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
