There is an urgent need to better understand the problem of vitamin D deficiency, and its health effects, in population groups of different ethnicity. The principal aim of this project was to examine vitamin D status, sunlight exposure, and health outcomes in UK dwelling South Asian and Caucasian women. A cohort of 80 postmenopausal and 32 premenopausal South Asian and Caucasian women were assessed for vitamin D status (serum 25-hydroxyvitamin D; 25(OH)D), musculoskeletal health, light exposure and sleep-wake cycles. In postmenopausal women, South Asians had a significantly lower vitamin D concentration than Caucasians (p=0.002), with 83% of Asians vs. 24% of Caucasians below 50nmol/l for 25(OH)D. Despite adaptations in tibial bone structure of the South Asians to improve bone strength, their bones were weaker by 38% compared with Caucasians (p<0.001). Stand-to-walk time (Asian mean (±SD) time 8.1 s ± 1.8 vs. Caucasian mean (±SD) time 6.9 s ± 1.4); p=0.002) and grip strength (Asian strength=70% of Caucasian strength, p<0.001) were worse in the South Asians. For both premenopausal and postmenopausal women, Caucasians showed a significantly higher actigraphic sleep efficiency (p<0.001) and lower sleep fragmentation (p=0.002) than Asians. There was a higher outdoor light exposure (over 1000 lux) in premenopausal and postmenopausal Caucasians than in same-age Asians (p=0.052). Qualitative analysis of interview data suggested that religious and cultural influences on family, work and community life may partly explain the reduced sunlight exposure in South Asian women, which contributes to vitamin D deficiency. The implications of this work are that older South Asian women are in need of intervention to improve vitamin D status. There is also some evidence for poorer musculoskeletal health, lower light exposure and poorer sleep in this group. The qualitative research included in the current study offers future intervention options to improve the health of UK dwelling South Asian women.

Chronic oxidative stress and oxidative damage has become one of the most convincing theories in ageing pathology. NADPH oxidase 2 (Nox2) is a reactive oxygen species (ROS) generating enzyme expressed constitutively in the vasculature and the central nervous system, however the role of this enzyme in ageing-related cardiovascular dysfunction and neurodegenerative diseases remains unclear. Therefore, the overall aim of this PhD research project is to investigate the role of Nox2-induced oxidative stress in ageing-associated metabolic syndrome, endothelial dysfunction and neurodegeneration using age-matched littermates of wild-type (WT) versus Nox2 null (Nox2-/-) mice on a (5781/6 background at young (3 -4 months), middle aged (10-12 months) and ageing (20•22 months). Compared to young mice, there were ageing-related increases in bodyweight and fasting insulin levels along with impaired glucose tolerance, hyperlipidaemia and hypertension in WT ageing mice (p<0.05). These metabolic syndrome risk factors were accompanied by significant increases in aortic ROS production and Nox2 expression and a significant decrease in the endothelium-dependent relaxation to acetylcholine (Emax 75 % for young and 64 % for ageing, p<0.05) , ). However, all these ageing-related metabolic and endothelial abnormalities were significantly reduced in Nox2-1- ageing mice. We then examined the role of Nox2 in ageing-related neurodegeneration and found that compared to young mice, there was a significantly reduced locomotor activity and dopaminergic neuron firing frequency accompanied by increased brain ROS production in WT but not in Nox2-/- mouse brain. Ageing-associated increases in brain ROS production was further confirmed using human post-mortem brain tissues. In conclusion, Nox2-derived oxidative stress plays an important role in ageing-associated metabolic syndrome, vascular dysfunction, and neurodegeneration. Targeting Nox2 represents a valuable therapeutic strategy to treat these ageing-related diseases.

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No description available.

Cell studies and human cohort interventions have tried to elucidate underlying causes of the metabolic syndrome (MS); however exact molecular mechanisms are still poorly understood. Dietary fatty acids have emerged as major factors influencing the development of MS and have been examined through cellular and human investigations in this thesis. A functional marker for insulin sensitivity was developed in a human adipose cell line (SGBS cells) based on suppression of stimulated lipolysis through insulin (P< 0.001). Reduction of lipolysis was evident with arachidonic acid (AA), linoleic acid (LA) at lOOμM with docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) at lOμaM (P< 0.001). Sensitivity to insulin was accompanied by increased peroxisome proliferator activator receptor-γ (PPAR-γ) gene expression in EPA (P= 0.001) and AA (P= 0.05) treated cells. Significant decreases in insulin receptor substrate-l (lRS-1) (P= O.OOl) and reduced PPAR-γ gene expression was evident with palmitic acid (PA) at 25μiM. Fatty acid mixtures (saturated (SFA) and monounsaturated (MUFA) mixtures with / without EPA + DHA) significantly decreased noradrenaline stimulated lipolysis (P< 0.001) but PPAR-y expression was reduced with the SFA mixture (P< 0.05).

The South Asian population in the United Kingdom has been reported to be at high risk of developing cardiovascular diseases and type 2 diabetes. These two chronic diseases are the end result of a condition known as the metabolic syndrome (MS). Although MS and its association to dietary patterns has been reported in various studies, most research has focused on western countries and minority group populations have been overlooked to a great extent. The identification of dietary patterns and other ethnicity associated risk factors is especially relevant to the South Asian population due to their high prevalence of diet-related diseases and their susceptibility to increased risk of co-morbidities. In addition, South Asians present a distinctive metabolic phenotype as well as unique dietary intakes both at home and abroad. Using detailed dietary information collected from a sample of the local South Asian community in Leeds, UK, the objective of this work was to describe the dietary patterns of South Asians and to investigate their association with metabolic syndrome risk factors. Anthropometric data was collected to identify existing MS components. Further, the study aimed to recognize lifestyle risk factors associated to ethnicity including religion, culturally-acceptable physical activity practices and the process of acculturation as time of residency in the UK increases. Related aspects such as education level and income and their link to diet quality were also explored. Finally, comparison was made between the diet and ethnicity associated risk factors for MS in South Asians and the mainstream population in the UK. Although results were in accordance with the existing literature in terms of diet composition, the examination of additional risk factors demonstrates the importance of developing public health prevention strategies tailored to the different minority ethnic groups in the UK's heterogeneous population.

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L'infarctus du myocarde (IDM) est l'une des principales causes de morbi-mortalité dans le monde et ce malgré une revascularisation rapide de l’artère coronaire occlue. L'obésité est un facteur de risque majeur pour l’IDM, et concerne 15 % de la population française (enquête ObEpi-Roche/INSERM, 2012). L'objectif de notre étude a été d'étudier l'efficacité de stratégies cardioprotectrices comme l’exercice physique chronique ou l’administration d’un donneur de CO (CORM-3) dans un contexte d’obésité. Un effet cardioprotecteur de l'exercice physique chronique a été démontré sur un modèle d’ischémie-reperfusion chez la souris ob/ob (génétiquement dépourvu en leptine). Cet effet implique l’activation de la voie de signalisation cardioprotectrice RISK associée à une diminution des taux cytosoliques des protéines phosphatases inhibitrices correspondantes PTEN et MK3P ce qui aboutit à une amélioration des fonctions mitochondriales. Ce travail montre la capacité différentielle de stratégies à réduire la taille de l’infarctus en cas d’obésité. Par ailleurs, il souligne l’importance du rôle des mécanismes HCO3- dépendants dans le contrôle du pH intracellulaire à la reperfusion. Ils pourraient représenter une étape clef dans la cardioprotection. / Myocardial infarction (MI) remains the leading cause of morbidity and mortality in the developing countries despite significant therapeutic advances over the last years. Obesity is a major risk factor for coronary heart disease and concern 15% of the French population (ObEpi-Roche/INSERM survey, 2012). The aim of our studie was to investigate the efficacy of cardioprotective strategies such as regular treadmill exercice or CO donor administration (CORM-3) against MI during obesity. In ob/ob mice, regular exercise induces a robust cardioprotection by increasing kinase phosphorylation of RISK pathway, decreasing levels of corresponding phosphatases and improving the resistance of mitochondrial permeability transition pore opening. The present study shows differential capabilities of cardioprotective strategies at reducing myocardial infarct size with obesity. In addition, it underlines the role of HCO3- dependent mechanisms in the control of intracellular pH at reperfusion. They could represent a key step for mediating cardioprotection.

L'obésité, un problème de santé mondial, est associée à des comorbidités telles que le syndrome métabolique, la stéato-hépatite non alcoolique, la cardiomyopathie métabolique etc. Leur incidence et développement peuvent être le résultat des interactions gènes-environnement. Ces dernières années, une série d’études expérimentales et cliniques ont montré l’implication de donneurs de méthyles dans ces pathologies via la programmation fœtale. Notre travail a évalué, à la fois le rôle de donneurs de méthyles et le profil métabolique dans une population d’obèses, puis sur un modèle animal de ratons avec une carence en donneurs de méthyles, soumis à la vie adulte à un régime hyper-énergétique. Chez l’homme, nous avons démontré qu’une carence en vitamine B12 associée à un excès de folates est liée à l’insulino-résistance. Puis, nous avons observé des anomalies du métabolisme des acides gras. Chez l’animal, nous avons montré que la carence en donneurs de méthyles provoque une hypertension artérielle systémique et une fibrose cardiaque, surtout chez les femelles. Par contre, chez les mâles, nous avons observé une stéatose hépatique dans le groupe des rats mâles carencés et soumis à un régime hyper-énergétique. En conclusion, la carence en donneurs de méthyles est associée aux maladies chronico-dégénératives. / Obesity, is global health problem, is associated with comorbidities such as metabolic syndrome, nonalcoholic steatohepatitis, metabolic cardiomyopathy etc. Their incidence and development may be the result of gene-environment interactions. In the last years, the experimental and clinical studies have shown the involvement of methyl donors in these pathologies via « fetal programming ». Our work has evaluated the role of methyl donor on metabolic profile in obese subjects, and also in an animal model of pups with a deficiency of methyl donors, subject to high-fat diet in adulthood. In humans, we have demonstrated that vitamin B12 deficiency associated with excess in folates, is linked to insulin resistance. Also the methyl donors have an influence on fatty acid metabolism. In animals, we have shown that deficiency of methyl donors causes systemic hypertension and cardiac fibrosis, especially in females. In contrast, the males methyl donor deficient with a high fat diet had an important steatosis. In conclusion, the methyl donor shortage is associated with chronic degenerative diseases.