Coeliac disease is defined as a permanent gluten sensitive enteropathy. The classical mucosal lesion is of villous atrophy, crypt hypertrophy and lymphocyte infiltration of the epithelium. It is now generally agreed that a spectrum of mucosal damage exits ranging from total villous atrophy to normal villous architecture with increased numbers of intraepithelial lymphocytes (IEL). Gluten sensitivity can still be demonstrated in this minimal lesion, with the IEL count falling with withdrawal of gluten and rising again on gluten challenge. In the first part of this thesis I will present work validating computerised image analysis as a method for quantifying IEL in small bowel biopsy in order to identify individuals with minimal change given gluten sensitive pathology. Antibodies to the gliadin fraction of gluten and also to an as yet unidentified tissue antigen occur in coeliac disease. These antibodies are useful in the initial diagnosis of coeliac disease as well as in monitoring response to treatment and timing of biopsy following oral gluten challenge. They are also used in the screening of individuals who have a higher incidence of coeliac disease. In the next section of my thesis I will describe the development of a newly described assay for antiendomysium antibody both for research and also for the routine NHS clinical service in Lothian. Progress in the application of strict criteria for the diagnosis of gluten sensitivity has been hampered by the fact that currently the only evidence is based on clinical and pathological effects of gluten withdrawal and challenge which may take several months or years and requires multiple invasive small bowel biopsies. For this reason rectal challenge with gluten is being considered as a possible alliterative method for demonstrating gluten sensitivity. Currently this requires computerised image analysis of multiple rectal biopsies.

Obesity in youth is associated with many psychological adversities yet psychological well-being is infrequently monitored as a primary outcome in weight management programmes. Such programmes have been specifically criticised for increasing the risk of eating disorders (ED) in adolescents who are overweight and have obesity. Therefore this study aimed to look at psychological well-being in a sample of adolescents from the community using a group-based weight management programme. Eighty-two young people aged 13-17 participated in an online survey assessing depressive symptoms, body dissatisfaction, self-esteem, quality of life and eating disorder psychopathology. A cross sectional and longitudinal design was utilised to assess psychological well-being change over the monitoring period of 3 months and relate to weight change. Psychological impairment was evident within the sample: 36% showed depressive symptoms, 68% poor quality of life (QoL) and 28 % had disordered eating psychopathology. High ED risk was associated with depressive symptoms, body dissatisfaction and a poorer QoL in comparison to those at low risk of ED. No significant changes were noted across weight status and well-being between phase 1 and phase 2 of the study and change in well-being was not associated with a change in weight. Psychological-wellbeing is impaired in some adolescents using these programmes therefore it is recommended that the impact of psychopathology is considered more thoroughly by monitoring psychological well-being regularly during young peoples’ engagement in these. This will aid evaluative practices and will increase our understanding in this area.

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Obesity is a global problem, with significant rises in obesity levels observed in recent years. This is owing to our modern lifestyles, associated with diminished physical activity and increased calorific intake. The increase in obesity is closely linked with type 2 diabetes mellitus (T2DM), leptin and insulin resistance, impaired glucose homeostasis and often inflammation and endoplasmic reticulum stress. Worryingly, obesity and T2DM are also risk factors for Alzheimer’s disease (AD). The β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is critically involved in AD development, cleaving the amyloid precursor protein (APP) to generate amyloid-β (Aβ), which drives progression of the hallmark pathologies of AD. Consequently, higher BACE1 levels/activity is considered a primary causative factor for AD. Increased BACE1 is driven by chronic stress (e.g. hypoxia, oxidative and metabolic) also associated with obesity and T2DM. Thus, impaired glucose homeostasis and insulin resistance is common to all three disease states, suggesting that BACE1 and Aβ may contribute to the progression of metabolic disease. Consequently, BACE1 knock-out mice have been demonstrated to be protected against diet-induced obesity (DIO) and have improved insulin and leptin sensitivity. Here we show that pharmacological inhibition of BACE1 improves metabolic syndrome in mice, and that elevations in BACE1, through altered APP processing, may exacerbate obesity and the metabolic syndrome. Furthermore, we show that BACE1 is present in hypothalamic nuclei and neuronal populations that control energy balance. Taken together, these data suggest BACE1 activity alters energy metabolism through actions on the neuronal circuitry regulating energy balance, and chronically raised BACE1 levels/activity may result in dysregulation of these circuits and consequent metabolic disorder. Accordingly, a better understanding of the role of APP processing and BACE1 activity under physiological and pathophysiological conditions may provide evidence for repurposing BACE1 inhibitors, currently in clinical trials for AD, towards treatment of obesity and T2DM.

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