Background and aims: Leptin has been associated with adverse effects on cardiovascu-lar disease, but the effect of confounding by body fat in these associations remains unclear. To investigate... Show moreBackground and aims: Leptin has been associated with adverse effects on cardiovascu-lar disease, but the effect of confounding by body fat in these associations remains unclear. To investigate associations between leptin and heart function and subclinical cardiovascular disease adjusted for total body fat, and to investigate the causal relation between leptin and cardiovas-cular disease using Mendelian randomisation.Methods and results: Leptin concentrations, total body fat and diverse measures of subclinical car-diovascular disease were determined in participants of the Netherlands Epidemiology of Obesity study. Linear regression between leptin concentration and measures of heart function, ECG mea-sures, and carotid intima media thickness as a measure of subclinical atherosclerosis was adjusted for potential confounding factors, and additionally including total body fat. We analysed the combined effects of genetic variants from a GWAS on leptin concentrations in publicly-available summary statistics of coronary heart disease GWAS (CARDIoGRAMplusC4D, n Z 184,305). As many as 6107 men and women, mean (SD) age 56 (6) years, BMI 26 (4) kg/ m2, and median leptin concentration 12.1 mg (IQR: 6.7-22.6) were included.In observational analyses, leptin was weakly associated with heart function and subclinical cardiovascular disease, but these associations attenuated when adjusting for total body fat. A doubling of genetically-determined leptin concentration was associated with an odds ratio of cardiovascular disease of 0.69 (0.37, 1.27).Conclusion: Observational associations between leptin and subclinical measures of cardiovascu-lar disease were largely explained by differences in total body fat. Results of analyses of genetically-determined leptin and coronary heart disease risk were inconclusive due to a large confidence interval. 2023 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Ital-ian 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
Overweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI)... Show moreOverweight and obesity are abnormal or excessive body fat accumulation that presents a risk to health. The World Health Organisation defines overweight and obesity with the Body Mass Index (BMI) classification, which is a measure of a person’s weight in kilograms (kg) divided by the square of height in meters (m2). Overweight is defined as a BMI of 25 kg/m2 or higher, whereas obesity is defined as a BMI of 30 kg/m2 or higher. It is estimated that one of every three individuals in the global population has overweight. The prevalence of obesity is increased threefold from 1975 to 2016, with a faster-growing pace in low- and middle-income countries than high-income countries. One common complication of obesity is the metabolic syndrome, which is defined as the co-occurrence of at least three out of five cardiometabolic abnormalities (abdominal obesity, hypertension, hyperglycaemia, hypertriglyceridemia, and low HDL-cholesterol). The metabolic syndrome is a strong risk factor for type 2 diabetes and cardiovascular diseases, and is considered a pathway from obesity to the cardiometabolic diseases occurrence. Thus, if metabolic syndrome or its components are identified and treated early, type 2 diabetes and cardiovascular diseases may be prevented. In this multi-ethnic global population, it is well-established that different ethnic populations have different cardiometabolic risks. Studies have shown that Asian populations develop cardiometabolic complications earlier at the same amount of adiposity as the Western populations. Show less
In this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin... Show moreIn this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin gene on cachexia and diabetes in rodent and zebrafish animal models. 3) how tuberculosis infection and resulting metabolic reprogramming are dependent on leptin signaling in mice and zebrafish larvae. Show less
In this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and... Show moreIn this thesis, two potential therapeutic targets for diabetic nephropathy were dentified and investigated. First, we show that glomerular clusterin is upregulated in diabetic nephropathy and demonstrated that recombinant clusterin protein can protect the podocytes against oxidative stress in vitro. Second, we reveal that hCN1 overexpression accelerated and aggravated diabetic nephropathy in BTBR ob/ob mice. We also studied two novel zebrafish models to investigate chronic kidney disease. We showed that lepb-/- adult zebrafish have the early signs of human diabetic nephropathy, and we demonstrated that ctns mutant adult zebrafish have the kidney pathologic features of human nephropathic cystinosis. Show less
Sigit, F.S.; Trompet, S.; Tahapary, D.L.; Sartono, E.; Dijk, K.W. van; Yazdanbakhsh, M.; ... ; Mutsert, R. de 2021
Background and aims: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived... Show moreBackground and aims: At the same BMI, Asian populations develop cardiometabolic complications earlier than Western populations. We hypothesized that a different secretion of the adipocyte-derived hormones leptin and adiponectin plays a role and investigated the associations of the two hormones with the metabolic syndrome (MetS) in an Indonesian and a Dutch population. Methods and results: We performed cross-sectional analyses of the Netherlands Epidemiology of Obesity Study (n = 6602) and the SUGAR Scientific Programme Indonesia-Netherlands Study (n = 1461). We examined sex-stratified associations of leptin and adiponectin with MetS, using multivariate logistic regression including adjustment for total body fat. The mean (SD) leptin (mcg/L) were 4.7 (6.0) in Indonesian men, 18.6 (12.0) in Indonesian women, 9.1 (7.7) in Dutch men, and 23.4 (17.4) in Dutch women. The mean (SD) adiponectin (mg/L) were 5.7 (5.4), 7.5 (7.1), 6.6 (3.3), and 11.3 (4.9), respectively. Within the same BMI category, leptin concentrations were similar in the two populations, whereas adiponectin was lower in the Indonesian population. Per SD of leptin, adjusted prevalence odds ratios (ORs, 95%CI) of MetS were 0.9 (0.6-1.2) in Indonesian men, 1.1 (0.9-1.4) in Indonesian women, 2.2 (1.6-2.8) in Dutch men, and 1.2 (1.0-1.5) in Dutch women. Per SD of adiponectin, the ORs were 0.9 (0.7-1. 2), 0.8 (0.7-1.0), 0.6 (0.6-0.8), and 0.4 (0.4-0.5), respectively. Conclusions: Despite lower adiponectin levels, adiponectin was not related to the MetS in the Indonesian population and can not explain their increased cardiometabolic risk at the same BMI. (c) 2021 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
The aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as... Show moreThe aim of this thesis was to unravel a selection of a multitude of potential causal pathways that may underlie the association between excess body fat and cardiovascular disease, such as adipokines, inflammation, HDL-cholesterol and postprandial triglyceride response, and cholesteryl ester transfer protein (CETP). We showed that hs-CRP and GlycA as measures of inflammation, adiponectin, and leptin are not associated with clinical and subclinical cardiovascular disease in the general population. However, all may be relevant markers of disease risk. Also, postprandial triglyceride excursions, genetically-determined CETP and HDL-cholesterol, while not related with subclinical atherosclerosis in the general population, may be interesting targets to pursue in women and men separately, and in subgroups of individuals at high-cardiovascular risk. Show less
Rafiq, R.; Haddaoui, H. el; Mutsert, R. de; Rosendaal, F.R.; Hiemstra, P.S.; Cobbaert, C.M.; ... ; Jongh, R.T. de 2020
Objective: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C... Show moreObjective: The role of adiposity in the relationship between vitamin D and inflammation is unknown. Our aim was therefore to assess the association of serum 25-hydroxyvitamin D (25(OH)D) with C-reactive protein (CRP), leptin and adiponectin and the role of adiposity in this relationship.Methods: This is a cross-sectional analysis of The Netherlands Epidemiology of Obesity Study (NEO), a population-based cohort study in men and women aged 45 to 65 years. Main outcome measures were CRP, leptin and adiponectin. In the linear regression analyses we adjusted for age, sex, ethnicity, creatinine, education, alcohol use, smoking status, physical activity, number of chronic diseases, season, total body fat and waist circumference.Results: Of the 6287 participants, 21% were vitamin D deficient (serum 25(OH)D < 50 nmol/L). Mean (SD) age and BMI were 56 (6) years and 26.3 (4.4) kg/m(2), respectively. Although after adjustment for most examined potential confounders, each 10 nmol/L increase in serum 25(OH)D was associated with 2.3% (95%CI: -4.0 to -0.5) lower CRP, 3.5% (-4.7 to -2.2) lower leptin, and 0.13 ng/mL (0.04-0.21) higher adiponectin, most of these associations seemed to largely stem from an additional potential confounder - adiposity - as they either disappeared (leptin and CRP) or were largely diminished (adiponectin) upon further adjustment for adiposity indices (total body fat and waist circumference).Conclusion: We found that measures of adiposity largely explained the negative association of serum 25(OH)D with the pro-inflammatory CRP and leptin, and the positive association with the anti-inflammatory adiponectin. These results suggest that future studies should take the effect of adiposity into account. Show less
Background: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to... Show moreBackground: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study.Methods: We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat.Results: In multivariable adjusted analyses a 1 mu g/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses.Discussion: This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant. Show less
Christen, T.; Trompet, S.; Noordam, R.; Klinken, J.B. van; Dijk, K.W. van; Lamb, H.J.; ... ; Mutsert, R. de 2018
The main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of... Show moreThe main objective of this thesis is to improve understanding of the role of helminth infections in the development of insulin resistance (IR), hence Type 2 Diabetes (T2D), in the light of increasing urbanization in Indonesia. Our large-scale cluster-randomized controlled trial was performed in a rural area of Indonesia, which is endemic for soil-transmitted helminth (STH), and has been previously reported to have a low prevalence of IR and T2D. In STH-infected subjects, as assessed by microscopy, 12-month anthelmintic treatment increased IR, which was mediated by an increase in BMI and leptin to adiponectin ratio, as well as reduction in eosinophil count. Next, we also aimed to assess the different metabolic profile between populations living in rural and urban area, and to study the relative protective effect of rural environment to high-fat diet (HFD). In comparison to those living in rural area, individuals living in urban area had higher whole body IR, which was mainly mediated by the higher adiposity and leptin level, which were progressively increased with increased duration of time spent in urban area. Different environmental factors (including past or current exposure to STH) did not seem to affect the metabolic response to HFD intervention, independent from adiposity. Show less
Hannema, S.E.; Wit, J.M.; Houdijk, M.E.C.A.M.; Haeringen, A. van; Bik, E.C.; Verkerk, A.J.M.H.; ... ; Losekoot, M. 2016
Nowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the... Show moreNowadays, obesity has reached epidemic proportions globally. It can lead to several chronic diseases, including insulin resistance/type 2 diabetes mellitus. Feeding behaviour is regulated in the hypothalamus of the brain by two opposing pathways: NPY/AgRP neurons vs. POMC/CART neurons. In addition, there are numerous peripheral signals, deriving from stomach, gut, pancreas and adipose tissue, that act on the hypothalamus and thereby contribute to the regulation of food intake. The aim of the studies we have performed, was to investigate the effects of some of these neuropeptides and peripheral signals that affect these neuropeptides, on insulin action. Our experiments showed, that NPY can cause insulin resistance, specifically in the liver. The POMC pathway can improve insulin-mediated glucose disposal and does not affect hepatic insulin sensitivity. Therefore, both pathways are not completely opposing each other’s effects, but seem to have a different tissue-specific effect. Experiments with gut hormones like PYY and ghrelin showed that these hormones affect insulin sensitivity as well. Also leptin, and specifically leptin signalling in the brain, was found to be important for insulin sensitivity. In conclusion, this work showed that neuropeptides/hormones that are involved in the regulation of food intake also affect insulin sensitivity. Show less
The evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of... Show moreThe evolutionary advantage to conserve energy in the form of adipose issue in order to survive long periods of food shortage in the past, turned into a major health problem in current times of plenty. Excess accumulation of body fat, or "obesity", is associated with severely increased co-morbidity and mortality risks and is a global epidemical medical condition which is difficult to manage. The exact pathophysiologic mechanism of obesity remains elusive and various factors such as genetic, social, behavioral and physiological cues are involved in its development. From a biological point of view, obesity might be partly explained by differences in the regulation of energy intake, expenditure and storage (energy homeostasis) between obese and lean individuals. The neuroendocrine system provides a source of humoral messengers, which modulate energy homeostasis. This thesis will focus on changes of the neuroendocrine environment of obese women. First of all, spontaneous diurnal plasma hormone concentrations and secretion of different hormonal systems were studied. Secondly, the effect of weight loss on neuroendocrine perturbations of some of these hormonal axes was evaluated. Finally, the impact of modulation of potential physiological cues (increased circulating FFAs and deficit dopaminergic signaling), which might be involved in the neuroendocrine changes and metabolic alterations, was investigated. Show less
