Aims/hypothesis Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in... Show moreAims/hypothesis Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans. Methods Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 +/- 5.9 years, mean BMI 26.1 +/- 4.6 kg/m(2)) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME. Results A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses. Conclusions/interpretation Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism. Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. 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
As the obesity epidemic is still increasing, strategies to prevent and treat obesity and related pathologies are in great demand. Obesity-induced inflammation is thought to contribute to the... Show moreAs the obesity epidemic is still increasing, strategies to prevent and treat obesity and related pathologies are in great demand. Obesity-induced inflammation is thought to contribute to the development of metabolic disorders. Therefore, inflammatory pathways that play a role in obesity-induced inflammation are potential promising targets in the treatment of metabolic disorders. Extensive knowledge on obesity-induced inflammation and the role of inflammatory pathways in the development of metabolic disorders can benefit the development of these therapeutic strategies. Mouse models are widely used to study obesity and related disorders, however, to what extent mouse-derived results translate to humans has not been studied extensively yet. Obesity-induced inflammation and its role in the development of insulin resistance, as well as the similarities of these processes between humans and mice, have been addressed in this thesis. The new findings described in this thesis will be summarized and discussed in the final chapter. Additionally, clinical implications of obesity-induced inflammation as target to treat metabolic disorders and future perspectives will be addressed. Show less
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic.... Show moreNon-alcoholic fatty liver disease (NAFLD) has rapidly become the most common cause of chronic liver disease, and its worldwide prevalence continues to increase in parallel of the obesity epidemic. NAFLD comprises a wide spectrum of liver damage ranging fat accumulation (steatosis) to steatosis with inflammation (non-alcoholic steatohepatitis, NASH), which can further progress to fibrosis. In particular patients with NASH have increased risk to develop other metabolic complications, such as cardiovascular disease.NAFLD is a complex disease, in which the origin and molecular mechanisms controlling the progression of simple steatosis to NASH remain poorly understood. Nevertheless, it is thought that inflammation is a critical component of NAFLD progression. This inflammation may be triggered by metabolic surplus (excess of energy or nutrients) and is also referred to as “metabolic inflammation”. White adipose tissue (WAT) is assumed to be largely involved in the development of metabolic inflammation. The studies described in this thesis contributed to the understanding of the role of WAT in the development of NAFLD and provide insight into the molecular processes that cause metabolic inflammation. Show less
Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as... Show more Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as diabetes mellitus. In the first part of this thesis, the epidemiology of insulin resistance has been described. Since there is no clear definition for insulin resistance, the prevalence of IR remains unclear. In addition, the use of IR in the screening for diabetes mellitus in obese children was evaluated. In the second part of the thesis, treatment of obese children with insulin resistance is discussed. In a randomized controlled trial of 18 months, children were treated with either metformin or placebo in addition to lifestyle intervention. Body mass index in children treated with metformin remained stable during the 18 months, whereas placebo-treated children had an increase in body mass index. Finally, the treatment with metformin under the strict circumstances of the clinical trial was compared to treatment with metformin in daily practice during 18 months. Both groups showed similar results regarding body mass index during metformin treatment. Show less
The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2... Show more The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance and hyperglycemia are associated with atherosclerosis and incident cardiovascular disease before the onset of type 2 diabetes. Obesity can be considered as a common cause of both insulin resistance and atherosclerosis. Therefore, we investigated to what extent associations between insulin resistance, hyperglycemia and atherosclerosis were explained by body fat. We further aimed to study the specific role of visceral fat in the development of insulin resistance and atherosclerosis, and directly assessed abdominal subcutaneous and visceral adipose tissue depots. Show less
In today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin... Show moreIn today__s world, more people die from complications of overweight than from underweight. But not all individuals are equally prone to develop metabolic complications, such as obesity and insulin resistance. This thesis focuses on the differences in the energy and fatty acid metabolism that play a role in the susceptibility for metabolic complications. We have investigated certain existing associations between genetic clues and a disturbed energy metabolism, in order to construct a more refined mechanism of action for this genetic association. This knowledge could be used to more precisely target the causal proteins and pathways involved in the development of obesity. We have also investigated the role of fatty acid metabolism in the fat tissue of obese humans and mice. In this way, we have found a direct link in both humans and mice between fatty acids and inflammation, which is relevant for metabolic diseases such as obesity and insulin resistance. Show less
Nearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T... Show moreNearly one quarter of the world__s population is infected with helminth parasites. A common feature of helminth infections is the manifestation of a type 2 immune response, characterized by T helper 2 (Th2) cells. In addition to their involvement in anti-helminth immunity, recent studies have shown that components of the type 2 immune responses can have additional functions. For example, recent evidence indicates that multiple facets of the type 2 immune response can regulate tissue-specific metabolic processes and whole-body nutrient homeostasis, and protect against insulin resistance. In this work we use omega-1, a glycosylated RNase excreted from Schistsoma mansoni eggs with strong Th2-inducing capacities, to study the requirements that equip DCs for Th2 skewing. In addition, we analyse the effect of chronic S. mansoni infection and administration of S. mansoni-derived egg antigens on metabolic homeostasis in diet-induced obese mice. Elucidating how helminths generate Th2 responses and contribute to metabolic homeostasis will not only shed light on the mechanisms that promote control of parasite infection, but may provide valuable leads for the development of pharmaceutical agents for the treatment of metabolic disorders. Show less
This thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients.... Show moreThis thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients. Because of the increasing number of patients with obesity and T2DM, more research is needed to identify patients at risk of developing T2DM and to elucidate specific therapeutic targets to improve insulin resistance. For now, the prevention of overweight and obesity is the most essential step in the fight against the worldwide obesity and T2DM epidemic Show less
Vroegrijk, I.O.C.M.; Diepen, J.A. van; Berg, S. van den; Westbroek, I.; Keizer, H.; Gambelli, L.; ... ; Voshol, P.J. 2011
The general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity... Show moreThe general aim of the studies described in this thesis is the effect evaluation of a family-based multidisciplinary cognitive behavioral treatment on several domains related to childhood obesity compared to standard care. The main findings from these studies are a modest long-term reduction of both total and abdominal adiposity accompanied by improved physical fitness, while unchanged adiposity in the untreated controls led to decreased physical fitness and deteriorating insulin sensitivity. In addition, we found significantly impaired health related quality of life in the obese children compared to their normal weight peers. We showed that our multidisciplinary lifestyle treatment improved health related quality of life of the obese children after 1 year. We observed a significantly increased postprandial ghrelin response after the multidisciplinary treatment, but no effect on inflammatory markers, nor on gut hormones PYY and GLP-1. Finally, we propose an alternative for the definition of the metabolic syndrome in children, since the usefulness of its current dichotomous form is questionable. We show that a multivariate prediction model based on the individual components of the metabolic syndrome expressed as standard deviation scores (SDS) has a good predictive value regarding increased HOMA-IR SDS. Show less
This thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East... Show moreThis thesis focuses on the incidence and risk factors for nephropathy in diabetic and non-diabetic Surinamese South Asians. The Surinamese South Asians, originally descended from the North-East India. Due to the former colonial bounds with the Netherlands, a relatively young South Asian migrant population settled in the Netherlands. South Asians have a high prevalence of central obesity and an eight-fold higher prevalence for type 2 diabetes mellitus. We found the following conclusions: 1.Surinamese South Asian persons have a nearly 40-fold higher risk for end-stage diabetic nephropathy in comparison to Dutch European persons. 2.There was no familial predisposition for diabetic nephropathy among South Asian families. 3.South Asian type 2 diabetic patients have a three-fold higher risk for diabetic nephropathy and faster progression of renal insufficiency in comparison to Dutch European patients. 4.Central obesity is an early and independent risk factor for increased albuminuria in normoglycemic South Asian subjects. We assume that the nearly 40-fold higher risk of end-stage diabetic nephropathy in South Asian migrants is primarily caused by central obesity which leads to: a. Early renal injury in the pre-diabetic state. b. Eight-times higher prevalence of type 2 diabetes mellitus. b. More diabetic nephropathy and faster decline in renal function. Show less
The metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are... Show moreThe metabolic syndrome is an increasing problem in our Western society. Many of the features of the metabolic syndrome, like obesity, insulin resistance, dyslipidemia, and hepatic steatosis are established risk factors for cardiovascular disease. Growing evidence supports the important role of body free fatty acid handling and/or body distribution of triglycerides in the pathogenesis of the metabolic syndrome-associated problems. We used several different approaches to study the development of obesity, insulin resistance, dyslipidemia, and liver steatosis. In chapter 2 we found that absence of apoC3, a natural LPL inhibitor, enhances FA uptake from plasma triglycerides in adipose tissue leading to increased susceptibility to diet-induced obesity, followed by more severe development of insulin resistance. Therefore, we have shown that regulation of body distribution of triglycerides, in a LPL-dependent process, plays an important role in obesity development. In chapter 3 we found that acute inhibition of the β-oxidation of FA indeed increases hepatic lipid content, but neither stimulates hepatic VLDL secretion nor reduces insulin sensitivity. In chapter 4 we showed that the combination of proteomics with relevant physiological parameters in a sensitive animal model, is a powerful tool, which will aid in identifying workingmechanisms of various dietary FA. In chapter 5 we found that sphingolipids protect the liver from fat and cholesterol-induced steatosis. Since sphingolipids are nutritional compounds present in several daily foods, such as milk and meat, addition of sphingolipids to the diet may decrease traditional cardiovascular risk factors, such as plasma cholesterol and triglycerides. Show less
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
