In this thesis, the importance of visceral obesity in the relation of obesity with cardiometabolic risk factors (chapter 2) was confirmed and it was shown that in individuals free of known... Show moreIn this thesis, the importance of visceral obesity in the relation of obesity with cardiometabolic risk factors (chapter 2) was confirmed and it was shown that in individuals free of known cardiovascular disease clustering of cardiometabolic risk factors is associated with changes in electrocardiographic parameters indicative of subclinical cardiovascular disease (chapter 3). The findings from chapter 3 also point to the importance of the prevention of these metabolic syndrome components, not only in obese, but also in non-obese individuals. Furthermore, both overall and abdominal adiposity were found to be associated with these deleterious changes in electrocardiographic parameters (chapter 4). Borderline Q-waves were associated with a negative cardiovascular risk profile and increased pulse wave velocity and intima-media thickness (chapter 5). Chapter 6 shows that several cardiovascular risk factors were associated with a wider spatial QRS-T angle, which reflects ventricular electrophysiological heterogeneity. Both carotid intima-media thickness, as measure of subclinical atherosclerosis, and pulse wave velocity, as measure of arterial stiffness, were associated with a wider spatial QRS-T angle. In chapter 7, improvement of electrocardiographic detection of left ventricular hypertrophy with conventional electrocardiographic criteria by taking into account body mass index and the spatial QRS-T angle is shown. Show less
Obesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a... Show moreObesity, type 2 diabetes and cardiovascular diseases are major public health problems. South Asians are specifically at risk for the development of (cardio)metabolic diseases, due to a combination of known and unknown risk factors. Since effective long-term treatment strategies are currently lacking, the search for additional risk factors and development of targeted treatment strategies to combat these (cardio)metabolic diseases is warranted. An attractive approach seems to be activation of energy-combusting brown adipose tissue (BAT), which can result in increased energy expenditure and improvement in glucose and lipid metabolism. In this thesis, we aimed to address two key objectives: 1) unravelling the underlying mechanisms that could explain the increased predisposition for metabolic disease in the South Asian population, and 2) identifying novel pharmacological strategies that activate BAT and increase energy expenditure in risk populations, including South Asians and individuals with overweight and prediabetes. The studies described in this thesis have highlighted some novel factors, such as endocannabinoids and angiopoitein-like-protein-4, that might in part explain to unbeneficial metabolic phenotype of South Asians. In addition, novel potential therapeutic strategies were identified to combat metabolic disease, such as treatment with a β3-adrenergic receptor agonist and a dipeptidyl-peptidase-4 inhibitor. Show less
Immunometabolism focusses on the interplay between immunological and metabolic processes, both at a systemic and a cellular level. This thesis is divided into two parts based on these two... Show moreImmunometabolism focusses on the interplay between immunological and metabolic processes, both at a systemic and a cellular level. This thesis is divided into two parts based on these two levels. The first part focusses on the infrapatellar fat pad (IFP), an adipose tissue located in the knee, and the potential role in the pathophysiology of osteoarthritis. Therefore, we characterized the IFP based on a cellular and molecular level and found that the inflammatory state of the joint does affect the cellular load of the IFP, however, the secretory profile of the IFP does not seem to be affected. Furthermore, obesity-related changes normally found in adipose tissue were not present in the IFP. When characterizing the IFP we found two interesting cell populations, IL-6-secreting T cells and macrophages with an anti-inflammatory phenotype secreting pro-inflammatory cytokines. Both populations could be involved in the pathophysiology of the osteoarthritic joint. Furthermore, in the second part we focussed on cellular metabolism where we determined the mechanism by which fatty acids exert their effect on T cells. We found that fatty acids are not served as energy, however, whether it is used for daughter cells or influencing cell signalling remains to be elucidated. Show less
The worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease,... Show moreThe worldwide prevalence of obesity is steadily increasing. Obesity leads to insulin resistance and atherosclerosis, which are the pathologies underlying type 2 diabetes and cardiovascular disease, respectively. Inflammation is an important factor connecting obesity to these disorders, but the exact mechanisms connecting obesity, the immune system, type 2 diabetes and cardiovascular disease are still under investigation. The research described in this thesis was performed 1) to gain more insight into the role of the immune system in obesity, dyslipidemia, insulin resistance and atherosclerosis, 2) to study whether inflammation contributes to the disadvantageous metabolic phenotype of a human population with a particularly high risk to develop type 2 diabetes and cardiovascular disease, and 3) to study the therapeutic potential of decreasing inflammation by pharmacological strategies to reduce obesity and improve glucose and lipid metabolism in pre-clinical models. The studies described in this thesis have increased our understanding of the role of inflammation in adipose tissue function and lipid metabolism during the development of type 2 diabetes and cardiovascular disease. Moreover, novel potential therapeutic strategies were identified to combat obesity, metabolic inflammation and associated metabolic disorders, such as treatment with interferons, salsalate and GPR120 agonists. Show less
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic.... Show moreNon-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic. NAFLD comprises a wide spectrum of liver damage ranging fat accumulation (steatosis) to steatosis with inflammation (non-alcoholic steatohepatitis, NASH), which can further progress to fibrosis. In particular patients with NASH have increased risk to develop other metabolic complications, such as cardiovascular disease.NAFLD is a complex disease, in which the origin and molecular mechanisms controlling the progression of simple steatosis to NASH remain poorly understood. Nevertheless, it is thought that inflammation is a critical component of NAFLD progression. This inflammation may be triggered by metabolic surplus (excess of energy or nutrients) and is also referred to as “metabolic inflammation”. White adipose tissue (WAT) is assumed to be largely involved in the development of metabolic inflammation. The studies described in this thesis contributed to the understanding of the role of WAT in the development of NAFLD and provide insight into the molecular processes that cause metabolic inflammation. 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
