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Title: Intra-adipose steroid metabolism in human obesity
Author: Wake, Deborah Jane
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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Glucocorticoid excess causes obesity, dyslipidaemia, insulin resistance and hypertension as seen in Cushing's syndrome. In idiopathic obesity, circulating Cortisol levels are not elevated but Cortisol metabolism is altered. liphydroxysteroid dehydrogenase type 1 (11HSD1) is an intracellular enzyme that converts inactive cortisone into active Cortisol. Data from animals suggests that elevated adipose 11HSD1 may generate more glucocorticoid within adipose tissue and be an important mediator of obesity and the associated metabolic consequences (diabetes, dyslipidaemia and hypertension). This thesis addresses whether adipose IIHSD1 is elevated in human obesity, investigates if this occurs through altered transcription, and assesses the downstream impact (changes in downstream target genes and metabolic outcomes). Regulation of 11HSD1 mRNA in animal and cell models (eg by high fat feeding, insulin, and PPAR agonists), and putative control of enzyme direction by NADPH generation (via hexose-6-phosphate dehydrogenase), suggest a dynamic role for 11HSD1 in the adaptive response of adipose to altered nutrition. The importance of these potential regulators in lean and obese humans is also addressed in this thesis. In subcutaneous adipose biopsies from male and female healthy volunteers from Finland (n=19), Sweden (n=27) and USA (n=35) 11HSD1 activity (in vitro conversion of Cortisol to cortisone in presence of NADP) and mRNA (by real time PCR) was increased in association with generalised and 'central' obesity (which is most strongly associated with increased cardiovascular risk), and predicted insulin resistance. However, glucocorticoid receptor mRNA was negatively associated with obesity and insulin resistance. Adipose mRNAs for a number of key functional adipose targets (adiponectin, LPL, HSL, angiotensinogen, resistin, aromatase, PPARy) were not significantly associated with 11HSD1 expression or activity. To investigate 11HSD1 regulation, a series of randomised controlled studies in vivo in healthy male volunteers were performed to assess the regulatory effects of insulin (euglycaemic clamp) or lipid (20% Intralipid iv) over 3.5 hours and PPAR agonists (rosiglitazone or fenofibrate for 7 d). Deuterated-cortisol tracer with GCMS analysis was used to measure whole body Cortisol turnover and urinary metabolite excretion, and intra adipose microdialysis was used to assess in vivo s.c. adipose 11HSD1 activity and directionality. Hyperinsulinaemia increased the rate of appearance of 9,12,12-[2H]3-cortisol in plasma, indicating increased regeneration of Cortisol by 11HSD1. Within adipose tissue, the predominant reaction was conversion of cortisone to Cortisol rather than Cortisol to cortisone; both activities fell during the first hour of hyperinsulinaemia but subsequently increased. Intralipid infusion had no significant effects on deuterated Cortisol metabolism, but increased intra-adipose conversion of cortisone to Cortisol. The PPARy agonist rosiglitazone lowered adipose 11HSD1 reductase activity. The PPARa agonist fenofibrate had no effect on adipose 11HSD1 activity although urinary ratios of Cortisol/ cortisone metabolites and endogenous Cortisol clearance were reduced. These findings may be suggestive of decreased liver 5alpha-reductase activity. There were no significant changes in plasma tracer kinetics with PPAR agonists. In addition to altered glucocorticoid metabolism, changes in sex steroid metabolizing enzymes dictating oestrogen (aromatase) and androgen (AKR1C2/3) action were found to be associated with fat distribution in s.c biopsies from Swedish (n=27) and Finnish (n=19) volunteers. Further studies to determine the functional relevance of these associations are planned. These studies implicate dysregulation of 11HSD1 transcription in the pathogenesis of human obesity and the metabolic syndrome although the downstream impact of enzyme dysregulation remains unclear. They also suggest that 11HSD1 is involved in the adaptive response to nutrition, and that alteration in tissue glucocorticoids may contribute to the therapeutic action of PPAR agonists. This understanding of enzyme regulation in humans will allow further studies to dissect the basis of dysregulation in obesity. Inhibition of adipose 11HSD1 remains an intriguing target for the treatment of obesity and its metabolic complications but its physiological importance will best be determined by the development of specific adipose 11HSD1 inhibitors.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available