BackgroundAffective (i.e. depressive and anxiety) disorders often co-occur with immunometabolic diseases and related biological pathways. Although many large population-based and meta-analytic... Show moreBackgroundAffective (i.e. depressive and anxiety) disorders often co-occur with immunometabolic diseases and related biological pathways. Although many large population-based and meta-analytic studies have confirmed this link in community and clinical samples, studies in at-risk samples of siblings of persons with affective disorders are lacking. Furthermore, this somatic-mental co-occurrence may be partially explained by familial clustering of the conditions. First, we examined whether the association between a wide range of immunometabolic diseases and related biomarker based risk-profiles with psychological symptoms replicates in at-risk siblings of probands with affective disorders. Second, leveraging on a sibling-pair design, we disentangled and quantified the effect of probands’ immunometabolic health on siblings’ psychological symptoms and on the association between immunometabolic health and these symptoms in siblings.MethodsThe sample included 636 participants (Mage = 49.7; 62.4% female) from 256 families, each including a proband with lifetime depressive and/or anxiety disorders and at least one of their sibling(s) (N = 380 proband-sibling pairs). Immunometabolic health included cardiometabolic and inflammatory diseases, body mass index (BMI), and composite metabolic (based on the five metabolic syndrome components) and inflammatory (based on interleukin-6 and C-reactive protein) biomarker indices. Overall affective symptoms and specific atypical, energy-related depressive symptoms were derived from self-report questionnaires. Mixed-effects analyses were used to model familial clustering.ResultsIn siblings, inflammatory disease (γ = 0.25, p = 0.013), higher BMI (γ = 0.10, p = 0.033) and metabolic index (γ = 0.28, p < 0.001) were associated with higher affective symptoms, with stronger associations for atypical, energy-related depressive symptoms (additionally associated with cardiometabolic disease; γ = 0.56, p = 0.048). Immunometabolic health in probands was not independently associated with psychological symptoms in siblings nor did it moderate the association between immunometabolic health and psychological symptoms estimated in siblings.ConclusionsOur findings demonstrate that the link between later life immunometabolic health and psychological symptoms is consistently present also in adult siblings at high risk for affective disorders. Familial clustering did not appear to have a substantial impact on this association. Instead, individual lifestyle, rather than familial factors, may have a relatively higher impact in the clustering of later life immunometabolic conditions with psychological symptoms in at-risk adult individuals. Furthermore, results highlighted the importance of focusing on specific depression profiles when investigating the overlap with immunometabolic health. Show less
The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and... Show moreThe research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.Leptin plays an important role during TB infection and has a huge impact on insulin sensitivity in zebrafish larvae. Similarly to what has been observed in the murine model, leptin deficiency in zebrafish increased the bacterial burden and mortality during the infection, leading to hyperglycemia and the development of insulin resistance. In addition, a novel SHP-1/SHP-2 inhibitor, NSC-87877, was shown to represent a promising anti-diabetic drug that can be used for further DM2 research, as it is able to rescue the phenotype of the leptin-deficient zebrafish and to restore glucose transport to the tissues. In contrast to metformin, NSC-87877 can act at very early developmental stages and inhibits the function of SHP-1 and factors that underlay impaired glucose metabolism, whereas metformin is mostly known to improve insulin sensitivity. Additionally, treatment with the glucocorticoid beclomethasone attenuates the metabolic changes associated with the infection, and transcriptional alterations induced by beclomethasone treatment suggest that genes involved in glucose metabolism, insulin and leptin signaling all play an important role in the modulation of the metabolism.Our data show that zebrafish larvae represent an interesting model system to investigate the complex pathology of TB, and the studies described in this thesis in which this model has been used have provided novel insights into the molecular mechanisms underlying wasting syndrome and the possibilities for adjunctive glucocorticoid therapy to alleviate this metabolic state. Show less
Kroon, J.; Viho, E.M.G.; Gentenaar, M.; Koorneef, L.L.; Kooten, C. van; Rensen, P.C.N.; ... ; Meijer, O.C. 2021
Glucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including... Show moreGlucocorticoids regulate numerous processes in human physiology, but deregulated or excessive glucocorticoid receptor (GR) signaling contributes to the development of various pathologies including metabolic syndrome. For this reason, GR antagonists have considerable therapeutic value. Yet, the only GR antagonist that is clinically approved to date - mifepristone - exhibits cross-reactivity with other nuclear steroid receptors like the progesterone receptor. In this study, we set out to identify novel selective GR antagonists by combining rational chemical design with an unbiased in vitro and in vivo screening approach. Using this pipeline, we were able to identify CORT125329 as the compound with the best overall profile from our octahydro series of novel GR antagonists, and demonstrated that CORT125329 does not exhibit cross-reactivity with the progesterone receptor. Further in vivo testing showed beneficial activities of CORT125329 in models for excessive corticosterone exposure and short- and long-term high-fat diet-induced metabolic complications. Upon CORT125329 treatment, most metabolic parameters that deteriorated upon high-fat diet feeding were similarly improved in male and female mice, confirming activity in both sexes. However, some sexually dimorphic effects were observed including male-specific antagonism of GR activity in brown adipose tissue and female-specific lipid lowering activities after short-term CORT125329 treatment. Remarkably, CORT125329 exhibits beneficial metabolic effects despite its lack of GR antagonism in white adipose tissue. Rather, we propose that CORT125329 treatment restores metabolic activity in brown adipose tissue by stimulating lipolysis, mitochondrial activity and thermogenic capacity. In summary, we have identified CORT125329 as a selective GR antagonist with strong beneficial activities in metabolic disease models, paving the way for further clinical investigation. Show less
Background: Major depressive disorder (MDD) is linked to higher cardio-metabolic comorbidity that may in part be due to the low-grade inflammation and poorer metabolic health observed in MDD.... Show moreBackground: Major depressive disorder (MDD) is linked to higher cardio-metabolic comorbidity that may in part be due to the low-grade inflammation and poorer metabolic health observed in MDD. Heterogeneity of MDD is however large, and immune-inflammatory and metabolic dysregulation is present in only part of the MDD cases. We examined the associations of four depression dimensional profilers (atypical energy-related symptom dimension, melancholic symptom dimension, childhood trauma severity, and anxious distress symptom dimension) with immuno-metabolic outcomes, both cross-sectionally and longitudinally.Methods: Three waves covering a 6-year follow-up (>7000 observations) of the Netherlands Study of Depression and Anxiety (NESDA) were used. Depression profilers were based on the Inventory of Depressive Symptomatology, the Beck Anxiety Inventory, and the Childhood Trauma index. An inflammatory index (based on IL-6 and CRP), a metabolic syndrome index (based on the five metabolic syndrome components), and a combination of these two indices were constructed. Mixed models were used for cross-sectional and longitudinal models, controlling for covariates.Results: Of the four depression profilers, only the atypical, energy-related symptom dimension showed robust associations with higher scores on the inflammatory, metabolic syndrome and combined inflammatory-metabolic indexes cross-sectionally, as well as at follow-up. The melancholic symptom dimension was associated with lower scores on the metabolic syndrome index both cross-sectionally and longitudinally.Conclusion: The atypical energy-related symptom dimension was linked to poorer immune-inflammatory and metabolic health, while the melancholic symptom dimension was linked to relatively better metabolic health. Persons with high atypical energy-related symptom burden, representing an immuno-metabolic depression, may be the most important group to target in prevention programs for cardiometabolic disease, and may benefit most from treatments targeting immuno-metabolic pathways. Show less
Caselli, C.; Turco, S. del; Ragusa, R.; Lorenzoni, V.; Graaf, M. de; Basta, G.; ... ; Neglia, D. 2019
Objective Aim of this study was to evaluate the relationship of plasma PCSK9 with metabolic and inflammatory profile and coronary atherosclerotic burden in patients with suspected CAD enrolled in... Show moreObjective Aim of this study was to evaluate the relationship of plasma PCSK9 with metabolic and inflammatory profile and coronary atherosclerotic burden in patients with suspected CAD enrolled in the EVINCI study. Methods PCSK9 was measured in 539 patients (60.3 +/- 8.6 years, 256 males) with symptoms of CAD characterized by risk factors, bio-humoral profiles, and treatment. N = 412 patients underwent coronary computed tomography angiography (CTA) to assess the presence and characteristics of coronary atherosclerosis. A CTA score, combining extent, severity, composition, and location of plaques was computed. Results Patients were divided according to PCSK9 quartiles: I (< 136 ng/mL), II-III (136-266 ng/mL), and IV quartile (> 266 ng/mL). Compared with patients in quartile IV, patients in quartile I had a higher prevalence of the metabolic syndrome and higher values of body mass index. LDL- and HDL-cholesterol were significantly lower in patients in the quartile I than in those in quartile IV. Coronary CTA documented normal vessels in 30% and obstructive CAD in 35% of cases without differences among PCSK9 quartiles. Compared with patients with the highest levels, patients with the lowest PCSK9 levels had a higher CTA score mainly due to higher number of mixed non-obstructive coronary plaques. At multivariable analysis including clinical, medications, and lipid variables, PCSK9 was an independent predictor of the CTA score (coefficient - 0.129, SE 0.03, P < 0.0001), together with age, male gender, statins, interleukin-6, and leptin. Conclusion In patients with stable CAD, low PCSK9 plasma levels are associated with a particular metabolic phenotype (low HDL cholesterol, the metabolic syndrome, obesity, insulin resistance and diabetes) and diffuse non-obstructive coronary atherosclerosis. Trial registration ClinicalTrials.gov NCT00979199. Registered September 17, 2009 Show less
Background: Metabolic syndrome (MetS) has been associated with both early- and late-life depression. This study investigated whether baseline MetS and its individual components are associated with... Show moreBackground: Metabolic syndrome (MetS) has been associated with both early- and late-life depression. This study investigated whether baseline MetS and its individual components are associated with the course of depression over six years among older persons with a formal depression diagnosis.Methods: Data were used from 378 older persons with a depressive disorder from the Netherlands Study of Depression in Old age (NESDO) with a 6-year follow-up. A formal depression diagnosis according to DSM-IV-TR criteria was ascertained with the Composite International Diagnostic Interview. Severity of depressive symptoms was assessed with the Inventory of Depressive Symptomatology at 6-month intervals. Metabolic syndrome (MetS) was defined according the modified National Cholesterol Education Programme - Adult Treatment Panel III criteria. Primary outcome was time to remission from depression. We applied cox regression analysis for the primary outcome and linear mixed models for secondary analyses.Results: Neither MetS nor its individual components were associated with time to remission from depression (MetS: HR = 1.03; 95% CI = 0.74 - 1.44; p = 0.85), or with depression severity (MetS: B = 0.02; SE = 0.04; p = 0.64) and course of depressive symptoms (MetS: B = -0.01; SE = 0.01; p = 0.23) over 6-years follow-up.Limitations: Attrition was relatively high (46.8%). Furthermore, we only had information on formal depression diagnosis at baseline, 2-year, and 6-year follow-up.Conclusions: We found no evidence for an effect of baseline presence of metabolic dysregulation on the course of formally diagnosed depression in older persons. Metabolic syndrome in depressed patients should be clinically monitored for other reasons than predicting chronicity or severity of depression. Show less
Aims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing... Show moreAims/hypothesisAnimal studies have indicated that disturbed diurnal rhythms of clock gene expression in adipose tissue can induce obesity and type 2 diabetes. The importance of the circadian timing system for energy metabolism is well established, but little is known about the diurnal regulation of (clock) gene expression in obese individuals with type 2 diabetes. In this study we aimed to identify key disturbances in the diurnal rhythms of the white adipose tissue transcriptome in obese individuals with type 2 diabetes.MethodsIn a case-control design, we included six obese individuals with type 2 diabetes and six healthy, lean control individuals. All participants were provided with three identical meals per day for 3days at zeitgeber time (ZT, with ZT 0:00 representing the time of lights on) 0:30, 6:00 and 11:30. Four sequential subcutaneous abdominal adipose tissue samples were obtained, on day 2 at ZT 15:30, and on day 3 at ZT 0:15, ZT 5:45 and ZT 11:15. Gene expression was measured using RNA sequencing.ResultsThe core clock genes showed reduced amplitude oscillations in the individuals with type 2 diabetes compared with the healthy control individuals. Moreover, in individuals with type 2 diabetes, only 1.8% (303 genes) of 16,818 expressed genes showed significant diurnal rhythmicity, compared with 8.4% (1421 genes) in healthy control individuals. Enrichment analysis revealed a loss of rhythm in individuals with type 2 diabetes of canonical metabolic pathways involved in the regulation of lipolysis. Enrichment analysis of genes with an altered mesor in individuals with type 2 diabetes showed decreased activity of the translation initiating pathway EIF2 signaling'. Individuals with type 2 diabetes showed a reduced diurnal rhythm in postprandial glucose concentrations.Conclusions/interpretationDiurnal clock and metabolic gene expression rhythms are decreased in subcutaneous adipose tissue of obese individuals with type 2 diabetes compared with lean control participants. Future investigation is needed to explore potential treatment targets as identified by our study, including clock enhancement and induction of EIF2 signalling.Data availabilityThe raw sequencing data and supplementary files for rhythmic expression analysis and Ingenuity Pathway Analysis have been deposited in NCBI Gene Expression Omnibus (GEO series accession number GSE104674). Show less
Surowiec, I.; Noordam, R.; Bennett, K.; Beekman, M.; Slagboom, P.E.; Lundstedt, T.; Heemst, D. 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
The aim of this thesis was to develop advanced body MR techniques that can contribute to the knowledge of the metabolic syndrome (MetS). Such techniques are important since the incidence of... Show moreThe aim of this thesis was to develop advanced body MR techniques that can contribute to the knowledge of the metabolic syndrome (MetS). Such techniques are important since the incidence of the metabolic syndrome is reaching pandemic proportions. We looked In the first part of this thesis, consisting of chapters 2, 3 and 4, new techniques for body MR were developed. Firstly high dielectric passive shimming was developed and applied on liver imaging to increase image quality. Furthermore, the required power was reduced by applying the passive shimming method. Secondly MR spectroscopy was optimized to reliably measure lipid levels in the heart and kidney. By looking at the various parameters and optimizing them individually very high measurement reproducibility was reached. Even though MR spectroscopy is a great tool for studying MetS the complexity of the technique hampers broad application therefore, extra emphasis was placed on the ease of use of the developed protocol. In the second part of the thesis the previously mentioned methods were applied in a more clinical setting. Show less
Glycosylation is an important way in which proteins, the functional agents of our body, can be modified to alter and expand their functional repertoire. Glycans consist of monosaccharides that... Show moreGlycosylation is an important way in which proteins, the functional agents of our body, can be modified to alter and expand their functional repertoire. Glycans consist of monosaccharides that are linked in a chained and branching fashion, often to form specific epitopes that are of clinical and biopharmaceutical interest. In order to study glycosylation, there is a need for high-throughput analysis methodology. Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) is a prominent example of this, as it can rapidly provide information on the monosaccharide compositions of glycans. However, it is challenging for the method to yield information on the structural aspects of glycosylation, as well as on glycans carrying sialic acids. These sialylated glycans are prone to in-source and metastable decay, and tend to require chemical derivatization to allow their analysis. The aim of this thesis is the development and application of new methodology for MALDI-MS N-glycomics, and, with a focus on metabolic syndrome and rheumatoid arthritis, to increase our understanding of the role of N-glycosylation in health and disease. A principal outcome of the work is a sialic acid derivatization protocol that allows the mass-based discrimination of alpha-2,3- and alpha-2,6-linked sialic acids, facilitating their study in a high-throughput setting. Show less
Depression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated... Show moreDepression and cardiovascular disease (CVD) are among the most prevalent health problems worldwide, with a significant burden of disease. Both conditions are associated and thought to be mediated by the metabolic syndrome (MetSyn), a cluster of cardiovascular risk factors (waist circumference, blood sugar, cholesterol, triglycerides, blood pressure) and related parameters (BMI, waist-hip-ratio and LDL-cholesterol). Better insights in this association are important in order to better prevent and treat both conditions. This thesis focuses on the association between depression and metabolic disturbances. The results show that there is a significant and longitudinal and bidirectional association between depression and obesity, which is most pronounced among those with a clinical diagnosis depression. When subjects are approached not based on the presence or absence of the diagnosis, but based on the most prevalent symptoms, results show that only __Somatic Arousal__ symptoms (palpitations, dizziness, tension, shortness of breath) are associated with most MetSyn components. Comparing depressed inpatients to depressed outpatients, inpatients show more adverse metabolic disturbances in the lipid-spectrum, while blood pressure is more favorable. Further, inpatients show higher cortisol levels, which are considered to be a measure of the HPA-axis, an important stress-system in the onset and natural course of depression. Show less
In this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long... Show moreIn this thesis, a number of observations are described in acromegaly patients with cured or biochemically well-controlled disease during long-term follow-up. These observations focus on the long-term consequences of the disease on joints and bone. In addition, we investigated the role of the Growth Hormone (GH)/Insulin-like Growth Factor-1 (IGF-1) axis, including the possible effects of the exon 3 deleted GH receptor (d3-GHR) polymorphism, in patients with primary osteoarthritis (OA) that have serum IGF-1 levels within the normal range. Finally, we studied the long-term consequences of recombinant human GH (rhGH) replacement in GH Deficient (GHD) adults, focusing on the cardiovascular effects and the effects on bone in comparison to healthy controls. Show less
The studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell... Show moreThe studies described in this thesis were performed to investigate the short and long-term effects of chemotherapy on bone metabolism, fat metabolism and cardiovascular risk in testicular germ cell tumour (GCT) patients. We report a twofold increased prevalence of Metabolic Syndrome (MetS) in GCT patients who received chemotherapy compared to that in patients with stage 1 disease who did not receive chemotherapy, or to that in healthy controls. Thereafter, we describe disadvantageous metabolic changes and acute alterations in diastolic heart function in GCT patients treated with cisplatin-based chemotherapy. In the same group of patients we show that, during chemotherapy administrations, serum non-protein bound iron concentrations were inversely related to the latent iron-binding capacity and serum iron concentrations. This suggests that chemotherapy-associated iron overload may play a role in short and long-term chemotherapy induced toxicity in GCT patients. The study on bone metabolism shows an increased prevalence of vertebral fractures, independent of BMD and anticancer treatment, in newly diagnosed as well as long term survivors of testicular cancer. The last chapter reports on a significant decline in lumbar and femoral BMD in metastatic GCT patients one year after chemotherapeutic treatment. Show less
Osteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular... Show moreOsteoarthritis (OA) is a frequently occurring joint disorder with great impact on the quality of life. In general, OA is described as a heterogeneous disease with degeneration of articular cartilage as main outcome. Despite extensive research on the pathogenesis of OA, there is until now no cure and treatments are primarily aimed at reducing pain. Evidence starts to appear that mild inflammation and obesity-related biochemical changes are involved in OA pathology. It is uncertain what the relative contribution of these processes is and if they characterize a certain type of OA patients. We identified obesity, high cholesterol and systemic inflammation associated with these conditions as major players in OA development, which may activate joint tissues to secrete inflammatory mediators and contribute to the initiation and progression of OA. Our work suggests that a stratification of OA patients with (features of) the metabolic syndrome as underlying mechanism is recommendable, to optimize the efficacy of clinical trials. Approaching OA as a disease induced by whole body metabolism, and integrating knowledge about different potentially active tissues in the OA process, will provide new insights for possible pharmacological interventions. Show less
In this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2... Show moreIn this thesis we reported our investigations of the relationship between soil-transmitted helminths (STH) and a number of outcomes, in particular malaria, insulin resistance (a marker for type-2 diabetes (T2D)) and atherosclerosis (a marker for cardiovascular diseases (CVD)) on Flores island, Indonesia. In the study on Flores Island, the use of albendazole as a single dose at three monthly intervals decreased helminth infections significantly. However, this intensive deworming could not eliminate helminth infections. Despite no effect on malaria parasitemia and clinical symptoms was found, we noted that in vitro immune responses were improved after albendazole treatment and significant increases in malaria-specific and mitogen-induced tumor necrosis factor and interferon _ cytokine production were observed. We also reported that helminth infections are associated with improved insulin sensitivity and lower risk factors for CVD. A possible approach to confirm our results will be a long-term, well-powered, placebo controlled (adequate) anthelminthic trials to investigate asymptomatic malaria (in area where clinical malaria is highly prevalent); as well as to study whether alleviation of helminthic pressure is inversely correlated with anti-inflammation, lipid levels and insulin sensitivity, and therefore leads to an accelerated development of T2D and CVD. Show less
