals with binge eating disorder. The second aim was to investigate the discriminative validity of the EDE-Q. A sample of females with an ED (N=935), women from the general population without an ED (N=235), and obese females without an ED (N=321) completed the EDE-Q Explorative factor analyses did not support the theorized four subscales of the EDE-Q. Norms for EDE-Q global scores were provided for each of the three samples. Within the ED sample, norms were provided separately for patients with different ED diagnoses. Receiver operating characteristic analyses showed the EDE-Q global score to be highly accurate in discriminating individuals with an ED from those without, and moderately accurate in discriminating individuals with binge eating disorder from those with obesity. The presented norms contribute to a more accurate interpretation of EDE-Q scores, providing an index of the severity level of ED psychopathology. Furthermore, these norms can be used to assess clinical significant change during treatment. In addition, this study demonstrates that the EDE-Q when using its global score, is a valid instrument to assess levels of ED psychopathology. (C) 2012 Elsevier Ltd. All rights reserved. Show less
The aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our... Show moreThe aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our findings indicate that people with more severe symptoms of depression and anxiety are at particular risk of progressive dyslipidemia and (abdominal) obesity. The higher rates of smoking and systemic inflammation among people with depression or anxiety partially accounted for their adverse metabolic profile. Dysregulations of the autonomic nervous system partly explained why users of tricyclic antidepressants displayed an increased risk of dyslipidemia and (abdominal) obesity as well, and also of hypertension. These important findings shed light on useful avenues for future research, and on preventive and therapeutic insights and directions. Show less
The introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a... Show moreThe introduction of systems biology in combination with the profiling of numerous biochemical components (e.g. lipid metabolites, herbal products) enables the study of living systems from a holistic perspective. In this thesis we explored systems biology-based platforms to investigate the therapeutic effects of chemical drugs and herbal medicines on animal models with high-fat diet-induced obesity and genetic manipulated diabetes. The aim of the work was to better understand the working mechanisms of both treatments on metabolic syndrome from a holistic point of view and to evaluate the potentials of __omics__ technologies to this effort. Our results showed that lipidomics approach with appropriate bioinformatics tools are essential to describe the global, dynamic metabolic response of living systems, e.g. from homeostasis via sub-optimal health and ultimately to dysfunction. These studies pointed hints to disco ver lipid biomarkers in relation to health promotion and disease prevention and facilitated the understanding of the complex regulatory mechanisms in humans or animals. Particularly, the introduction of the systems biology view will not only provide in-depth insights into the multi-target synergetic effects (which have hardly been used in modern drug discovery) but also can bridge Chinese Medicine (multi-target therapy) and Western Medicine (molecular pharmacology). Show less
Over the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk... Show moreOver the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk factors like female hormones, thyroid hormone and obesity result in a hypercoagulable state and increased risk for venous thrombosis, since these are currently poorly understood. As these risk factors are all, to a certain extent, able to interfere with liver metabolism we hypothesized that they modulate hepatic transcription of coagulation genes, either directly via nuclear hormone receptors and hormone response elements in target genes (female hormones and thyroid hormone), or indirectly as a result of altered liver homeostasis (obesity). To study these hypotheses, we used an in vivo approach, which not only gives the opportunity to study the risk factor-mediated transcriptional modulation of coagulation genes, but also allowed us to study the relation between transcriptional changes on the one hand and plasma protein levels and a thrombotic tendency on the other. The data presented in this thesis clearly demonstrate that modulation of hepatic coagulation gene transcription is a key mechanism by which acquired risk factors for venous thrombosis impact the hemostatic balance. Show less
