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
Worldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of... Show moreWorldwide, there is an strong rise of cardiometabolic disorders, which mainly comprise obesity, cardiovascular disease (CVD) and type 2 diabetes. Therefore, the development and improvement of preventive and curative strategies for cardiometabolic disease is eagerly warranted. With the studies describes in this thesis, we aimed to disentangle the interwoven physiological, environmental and genetic factors that determine cholesterol and energy metabolism to increase our understanding of their contribution to cardiometabolic disease risk. The first part of this thesis focussed on the cholesteryl ester transfer protein (CETP). The lipid transfer properties of CETP induce a proatherogenic lipoprotein profile. Therefore, CETP inhibitory molecules have been developed and tested in clinical trials for their capability to improve the lipoprotein profile and reduce CVD risk. To fully understand the role of CETP in CVD, its physiology and biological function should be fully unravelled. The focus of the second part of this thesis was on the role of energy metabolism in cardiometabolic health. Specifically, we aimed to study the association of environmental and genetic factors, which were previously described to influence brown adipose tissue (BAT) activity, with energy expenditure and disease outcomes. Show less
The glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this... Show moreThe glycocalyx is a thin layer consisting of sugar moieties on the endothelium of the whole vasculature. This layer has been shown to play a role in diabetic kidney disease and beyond. In this thesis we studied structural and compositional changes of the endothelial glycocalyx upon diabetes in mice and in vitro. In glomerular capillaries, the endothelial glycocalyx contributes to the filtration barrier in the glomeruli. In diabetes the glycocalyx is damaged but can be restored via several pharmacological compounds that subsequently results in a shift from inflammatory towards anti-inflammatory macrophage function (chapter 2-3). In our model this appeared not to a result of changes in nitric oxide availability, affirming the potential overruling role for glomerular macrophages in glycocalyx degradation in diabetic nephropathy (chapter 4). Enzymatic cleavage of heparan sulfates reduced the total amount of luminal glycosaminoglycan content, but increased inflammatory heparan sulfate epitopes in vitro and in zebrafish (chapter 5). In chapter 6 we demonstrate that endothelial-specific loss of hyaluronan, another glycocalyx constituent, results in loss of endothelial barrier function. Overall, this thesis provides evidence that inhibition of glycocalyx degrading enzymes is a potent treatment option in diabetic nephropathy and other vascular diseases. Show less
