In this thesis, we have addressed two key objectives: 1) to gain more insight in various pathophysiological aspects of cardiometabolic diseases including in the disease proneSouth Asian population,... Show moreIn this thesis, we have addressed two key objectives: 1) to gain more insight in various pathophysiological aspects of cardiometabolic diseases including in the disease proneSouth Asian population, and 2) to study the physiological effects of cold exposure and identify a novel pharmacological approach to directly target BAT. Show less
Aims/hypothesisThe aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters:... Show moreAims/hypothesisThe aim of this study was to identify differentially expressed long non-coding RNAs (lncRNAs) and mRNAs in whole blood of people with type 2 diabetes across five different clusters: severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), mild diabetes (MD) and mild diabetes with high HDL-cholesterol (MDH). This was to increase our understanding of different molecular mechanisms underlying the five putative clusters of type 2 diabetes.MethodsParticipants in the Hoorn Diabetes Care System (DCS) cohort were clustered based on age, BMI, HbA1c, C-peptide and HDL-cholesterol. Whole blood RNA-seq was used to identify differentially expressed lncRNAs and mRNAs in a cluster compared with all others. Differentially expressed genes were validated in the Innovative Medicines Initiative DIabetes REsearCh on patient straTification (IMI DIRECT) study. Expression quantitative trait loci (eQTLs) for differentially expressed RNAs were obtained from a publicly available dataset. To estimate the causal effects of RNAs on traits, a two-sample Mendelian randomisation analysis was performed using public genome-wide association study (GWAS) data.ResultsEleven lncRNAs and 175 mRNAs were differentially expressed in the MOD cluster, the lncRNA AL354696.2 was upregulated in the SIDD cluster and GPR15 mRNA was downregulated in the MDH cluster. mRNAs and lncRNAs that were differentially expressed in the MOD cluster were correlated among each other. Six lncRNAs and 120 mRNAs validated in the IMI DIRECT study. Using two-sample Mendelian randomisation, we found 52 mRNAs to have a causal effect on anthropometric traits (n=23) and lipid metabolism traits (n=10). GPR146 showed a causal effect on plasma HDL-cholesterol levels (p = 2×10–15), without evidence for reverse causality.Conclusions/interpretationMultiple lncRNAs and mRNAs were found to be differentially expressed among clusters and particularly in the MOD cluster. mRNAs in the MOD cluster showed a possible causal effect on anthropometric traits, lipid metabolism traits and blood cell fractions. Together, our results show that individuals in the MOD cluster show aberrant RNA expression of genes that have a suggested causal role on multiple diabetes-relevant traits. Show less
Rozendaal, Y.J.W.; Wang, Y.N.; Hilbers, P.A.J.; Riel, N.A.W. van 2019
BackgroundA positive energy balance is considered to be the primary cause of the development of obesity-related diseases. Treatment often consists of a combination of reducing energy intake and... Show moreBackgroundA positive energy balance is considered to be the primary cause of the development of obesity-related diseases. Treatment often consists of a combination of reducing energy intake and increasing energy expenditure. Here we use an existing computational modelling framework describing the long-term development of Metabolic Syndrome (MetS) in APOE3L.CETP mice fed a high-fat diet containing cholesterol with a human-like metabolic system. This model was used to analyze energy expenditure and energy balance in a large set of individual model realizations.ResultsWe developed and applied a strategy to select specific individual models for a detailed analysis of heterogeneity in energy metabolism. Models were stratified based on energy expenditure. A substantial surplus of energy was found to be present during MetS development, which explains the weight gain during MetS development. In the majority of the models, energy was mainly expended in the peripheral tissues, but also distinctly different subgroups were identified.In silico perturbation of the system to induce increased peripheral energy expenditure implied changes in lipid metabolism, but not in carbohydrate metabolism. In silico analysis provided predictions for which individual models increase of peripheral energy expenditure would be an effective treatment.ConclusionThe computational analysis confirmed that the energy imbalance plays an important role in the development of obesity. Furthermore, the model is capable to predict whether an increase in peripheral energy expenditure - for instance by cold exposure to activate brown adipose tissue (BAT) - could resolve MetS symptoms. 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
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
Overgewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de... Show moreOvergewicht en obesitas kunnen leiden tot insulineresistentie (type 2 diabetes mellitus) en hyperlipidemie, een risicofactor voor atherosclerose (aderverkalking). Obesitas gaat ook gepaard met de ontwikkeling van een chronische ontsteking in vetweefsel en lever. Met dit promotieonderzoek laten we met behulp van onderzoek in muizen zien dat ontsteking een belangrijke rol speelt in het metabolisme en transport van vetten. We bekijken ook welk effect dit heeft op de ontwikkeling van atherosclerose en type 2 diabetes. In het eerste deel van dit promotieonderzoek laten we zien dat ontsteking een belangrijke rol speelt in vetmetabolisme en atherosclerose. De ontstekingsremmer aspirine zorgde voor een verlaging van de hoeveelheid vet in het bloed. Activatie van een onsteking in de lever leidde juist tot een verhoging van vet in het bloed, wat de ontwikkeling van atherosclerose in de vaatwand verergerde. In het tweede deel van dit promotieonderzoek bestuderen we het belang van het inflammasoom/caspase-1 complex (betrokken bij ontstekingsprocessen) in obesitas, insulineresistentie en vetmetabolisme. We laten zien dat muizen die een deel van dit eiwit-complex missen, beschermt zijn tegen de ontwikkeling van obesitas en insulineresistentie. Het inflammasoom/caspase-1 complex lijkt daarmee een potentieel target voor de behandeling van obesitas, insulineresistentie en type 2 diabetes. Show less
