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
Cardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the... Show moreCardiovascular diseases (CVD) are the leading cause of death worldwide, and disturbances in day-night rhythms have recently been implicated as a novel risk factor for CVD. We investigated the effects of modulating circadian rhythms on energy metabolism using animal models and by studying plasma metaoblites and lipids in humans. Using animal studies we observed that brown adipose tissue (BAT) is strongly regulated by the biological clock, possibly via circadian glucocorticoid rhythms, and attenuated BAT activity through prolonged light exposure increases adiposity. Research focusing on the rhythm in human BAT, and regulation thereof, is necessary to confirm the translational value of our findings. We also observed that mistimed light exposure enhances atherosclerosis development, which may provide a mechanistic link between the known association between shift work and CVD. We anticipate that living according to the natural circadian rhythms presumably contributes to cardiometabolic health. Since disturbances in day-night rhythms are inevitable in modern society, in the future we may advise individuals at risk for development of CVD refrain from shift work and short sleep duration. In addition, data in this thesis may be useful to design strategies to avoid the disadvantageous metabolic effects of shift work. 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
