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Title: Glucocorticoid metabolism in obesity
Author: Livingstone, Dawn E. W.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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Primary increased secretion of glucocorticoids causes obesity, and increased cortisol secretion has been noted in subjects with idiopathic obesity, especially if of central distribution. Observations in obese men suggest that peripheral glucocorticoid metabolism may be altered. The Zucker rat model of obesity has been utilised in this thesis to assess glucocorticoid metabolism in vitro and in vivo, and to study the mechanisms of its dysregulation. Of particular interest was activity of 11b-hydroxysteroid dehydrogenase type 1, which reactivates glucocorticoids and thus increases local glucocorticoid receptor activation eg in liver and adipose tissue. Obese animals had elevated plasma corticosterone (B), higher urinary B metabolites and heavier adrenal glands when compared with lean rats. They also had increased activity of hepatic 5a-reductase, decreased hepatic 11b-HSD1 and increased renal 11b-HSD2 activity. By contrast, 11b-HSD1 activity was not different in skeletal muscle or subcutaneous fat, and was higher in omental fat of obese animals. Urinary glucocorticoid metabolite profiles, assessed by GCMS, confirmed that metabolism of B by 5a-reductase is increased in obese animals and showed the balance of 11b-HSDs lies in favour of inactive 11-dehydrocorticosterone. Greater inactivation of B by 5a-reductase in liver and 11b-HSD2 in kidney, combined with impaired reactivation by 11b-HSD1 in liver, may decrease local B concentrations in these sites, and increase metabolic clearance rate of glucocorticoids, thus increasing drive to the hypothalamic-pituitary-adrenal axis (HPA). By contrast, increased 11b-HSD1 activity in omental adipose tissue may increase local glucocorticoid receptor activation and promote obesity. In conclusion, 11b-HSD1 activity, and therefore local glucocorticoid concentration, is altered in obesity. Manipulation of this enzyme, particularly in a tissue specific manner, may prove to be a useful therapeutic target in obesity and insulin resistance.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available