Chronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues,... Show moreChronic energy surplus causes obesity and promotes insulin resistance and type 2 diabetes (T2D). A major contributor to insulin resistance is chronic, low-grade inflammation in metabolic tissues, also coined metaflammation. In this context, white adipose tissue and liver-resident innate and adaptive immune cells produce proinflammatory cytokines that exacerbate inflammation and inhibit canonical insulin signaling. Among them, macrophages and dendritic cells were shown to play central roles in metaflammation, although the environmental and cellular changes dictating proinflammatory activation in the context of obesity are not fully understood. This thesis describes novel mechanisms by which macrophages and dendritic cells control metabolic homeostasis in obese mice. In addition, we show that immunomodulatory molecules derived from parasitic worm eggs promote an immune response in metabolic tissues that maintains insulin sensitivity. Finally, we describe the pleiotropic beneficial effects of a novel plant-derived nutritional supplement on metaflammation and metabolic homeostasis in obese mice. Altogether, this work may provide new leads for interventions aimed at improving immunological control of metabolic dysfunctions. Show less
Rios-Morales, M.; Vieira-Lara, M.A.; Homan, E.; Langelaar-Makkinje, M.; Gerding, A.; Li, Z.; ... ; Bakker, B.M. 2022
Skeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin... Show moreSkeletal muscle insulin resistance is a key pathophysiological process that precedes the development of type 2 diabetes. Whereas an overload of long-chain fatty acids can induce muscle insulin resistance, butyrate, a short -chain fatty acid (SCFA) produced from dietary fibre fermentation, prevents it. This preventive role of butyrate has been attributed to histone deacetylase (HDAC)-mediated transcription regulation and activation of mito-chondrial fatty-acid oxidation. Here we address the interplay between butyrate and the long-chain fatty acid palmitate and investigate how transcription, signalling and metabolism are integrated to result in the butyrate -induced skeletal muscle metabolism remodelling. Butyrate enhanced insulin sensitivity in palmitate-treated, insulin-resistant C2C12 cells, as shown by elevated insulin receptor 1 (IRS1) and pAKT protein levels and Slc2a4 (GLUT4) mRNA, which led to a higher glycolytic capacity. Long-chain fatty-acid oxidation capacity and other functional respiration parameters were not affected. Butyrate did upregulate mitochondrial proteins involved in its own oxidation, as well as concentrations of butyrylcarnitine and hydroyxybutyrylcarnitine. By knocking down the gene encoding medium-chain 3-ketoacyl-CoA thiolase (MCKAT, Acaa2), butyrate oxidation was inhibited, which amplified the effects of the SCFA on insulin sensitivity and glycolysis. This response was associated with enhanced HDAC inhibition, based on histone 3 acetylation levels. Butyrate enhances insulin sensitivity and induces glycolysis, without the requirement of upregulated long-chain fatty acid oxidation. Butyrate catabolism functions as an escape valve that attenuates HDAC inhibition. Thus, inhibition of butyrate oxidation indirectly prevents insulin resistance and stimulates glycolytic flux in myotubes treated with butyrate, most likely via an HDAC-dependent mechanism. Show less
Wang, W.Y.; Dijk, K.W. van; Wijsman, C.A.; Rozing, M.P.; Mooijaart, S.P.; Beekman, M.; ... ; Heemst, D. van 2021
Background Insulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on... Show moreBackground Insulin is the key regulator of glucose metabolism, but it is difficult to dissect direct insulin from glucose-induced effects. We aimed to investigate the effects of hyperinsulemia on metabolomic measures under euglycemic conditions in nondiabetic participants. Methods We assessed concentrations of 151 metabolomic measures throughout a two-step hyperinsulinemic euglycemic clamp procedure. We included 24 participants (50% women, mean age = 62 [s.d. = 4.2] years) and metabolomic measures were assessed under baseline, low-dose (10 mU/m(2)/min) and high-dose (40 mU/m(2)/min) insulin conditions. The effects of low- and high-dose insulin infusion on metabolomic measures were analyzed using linear mixed-effect models for repeated measures. Results After low-dose insulin infusion, 90 metabolomic measures changed in concentration (p < 1.34e(-4)), among which glycerol (beta [Confidence Interval] = - 1.41 [- 1.54, - 1.27] s.d., p = 1.28e(-95)) and three-hydroxybutyrate (- 1.22 [- 1.36, - 1.07] s.d., p = 1.44e(-61)) showed largest effect sizes. After high-dose insulin infusion, 121 metabolomic measures changed in concentration, among which branched-chain amino acids showed the largest additional decrease compared with low-dose insulin infusion (e.g., Leucine, - 1.78 [- 1.88, - 1.69] s.d., P = 2.7e(-295)). More specifically, after low- and high-dose insulin infusion, the distribution of the lipoproteins shifted towards more LDL-sized particles with decreased mean diameters. Conclusion Metabolomic measures are differentially insulin sensitive and may thus be differentially affected by the development of insulin resistance. Moreover, our data suggests insulin directly affects metabolomic measures previously associated with increased cardiovascular disease risk. Show less
Luo, J.; Meulmeester, F.L.; Martens, L.G.; Ashrafi, N.; Mutsert, R. de; Mook-Kanamori, D.O.; ... ; Heemst, D. van 2021
Background & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (alpha-tocopherol, alpha-TOH) competitively reacts with lipid peroxyl... Show moreBackground & aims: Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (alpha-tocopherol, alpha-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between alpha-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. Methods: This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. alpha-TOH metabolites in blood (alpha-TOH and alpha-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both alpha-TLHQ (oxidized) and alpha-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MSeMS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of alpha-TOH metabolites and measures of glucose homeostasis. Results: We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood alpha-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (alpha-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher alpha-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary alpha-TLHQ to alpha-CEHC ratio as a measure of oxidized-over-enzymatic conversion of alpha-TOH. Conclusion: Higher urinary levels of oxidized alpha-TOH metabolites as well as higher oxidized-to-enzymatic alpha-TOH metabolite ratio, but not circulating alpha-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating alpha-TOH, estimates of the conversion of alpha-TOH might be informative in relation to health and disease. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/ Show less
Background and aims: The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of... Show moreBackground and aims: The separate cardiovascular effects of type 2 diabetes and adiposity remain to be examined. This study aimed to investigate the role of insulin resistance in the relations of visceral (VAT), abdominal subcutaneous (aSAT) adipose tissue and total body fat (TBF) to cardiovascular remodeling.Methods and results: In this cross-sectional analysis of the population-based Netherlands Epidemiology of Obesity study, 914 middle-aged individuals (46% men) were included. Participants underwent magnetic resonance imaging. Standardized linear regression coefficients (95%CI) were calculated, adjusted for potential confounding factors. All fat depots and insulin resistance (HOMA-IR), separate from VAT and TBF, were associated with lower mitral early and late peak filling rate ratios (E/A): -0.04 (-0.09;0.01) per SD (54 cm(2)) VAT; -0.05 (-0.10;0.00) per SD (94 cm(2)) aSAT; -0.09 (-0.16;-0.02) per SD (8%) TBF; -0.11 (-0.17;-0.05) per 10-fold increase in HOMA-IR, whereas VAT and TBF were differently associated with left ventricular (LV) end-diastolic volume: -8.9 (-11.7;-6.1) mL per SD VAT; +5.4 (1.1;9.7) mL per SD TBF. After adding HOMA- IR to the model to evaluate the mediating role of insulin resistance, change in E/A was -0.02 (-0.07;0.04) per SD VAT; -0.03 (-0.08;0.02) per SD aSAT; -0.06 (- 0.13;0.01) per SD TBF, and change in LV end-diastolic volume was -7.0 (-9.7;-4.3) mL per SD VAT. In women, adiposity but not HOMA-IR was related to higher aortic arch pulse wave velocity.Conclusion: Insulin resistance was associated with reduced diastolic function, separately from VAT and TBF, and partly mediated the associations between adiposity depots and lower diastolic function. (C) 2020 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. Published by Elsevier B.V. All rights reserved. Show less
Heparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune... Show moreHeparanase is the predominant enzyme that cleaves heparan sulfate, the main polysaccharide in the extracellular matrix. While the role of heparanase in sustaining the pathology of autoimmune diabetes is well documented, its association with metabolic syndrome/type 2 diabetes attracted less attention. Our research was undertaken to elucidate the significance of heparanase in impaired glucose metabolism in metabolic syndrome and early type 2 diabetes. Here, we report that heparanase exerts opposite effects in insulin-producing (i.e., islets) vs. insulin-target (i.e., skeletal muscle) compartments, sustaining or hampering proper regulation of glucose homeostasis depending on the site of action. We observed that the enzyme promotes macrophage infiltration into islets in a murine model of metabolic syndrome, and fosters beta-cell-damaging properties of macrophages activated in vitro by components of diabetogenic/obese milieu (i.e., fatty acids). On the other hand, in skeletal muscle (prototypic insulin-target tissue), heparanase is essential to ensure insulin sensitivity. Thus, despite a deleterious effect of heparanase on macrophage infiltration in islets, the enzyme appears to have beneficial role in glucose homeostasis in metabolic syndrome. The dichotomic action of the enzyme in the maintenance of glycemic control should be taken into account when considering heparanase-targeting strategies for the treatment of diabetes. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
Noordam, R.; Boersma, V.; Verkouter, I.; Cessie, S. le; Christen, T.; Lamb, H.J.; ... ; Mutsert, R. de 2020
Background and aims: In the present study, we assessed the extent of mediation by low-grade systemic inflammation and adipokines in the association between abdominal adiposity and insulin... Show moreBackground and aims: In the present study, we assessed the extent of mediation by low-grade systemic inflammation and adipokines in the association between abdominal adiposity and insulin resistance.Methods and results: In this cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity study, total body fat (TBF) was measured in all (n = 5772) participants who did not have missing data and neither used glucose-lowering medication, and abdominal subcutaneous adipose tissue (aSAT) and visceral adipose tissue (VAT) were assessed by MRI in a random subgroup (n = 2448). C-reactive protein (CRP), adiponectin, and leptin were considered as potential mediators, and insulin resistance was assessed by Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). Mediation by CRP, adiponectin, and leptin was studied by including the mediators to the fully adjusted linear regression model. Participants had a mean (SD) age of 56 (6) years, TBF of 36 (9) %, VAT of 119 (61) cm2 and aSAT of 300 (111) cm2. Per SD of TBF, VAT and aSAT, HOMA-IR was 64% (95% confidence interval [CI]: 59-70), 33% (95% CI: 28-42) and 20% (95%CI: 14-26) higher, respectively. The association between aSAT and HOMA-IR fully disappeared after adjustment for leptin; the association between VAT and HOMA-IR attenuated after adjustment for leptin (22%) and adiponectin (15%). No mediation was observed by CRP, and mediation estimates were similar in men and women.Conclusion: Where leptin fully explained the aSAT-HOMA-IR association, the VAT-HOMA-IR association was only partly explained by leptin and adiponectin similarly in men and women. (C) 2020 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. Published by Elsevier B.V. All rights reserved. Show less
Background: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with... Show moreBackground: South Asians generally have an unfavourable metabolic phenotype compared with white Caucasians, including central obesity and insulin resistance. The Wnt protein family interacts with insulin signaling, and impaired Wnt signaling is associated with adiposity and type 2 diabetes mellitus. We aimed to investigate Wnt signaling in relation to insulin signaling in South Asians compared with white Caucasians.Methods: Ten Dutch South Asian men with prediabetes and overweight or obesity and 10 matched Dutch white Caucasians were included. Blood samples were assayed for the Wnt inhibitor sclerostin. Subcutaneous white adipose tissue (WAT) and skeletal muscle biopsies were assayed for Wnt and insulin signaling gene expression with quantitative reverse transcription polymerase chain reaction (Clinicaltrials.gov NCT02291458).Results: Plasma sclerostin was markedly higher in South Asians compared with white Caucasians (+65%, P < 0.01). Additionally, expression of multiple Wnt signaling genes and key insulin signaling genes were lower in WAT in South Asians compared with white Caucasians. Moreover, in WAT in both ethnicities, Wnt signaling gene expression strongly positively correlated with insulin signaling gene expression. In skeletal muscle, WNT10B expression in South Asians was lower, but expression of other Wnt signaling and insulin signaling genes was comparable between ethnicities. Wnt and insulin signaling gene expression also positively correlated in skeletal muscle, albeit less pronounced.Conclusion: South Asian men with overweight or obesity and prediabetes have higher plasma sclerostin and lower Wnt signaling gene expression in WAT compared with white Caucasians. We interpret that reduced Wnt signaling could contribute to impaired insulin signaling in South Asians. Show less
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
Schaft, N. van der; Schoufour, J.D.; Nano, J.; Kiefte-de Jong, J.C.; Muka, T.; Sijbrands, E.J.G.; ... ; Voortman, T. 2019
Obesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat... Show moreObesity has a great societal impact as it contributes to the development of type 2 diabetes and cardiovascular diseases. Activation of brown adipose tissue (BAT) is seen as a strategy to combat adiposity and related disorders, because of its capacity to combust nutrients and increase energy expenditure. To develop novel BAT activating methods, a better understanding of the pathophysiology of diet-induced obesity on BAT function and whole-body metabolism is required. Studies described in this thesis have increased our understanding of nutrient handling by brown adipocytes. We also generated immortalized brown adipocytes which can be used for future research. Furthermore, we gained more insight into the development of diet-induced obesity; feeding a high fat diet (HFD) rapidly made BAT insulin resistant and less active. In addition, HFD feeding increased synthesis of so-called endocannabinoids in both white and brown adipose tissue. Because endocannabinoids regulate both energy intake and expenditure, future research should determine whether inhibiting endocannabinoid signaling specifically in adipose tissue is a worthwhile strategy to pursue in combating obesity. Finally, quercetin, which naturally occurs in fruits and vegetables, induced ‘browning’ of white adipose tissue and thereby improved blood lipid levels. These studies pave the road for further development of BAT-activating strategies! Show less
Rodriguez-Calvo, R.; Girona, J.; Rodriguez, M.; Samino, S.; Barroso, E.; Gonzalo-Calvo, D. de; ... ; Masana, L. 2019
Objective: Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone involved in the crosstalk between adipose and peripheral tissues, and it contributes to widespread insulin... Show moreObjective: Fatty acid binding protein 4 (FABP4) is an intracellular lipid chaperone involved in the crosstalk between adipose and peripheral tissues, and it contributes to widespread insulin resistance in cells, including cardiac cells. However, the role of this adipokine in regulating cardiac metabolism and myocardial neutral lipid content in patients with type 2 diabetes has not been elucidated.Methods: The impact of circulating FABP4 on the cardiac neutral lipid content was measured by proton magnetic resonance spectroscopy (H-1-MRS) in patients with type 2 diabetes. Additionally, circulating FABP4 and the cardiac triglyceride content were analysed in high-fat diet (FIFD)-fed mice, and the impact of the exogenous FABP4 was explored in HL-1 cardiac cells.Results: Serum FABP4 levels were higher in type 2 diabetic patients compared to healthy individuals. Circulating FABP4 levels were associated with myocardial neutral lipid content in type 2 diabetic patients. In FIFD-fed mice, both serum FABP4 and myocardial triglyceride content were increased. In FABP4-challenged HL-1 cells. extracellular FABP4 increased intracellular lipid accumulation, which led to impairment of the insulin-signalling pathway and reduced insulin-stimulated glucose uptake. However, these effects were partially reversed by FABP4 inhibition with BM5309403. which attenuated the intracellular lipid content and improved insulin signalling and insulin-stimulated glucose uptake.Conclusions: Taken together, our results identify FABP4 as a molecule involved in diabeticllipid-induced cardiomyopathy and indicate that this molecule may be an emerging biomarker for diabetic cardiomyopathy-related disturbances, such as myocardial neutral lipid accumulation. Additionally, FABP4 inhibition may be a potential therapeutic target for metabolic-related cardiac dysfunctions. (C) 2019 Elsevier Inc. All rights reserved. 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 main objective of this thesis is to improve the understanding of the role of helminth infections in the development of insulin resistance, hence type 2 diabetes, and to gain insight into the... Show moreThe main objective of this thesis is to improve the understanding of the role of helminth infections in the development of insulin resistance, hence type 2 diabetes, and to gain insight into the immunological mechanisms underlying this possible interaction. To this end, we initiated a large scale cluster randomized controlled trial, assessing the effect of anthelmintic treatment on insulin resistance and other metabolic, as well as immunological parameters, in a rural area of Indonesia. Deworming significantly reduced the prevalence of helminths, as well as infection intensity. Although treatment did not lead to an increase of whole-body insulin resistance at the community level, a significant increase in insulin resistance was observed among helminth-infected subjects. Furthermore, by comparing immune cells of helminth-infected Indonesians before and after treatment, we gained insight into the specific cell populations that participate in the type 2 and regulatory networks, and show that treatment affects specific cell subsets in these networks. Altogether, the studies described in this thesis show that helminth infections in humans, as well as the administration of helminth molecules in obese mice, have a beneficial effect on the insulin sensitivity, and have shed light on the immunomodulatory effects of helminths. Show less
Metabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an... Show moreMetabolic disease has become pandemic in the developed world. Given our lack of understanding of its molecular pathology, we are often unable to diagnose patients before they reach an irreversible state of diabetes or cardiovascular disease. Much research has been done on the role of insulin signaling in metabolic disease, as well as the resultant disturbed lipid homeostasis present in cardiovascular disease and atherosclerosis. Here we add to existing work by developing new tools and sketching out the pathology of dysregulated adipose insulin signaling. We discuss the mechanism of lipodystrophy by using adipocytes differentiated from patient-derived iPSCs. These cells mimic the clinical phenotype and hint at mechanism that reduced patients’ adipose tissue mass. In mice we find that if we knock out the adipose insulin receptor, there is disrupted adipose and liver metabolism. There is a protection from diet-induced obesity, but a dramatically reduced lifespan. We also establish a relationship between obesity and inflammation by transcriptomically assessing obese human adipocytes. We find that an immune factor is responsible for lipid droplet formation and content. Lastly, we develop a new differentiation and purification strategy for iPSC-derived hepatocytes, which we employ to in vitro model a SNP that protects against cardiovascular disease. 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
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
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
