Sensing and control of adipocyte function

This thesis has investigated adipocytes development and adipokine signalling with a view to enhance the understanding of tissue functionality and to identify possible targets or pathways for therapeutic intervention. Adipocyte isolation from human tissue samples was undertaken for these investigative studies, and the methodology was optimised. The resulting isolates of pre-adipocytes and mature adipocytes were characterised and evaluated. Major findings from these studies indicate that mature adipocytes undergo cell division post terminal differentiation. Gene studies indicated that subcutaneous adipose tissue exuded greater concentrations and fluctuations of adipokine levels than visceral adipose tissue, indicating an important adiposensing role of subcutaneous adipose tissue. It was subsequently postulated that the subcutaneous depot may provide the major focus for control of overall energy balance and by extension weight control. One potential therapeutic target, 11β-hydrosteroid dehydrogenase (11β-HSD1) was investigated, and prospective inhibitors of its action were considered (BVT1, BVT2 and AZ121). Selective reduction of adiposity of the visceral depot was desired due to its correlation with the detrimental effects of obesity. However, studies indicated that although the visceral depot tissue was not unaffected, the subcutaneous depot was more susceptible to therapeutic inhibition by these compounds. This was determined to be a potentially valuable therapeutic intervention in light of previous postulations regarding long-term energy control via the subcutaneous tissue depot.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Impact of Bariatric Surgical Intervention on Peripheral Blood Neutrophil (PBN) Function in Obesity.

AIM The aim of this study was to investigate the impact of weight loss following gastric band surgery on multiple measures of peripheral blood neutrophil (PBN) function. MATERIAL AND METHODS Twenty-three obese patients undergoing gastric band surgery were recruited to a longitudinal intervention study, alongside non-obese, healthy gender- and age-matched controls. Eighteen pairs of patients and controls completed all stages of the study. PBNs were isolated by density centrifugation and a comprehensive analysis of PBN function was undertaken at various stages of the patients' bariatric surgical care pathway. RESULTS Obese patients exhibited exaggerated PBN activity in response to various stimuli, characterised by higher reactive oxygen species (ROS) generation (n = 18, p < 0.001) and release of pro-inflammatory cytokines (n = 10, p < 0.05) and lower PBN extracellular trap (NET) formation (n = 18, p < 0.01). PBN chemotactic accuracy was also impaired prior to surgery (n = 18, p < 0.01). Weight loss was associated with normalised NET production and lower ROS production and cytokine release relative to healthy controls. However, chemotactic accuracy remained impaired in patients. CONCLUSIONS Weight loss following gastric band surgery was associated with a decrease in the pro-inflammatory activities of peripheral blood neutrophils (PBNs). A hyper-inflammatory PBN phenotype, involving excess ROS and cytokine release, reduced NET formation and chemotaxis, may lead to a reduced ability to eliminate infection, alongside inflammation-mediated tissue damage in obese individuals