De uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische... Show moreDe uitkomsten beschreven in dit proefschrift dragen bij aan de bestaande overtuiging dat een verfijndere classificatie voor depressie, op basis van symptoomprofielen en hun mogelijke biologische onderbouwing, overwogen dient te worden. Inmiddels wordt adipositas in de dagelijkse praktijk op meer dan alleen het BMI beoordeeld, namelijk ook de tailleomtrek en het lipidenprofiel. Echter, dergelijke aandacht bestaat nog niet voor de heterogeniteit van depressie. Een grotere bewustwording van de verschillende manifestaties van depressie-symptomatologie, die het gevolg kunnen zijn van uiteenlopende pathofysiologische mechanismen, is van essentieel belang. Wanneer een patiënt met depressie een atypisch energie-gerelateerd symptoomprofiel heeft, kan het nuttig zijn om diens metabole biomarkers te controleren om mogelijke ontwikkeling van cardiometabole ziekten te voorkomen. In de klinische praktijk moeten wij ons bij de behandeling van patiënten met depressie ook meer bewust worden van de correlatie tussen symptoomprofielen van depressie en afzonderlijke biologische en klinische manifestaties. Het is cruciaal om goed te kijken naar de symptomen die bij elke patiënt tot uiting komen. De resultaten van dit proefschrift tonen aan dat patiënten met een depressie die atypische energie-gerelateerde depressieve symptomen vertonen, genetisch en klinisch kwetsbaar zijn voor aan insulineresistentie gerelateerde ziekten (namelijk adipositas, metabole ontregelingen en diabetes mellitus type 2). Een gepersonaliseerde aanpak kan behulpzaam zijn in preventie van deze chronische en complexe ziekten. Hierbij dient er rekening gehouden worden met de heterogeniteit van depressie en de associatie tussen atypische energie-gerelateerde symptomen van depressie en deze ziekten. Show less
Alblas, G.; Lamb, H.J.; Rosendaal, F.R.; Hoek, B. van; Coenraad, M.J.; Mutsert, R. de 2023
Background and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination... Show moreBackground and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination of metabolic risk factors. We aimed to examine the prevalence of NAFLD, including groups with metabolic risk factors.Methods and results: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, liver fat content was assessed using proton magnetic resonance spectroscopy (H-MRS). Participants with excessive alcohol consumption or missing values were excluded, leaving a total of 1570 participants for the analyses. Mean (SD) age of the population was 55 years, BMI 25.9 (4.0) kg/m(2) and 46% were men. The prevalence of NAFLD was 27% (95% CI 24-30). The prevalence of NAFLD was increased in participants with hypertriglyceridemia (57%, 52-63), obesity (62%, 58-66) and diabetes (69%, 61-77). The prevalence of NAFLD was highest in those with diabetes and obesity (79%, 71-87), obesity and hypertriglyceridemia (81%, 76-86) and with diabetes and hypertriglyceridemia (86%, 77-95). NAFLD was also present in 12% (8-16) of participants without overweight.Conclusions: The prevalence of NAFLD in a middle-aged population in the Netherlands in 2010 was 27%. The prevalence of NAFLD is particularly increased in individuals with diabetes, obesity, and hypertriglyceridemia. This information may help clinicians and general practitioners in the risk stratification of their patients in daily practice.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Rapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate... Show moreRapid socio-economic growth accelerates urbanization in Indonesia, which changes many aspect of human lives, and potentially affect disease prevalence and outcome. This thesis aims to investigate the impacts of urbanization on human health, especially metabolic health and allergic disease, by incorporating many aspects of scientific investigation. Our cluster-randomized-controlled trial showed that, helminth infection, a characteristic feature of rural areas, and anthelmintic treatment, could significantly affect metabolic profiles and hormones. Thus, the ongoing deworming program in Indonesia require in parallel, monitoring of the metabolic health. Additionally, based on our prospective cohort study and analysis on a large scale nationally representative data, although Indonesian rural populations have relatively better metabolic profiles compared to urban, lifelong residence in rural areas does not protect their community members from adverse metabolic changes due to urbanization. Next, we observed that majority of individuals with diabetes in Indonesia were undiagnosed and untreated, especially in rural populations, which warrants extensive action plan from all related stakeholders. Lastly, high-dimensional data analyses on the systemic and nasal mucosal immune profiles revealed a stronger inflammatory immune responses in the nasal mucosal of Indonesian urban young adults with allergic rhinitis compared to their rural counterparts. Show less
Many children with psychiatric disorders display somatic symptoms, although these are frequently overlooked. As somatic morbidity early in life negatively influences long-term outcomes, it is... Show moreMany children with psychiatric disorders display somatic symptoms, although these are frequently overlooked. As somatic morbidity early in life negatively influences long-term outcomes, it is relevant to assess comorbidity. However, studies of simultaneous psychiatric and somatic assessment in children are lacking. The aim of this study was to assess the prevalence of somatic comorbidities in a clinical sample of children and adolescents with psychiatric disorders in a naturalistic design. Data were assessed from 276 children with various psychiatric disorders (neurodevelopmental disorders, affective disorders, eating disorders and psychosis) aged 6-18 years. These data were collected as part of routine clinical assessment, including physical examination and retrospectively analyzed. For a subsample (n = 97), blood testing on vitamin D3, lipid spectrum, glucose and prolactin was available. Results of this cross-sectional study revealed that food intake problems (43%) and insomnia (66%) were common. On physical examination, 20% of the children were overweight, 12% displayed obesity and 38% had minor physical anomalies. Blood testing (n = 97) highlighted vitamin D3 deficiency (< 50 nmol/L) in 73% of the children. None of the predefined variables (gender, age, medication and socioeconomic factors) contributed significantly to the prevalence of somatic comorbidities. The main somatic comorbidities in this broad child- and adolescent psychiatric population consisted of (1) problems associated with food intake, including obesity and vitamin D3 deficiency and (2) sleeping problems, mainly insomnia. Child and adolescent psychiatrists need to be aware of potential somatic comorbidities and may promote a healthy lifestyle. Show less
Chavanelle, V.; Langhi, C.; Michaux, A.; Ripoche, D.; Otero, Y.F.; Joubioux, F. le; ... ; Sirvent, P. 2023
Global prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke,... Show moreGlobal prevalence of obesity and type 2 diabetes are rapidly increasing to pandemic proportions. A novel supplement composed of 5 plant extracts from olive leaf, bilberry, artichoke, chrysanthellum, and black pepper was designed to prevent type 2 diabetes development in people at risk. It was previously shown to improve body weight and glucose control in preclinical rodent models, with these effects being accompanied by increased fecal energy excretion and in vitro inhibition of several digestive enzymes. Thus, we hypothesized that, in mice fed a high-fat diet (HFD), a single dose of this botanical supplementation would decrease the responses to oral fat and carbohydrate tolerance tests, and that chronic supplementation would result in increased fecal triglyceride content. We showed that acute administration in HFD-fed mice (1.452 g/kg body weight) markedly reduced circulating triglycerides following an oral lipid gavage, whereas glycemic responses to various carbohydrate tests were only mildly affected. When incorporated into the food (2.5%) of HFD-fed mice, chronic supplementation prevented body weight gain and improved glucose homeostasis and lipid tolerance. Fecal free fatty acid content, but not triglyceride, was significantly increased in supplemented animals, suggesting reduced lipid absorption in the digestive tract. Congruently, this botanical supplementation downregulated several genes associated with fatty acid transport whose expression was increased by HFD, principally in the jejunum. This study provides novel insights as for the mode of action behind the antiobesity effect of this plant-based supplementation, in HFD-fed mice. Show less
Introduction: Alectinib is a standard-of-care treatment for metastatic ALK+ NSCLC. Weight gain is an unexplored side effect reported in approximately 10%. To prevent or intervene alectinib-induced... Show moreIntroduction: Alectinib is a standard-of-care treatment for metastatic ALK+ NSCLC. Weight gain is an unexplored side effect reported in approximately 10%. To prevent or intervene alectinib-induced weight gain, more insight in its extent and etiology is needed. Methods: Change in body composition was analyzed in a prospective series of 46 patients with ALK+ NSCLC, treated with alectinib. Waist circumference, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and skeletal muscle were quantified using sliceOmatic software on computed tomography images at baseline, 3 months (3M), and 1 year (1Y). To investigate an exposure-toxicity relationship, alectinib plasma concentrations were quantified. Four patients with more than 10 kg weight gain were referred to Erasmus MC Obesity Center CGG for in-depth analysis (e.g., assessments of appetite, dietary habits, other lifestyle, medical and psycho social factors, and extensive metabolic and endocrine assessments, including resting energy expenditure).Results: Mean increase in waist circumference was 9 cm (9.7%, p < 0.001) in 1Y with a 40% increase in abdominal obesity (p = 0.014). VAT increased to 10.8 cm2 (15.0%, p = 0.003) in 3M and 35.7 cm2 (39.0%, p < 0.001) in 1Y. SAT increased to 18.8 cm2 (12.4%, p < 0.001) in 3M and 45.4 cm2 (33.3%, p < 0.001) in 1Y. The incidence of sarcopenic obesity increased from 23.7% to 47.4% during 1Y of treatment. Baseline waist circumference was a positive predictor of increase in VAT (p = 0.037). No exposure toxicity relationship was found. In-depth analysis (n = 4) revealed increased appetite in two patients and metabolic syndrome in all four patients.Conclusions: Alectinib may cause relevant increased sarcopenic abdominal obesity, with increases of both VAT and SAT, quickly after initiation. This may lead to many serious metabolic, physical, and mental disturbances in long surviving patients.& COPY; 2023 Published by Elsevier Inc. on behalf of International Association for the Study of Lung Cancer. Show less
Glucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic... Show moreGlucagon-like peptide-1 (GLP-1) receptor agonists are a relatively new treatment option for obesity and type 2 diabetes. Treatment has been shown to result in in weight loss and improved glycemic control. In this thesis, the effects of treatment on the different adipose tissue depots and on cardiac function are described. In a randomised controlled trial, we treated patients with type 2 diabetes from South Asian descent, a population with increased risk to develop type 2 diabetes and cardiovascular disease compared to Western Europeans, with liraglutide, a GLP-1 receptor agonist, or placebo, and studied these subjects with MRI. We concluded that liraglutide and possibly other GLP-1 receptor agonists can be a good strategy to reduce the volume of visceral adipose tissue. This reduction was accompanied by a significant improvement of glycemic control. Lastly, we provided evidence that liraglutide does not improve cardiac function and myocardial tissue characteristics and thus does not improve diabetic cardiomyopathy. In addition, in another study, we studied the mechanism behind GLP-1 receptor agonism induced weight loss and concluded that liraglutide induces weight loss in humans by decreasing energy intake rather than by activating brown adipose tissue or increasing energy expenditure. Show less
Cardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases... Show moreCardiometabolic health is tightly controlled by a complex network of organ communication. Dysfunction of these lines of communication is associated with the development of cardiometabolic diseases, indicating inter-organ cross-talk as a therapeutic target. Herein, I explored the therapeutic potential of targeting inter-organ communication in cardiometabolic diseases, including obesity, atherosclerotic cardiovascular disease and non-alcoholic steatohepatitis, based on which I proposed novel therapies to tackle these diseases. On one hand, strategies can focus on regulating the gut microbiota-centered inter-organ cross-talk. We demonstrated that dietary interventions are efficient to modulate the gut microbiota composition and function, thereby regulating the gut microbial metabolite production. In particularly, we showed that dietary supplementation of butyrate, a gut microbial metabolite, and choline, a nutrient enriched in red meat, can beneficially modulate the gut microbiota to alleviate adiposity. On the other hand, therapies can also focus on liver-centered inter-organ cross-talk. We showed that improving hepatocyte mitochondrial function by γ hydroxybutyric acid not only improves liver metabolic function, but also reverses obesity and its associated metabolic diseases. Besides, cardiometabolic health can be improved by regulating systemic levels of hepatokines (e.g. FGF21). We showed that FGF21-based pharmacotherapies can regulate the cross-talk between the liver and adipose tissue to improve cardiometabolic diseases, especially fibrotic non-alcoholic steatohepatitis and atherosclerotic cardiovascular disease. Thus, the findings described in this thesis emphasize the importance of inter-organ cross-talk for cardiometabolic diseases, and have improved our knowledge on the mechanisms that underlie the risk in the ever-increasing population of individuals who suffer from cardiometabolic diseases. Show less
Bone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly... Show moreBone morphogenetic protein (BMP)-9, a member of the TGF beta-family of cytokines, is believed to be mainly produced in the liver. The serum levels of BMP-9 were reported to be reduced in newly diagnosed diabetic patients and BMP-9 overexpression ameliorated steatosis in the high fat diet-induced obesity mouse model. Furthermore, injection of BMP-9 in mice enhanced expression of fibroblast growth factor (FGF)21. However, whether BMP-9 also regulates the expression of the related FGF19 is not clear. Because both FGF21 and 19 were described to protect the liver from steatosis, we have further investigated the role of BMP-9 in this context.We first analyzed BMP-9 levels in the serum of streptozotocin (STZ)-induced diabetic rats (a model of type I diabetes) and confirmed that BMP-9 serum levels decrease during diabetes. Microarray analyses of RNA samples from hepatic and intestinal tissue from BMP-9 KO-and wild-type mice (C57/Bl6 background) pointed to basal expression of BMP-9 in both organs and revealed a down-regulation of hepatic Fgf21 and intestinal Fgf19 in the KO mice. Next, we analyzed BMP-9 levels in a cohort of obese patients with or without diabetes. Serum BMP-9 levels did not correlate with diabetes, but hepatic BMP-9 mRNA expression negatively correlated with steatosis in those patients that did not yet develop diabetes. Likewise, hepatic BMP-9 expression also negatively correlated with serum LPS levels. In situ hybridization analyses confirmed intestinal BMP-9 expression. Intestinal (but not hepatic) BMP-9 mRNA levels were decreased with diabetes and positively correlated with intestinal E-Cadherin expression. In vitro studies using organoids demonstrated that BMP-9 directly induces FGF19 in gut but not hepatocyte organoids, whereas no evidence of a direct induction of hepatic FGF21 by BMP-9 was found. Consistent with the in vitro data, a correlation between intestinal BMP-9 and FGF19 mRNA expression was seen in the patients' samples.In summary, our data confirm that BMP-9 is involved in diabetes development in humans and in the control of the FGF-axis. More importantly, our data imply that not only hepatic but also intestinal BMP-9 associates with diabetes and steatosis development and controls FGF19 expression. The data support the conclusion that increased levels of BMP-9 would most likely be beneficial under pre-steatotic conditions, making supplemen-tation of BMP-9 an interesting new approach for future therapies aiming at prevention of the development of a metabolic syndrome and liver steatosis. Show less
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
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
