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
The metabolic syndrome is a multi-component condition that includes obesity hypertriglyceridemia and insulin resistance. The prevalence of the metabolic syndrome is rising world-wide and is... Show moreThe metabolic syndrome is a multi-component condition that includes obesity hypertriglyceridemia and insulin resistance. The prevalence of the metabolic syndrome is rising world-wide and is associated with an increased risk for the development of cardiovascular diseases and type 2 diabetes. In the past decades it has been discovered that obese persons have slightly elevated markers of inflammation in their plasma. This low-grade chronic inflammation, also called metabolic inflammation, is hypothesized to function as the link between the various components of the metabolic syndrome. In this thesis, it is evaluated how alterations in triglyceride (TG) and fatty acid (FA) metabolism and inflammatory pathways interact in the development of obesity and insulin resistance, which are both primary risk factors for the development of type 2 diabetes Show less
In this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between... Show moreIn this thesis we focused on the causes and consequences of hepatic steatosis. Epidemiological studies in humans, as well as experimental studies in animal models, have shown an association between visceral obesity and dyslipidemia, insulin resistance and type 2 diabetes mellitus. The mechanism underlying this association remains unclear. Recently, attention has focused on the role of excessive accumulation of triglycerides (TG) in the liver (hepatic steatosis) in this association. Hepatic steatosis was considered a benign condition until it was discovered that a nonalcoholic fatty liver is associated with many cardiovascular risk factors. Subsequently, many studies have shown a strong association between hepatic TG content and hepatic insulin resistance. The studies in this thesis show that hepatic steatosis is actively and passively involved in the metabolic disturbances in the glucose and lipid metabolism. The prevalence of hepatic steatosis in western countries is high and will certainly increase with the epidemics of obesity and diabetes. This will put an increasing number of subjects at risk for disturbances in the glucose and lipid metabolism and concomitantly for cardiovascular disease. Show less
