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Title: Inflammation and end-organ damage with obesity and gender
Author: Bloor, Ian David
ISNI:       0000 0004 2726 9317
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2012
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Latest epidemiological data suggests that 1.5 billion adults worldwide are obese or overweight. Excess weight and adipocyte hypertrophy have long been associated with contributing to low-grade systemic inflammation through elevated adipokine secretion. These increased endocrine signals further augment the metabolic dysfunction related to the presence of obesity. A chronic exposure to obesity mediated inflammation is also suggested to be responsible for progression of renal pathology and eventual end-stage organ failure. In human clinical statistics, these factors indicate a gender disparity, as males demonstrate much faster progression rates of obesity-linked renal disease than females. Therefore, the aim of this thesis was to investigate the role of gender in obesity mediated inflammation in the development of renal disease using a large animal model i.e. sheep. Post-natal female and male sheep were exposed to a lean or obesogenic environment by restricting physical activity from ≈3 months to ≈17 months of age. Analysis of body composition and adipose tissue physiology, morphology and deposition identified the development of moderate obesity following chronic exposure to a low physical environment, although no differences were observed with gender. With obesity, both genders demonstrated metabolic irregularities; males showed hyperinsulinaemia and females displayed hypercortisolism. Gene expression analysis identified an up-regulation of inflammatory related genes in perirenal adipose tissue (PAT) and kidney in obese males, a finding not seen in females, although obese females exhibited an up-regulation in glucocorticoid receptor abundance in PAT. Furthermore, the males demonstrated adaptations in renal structure and function with obesity, modifications not observed in females. The main conclusion of my thesis is that after the development of obesity, males appear much more sensitive to the metabolic, inflammatory and renal adaptations associated with an obese condition. Females displayed a down-regulation of inflammatory genes with obesity which I propose acts as a protective mechanism against the progression of renal disease, perhaps mediated by an immunosuppressive glucocorticoid action in adipose tissue. It is also possible that sex hormones play a role in obesity inflammatory renal disease development, postulated to occur through HPA activation and epigenetic alterations.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: WD Disorders of systemic, metabolic or environmental origin