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Title: Glucocorticoid metabolism in human obesity
Author: Wake, D. J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2006
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This thesis addresses whether adipose 11HSD1 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. In addition inflammatory cytokines elevate 11HSD1 in vitro. 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, PPARγ) were not significantly associated with 11HSD1 expression or activity. To investigate 11HSD1 regulation, a series of randomized 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, PPAR agonists (rosiglitazone or fenofibrate for 7 d), and anti-inflammatory agents (salsalate for 2 weeks). 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 PPARγ agonist rosiglitazone lowered adipose 11HSD1 reductase activity. The PPARα agonist fenofibrate had no effect on adipose 11HSD1 and, although urinary ratios of cortisol/cortisone metabolites (indicative of liver 11HSD1) were reduced, there were no significant changes in plasma tracer kinetics with PPAR agonists. Salsalate resulted in increased excretion of urinary cortisol metabolites in obese but not lean volunteers (p=0.06).
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available