INFLAMED FAT: immune modulation of adipose tissue and lipid metabolism

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, 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.SanofiLUMC / Geneeskund

Evaluation of a coagulation assay determining the activity state of factor VII in plasma

A coagulation assay is described that allows the measurement of the degree of activation of factor VII in circulating blood. The test is based on the use of both bovine and human brain thromboplastin, together with an artificial factor VII-deficient plasma. The latter can be prepared on a relatively large scale which makes it possible to measure factor VII activation in large series of patients. The determination of factor VII activation during incubation at 4 °C of plasma of women using oral contraceptives shows that the test described adequately measures factor VII activation. Differences in the time course of factor VII activation during this incubation in glass and plastic containers are found and implicate that rigorous standardization of blood sampling and test conditions is necessary. A possible mechanism that causes this critical dependence upon the test conditions is discussed

The activity state of factor VII in plasma:Two pathways for the cold promoted activation of factor VII

The apparent amount of factor VII as determined in a one-stage test depends on the type of thromboplastin used: bovine thromboplastin only reacts with human factor VIIa whereas human thromboplastin interacts with unactivated human factor VII as well. Therefore the ratio factor VII activity as measured with bovine thromboplastin divided by the factor VII activity as assessed with human thromboplastin reflects the state of activation of factor VII in plasma. This approach was used to study the process of cold promoted factor VII activation and the involvement of different clotting factors therein. It could be shown that cold promoted activation does not occur in the absence of factors II and XII and is reduced for about 50% in factor IX deficient plasma. The other coagulation factors have a minor influence on the process. The results indicate that the cold promoted factor VII activation is the result of activation by both activated contact products and thrombin

Targeting white, brown and perivascular adipose tissue in atherosclerosis development

Functional Genomics of Systemic Disorder

Competitive tendering and deregulation in the British bus

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Higher plasma sclerostin and lower Wnt signaling gene expression in white adipose tissue of prediabetic South Asian men compared with white Caucasian men

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 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.Diabetes mellitus: pathophysiological changes and therap

Categorizing Different Approaches to the Cosmological Constant Problem

We have found that proposals addressing the old cosmological constant problem come in various categories. The aim of this paper is to identify as many different, credible mechanisms as possible and to provide them with a code for future reference. We find that they all can be classified into five different schemes of which we indicate the advantages and drawbacks. Besides, we add a new approach based on a symmetry principle mapping real to imaginary spacetime.Comment: updated version, accepted for publicatio

Diluting Cosmological Constant In Infinite Volume Extra Dimensions

We argue that the cosmological constant problem can be solved in a braneworld model with infinite-volume extra dimensions, avoiding no-go arguments applicable to theories that are four-dimensional in the infrared. Gravity on the brane becomes higher-dimensional at super-Hubble distances, which entails that the relation between the acceleration rate and vacuum energy density flips upside down compared to the conventional one. The acceleration rate decreases with increasing the energy density. The experimentally acceptable rate is obtained for the energy density larger than (1 TeV)$^4$. The results are stable under quantum corrections because supersymmetry is broken only on the brane and stays exact in the bulk of infinite volume extra space. Consistency of 4D gravity and cosmology on the brane requires the quantum gravity scale to be around $10^{-3}$ eV. Testable predictions emerging within this approach are: (i) simultaneous modifications of gravity at sub-millimeter and the Hubble scales; (ii) Hagedorn-type saturation in TeV energy collisions due to the Regge spectrum with the spacing equal to $10^{-3}$ eV.Comment: 36 pages, 1 eps fig; 4 refs and comment adde