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Estrogen and Glucocorticoid Metabolism
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. (Tommy Olsson)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Cardiovascular disease (CVD) is the leading cause of death among women in Sweden. The risk of CVD increases rapidly after the menopause. A major contributing factor may be the redistribution of adipose tissue, from the peripheral to central depots, associated with menopause. This change in body composition is commonly attributed to declining estrogen levels but may also be affected by tissue-specific alterations in exposure to other steroid hormones, notably glucocorticoids – mainly cortisol in humans. Indeed, adipose tissue-specific overexpression of the glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) induces central obesity, insulin resistance and hypertension in mice. Interestingly, estrogen may regulate this enzyme. The aim of this thesis was to investigate putative links between estrogen and glucocorticoid activation by 11βHSD1. Materials and Methods: 11βHSD1 expression and/or activity in adipose tissue and liver, and adipose estrogen receptor α and β (ERα and ERβ) gene expression, were investigated in lean pre- and postmenopausal women and ovariectomized rodents with and without estrogen supplementation. In lean women measures of 11βHSD1 were correlated to risk markers for CVD. The association between adipose 11βHSD1 and ER mRNA expression was investigated in both lean women and rats and in an additional cohort of obese premenopausal women. In vitro experiments with adipocyte cell lines were used to explore possible pathways for estrogen regulation of 11βHSD1. Results: Subcutaneous adipose tissue transcript levels and hepatic activity of 11βHSD1 were higher in postmenopausal vs. premenopausal women. In rodents, estrogen treatment to ovariectomized rats decreased visceral adipose tissue 11βHSD1, resulting in a shift towards higher subcutaneous (vs. visceral) 11βHSD1 mRNA expression/activity. Increased adipose and hepatic 11βHSD1 were associated with increased blood pressure and a disadvantageous blood lipid profile in humans. We found significant positive associations between 11βHSD1 and ERβ transcript levels in adipose tissue. The in vitro experiments showed upregulation of 11βHSD1 mRNA expression and activity with estrogen or ERβ-agonist treatment at low (corresponding to physiological) concentrations. Conclusions: Our studies show for the first time increased local tissue glucocorticoid activation with menopause/age in women. This may contribute to an increased risk of CVD. Estrogen treatment in rodents induces a shift in 11βHSD1 activity towards the subcutaneous adipose tissue depots, which may direct fat accumulation to this metabolically “safer” depot. The in vitro studies suggest that low-dose estrogen treatment upregulates 11βHSD1 via ERβ. In summary, estrogen - glucocorticoid metabolism interactions may be key in the development of menopause-related metabolic dysfunction and in part mediate the beneficial effects of postmenopausal estrogen treatment on body fat distribution.

Place, publisher, year, edition, pages
Umeå: Institutionen för Folkhälsa och Klinisk Medicin , 2010. , 62 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1345
Keyword [en]
11β-Hydroxysteroid Dehydrogenase Type 1, Estrogen, Cortisol, Adipose tissue, Liver, Menopause, Ovariectomy, Adipocyte, Estrogen Receptor β
National Category
Endocrinology and Diabetes
Research subject
Medicine
Identifiers
URN: urn:nbn:se:umu:diva-33165ISBN: 978-91-7264-973-6 (print)OAI: oai:DiVA.org:umu-33165DiVA: diva2:310367
Public defence
2010-05-07, Sal B, Tandläkarhögskolan, Plan 9, By 1D, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2010-04-19 Created: 2010-04-13 Last updated: 2010-04-19Bibliographically approved
List of papers
1. Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women
Open this publication in new window or tab >>Tissue-specific increases in 11beta-hydroxysteroid dehydrogenase type 1 in normal weight postmenopausal women
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2009 (English)In: PloS one, ISSN 1932-6203, Vol. 4, no 12, e8475- p.Article in journal (Refereed) Published
Abstract [en]

With age and menopause there is a shift in adipose distribution from gluteo-femoral to abdominal depots in women. Associated with this redistribution of fat are increased risks of type 2 diabetes and cardiovascular disease. Glucocorticoids influence body composition, and 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) which converts inert cortisone to active cortisol is a putative key mediator of metabolic complications in obesity. Increased 11betaHSD1 in adipose tissue may contribute to postmenopausal central obesity. We hypothesized that tissue-specific 11betaHSD1 gene expression and activity are up-regulated in the older, postmenopausal women compared to young, premenopausal women. Twenty-three pre- and 23 postmenopausal, healthy, normal weight women were recruited. The participants underwent a urine collection, a subcutaneous adipose tissue biopsy and the hepatic 11betaHSD1 activity was estimated by the serum cortisol response after an oral dose of cortisone. Urinary (5alpha-tetrahydrocortisol+5beta-tetrahydrocortisol)/tetrahydrocortisone ratios were higher in postmenopausal women versus premenopausal women in luteal phase (P<0.05), indicating an increased whole-body 11betaHSD1 activity. Postmenopausal women had higher 11betaHSD1 gene expression in subcutaneous fat (P<0.05). Hepatic first pass conversion of oral cortisone to cortisol was also increased in postmenopausal women versus premenopausal women in follicular phase of the menstrual cycle (P<0.01, at 30 min post cortisone ingestion), suggesting higher hepatic 11betaHSD1 activity. In conclusion, our results indicate that postmenopausal normal weight women have increased 11betaHSD1 activity in adipose tissue and liver. This may contribute to metabolic dysfunctions with menopause and ageing in women.

Identifiers
urn:nbn:se:umu:diva-32457 (URN)10.1371/journal.pone.0008475 (DOI)20041117 (PubMedID)
Available from: 2010-03-11 Created: 2010-03-11 Last updated: 2011-04-26Bibliographically approved
2. Estrogen reduces 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous, adipose tissue in rats
Open this publication in new window or tab >>Estrogen reduces 11beta-hydroxysteroid dehydrogenase type 1 in liver and visceral, but not subcutaneous, adipose tissue in rats
2010 (English)In: Obesity (Silver Spring, Md.), ISSN 1930-7381, Vol. 18, no 3, 470-475 p.Article in journal (Refereed) Published
Abstract [en]

Following menopause, body fat is redistributed from peripheral to central depots. This may be linked to the age related decrease in estrogen levels. We hypothesized that estrogen supplementation could counteract this fat redistribution through tissue-specific modulation of glucocorticoid exposure. We measured fat depot masses and the expression and activity of the glucocorticoid-activating enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in fat and liver of ovariectomized female rats treated with or without 17beta-estradiol. 11betaHSD1 converts inert cortisone, or 11-dehydrocorticosterone in rats into active cortisol and corticosterone. Estradiol-treated rats gained less weight and had significantly lower visceral adipose tissue weight than nontreated rats (P < 0.01); subcutaneous adipose weight was unaltered. In addition, 11betaHSD1 activity/expression was downregulated in liver and visceral, but not subcutaneous, fat of estradiol-treated rats (P < 0.001 for both). This downregulation altered the balance of 11betaHSD1 expression and activity between adipose tissue depots, with higher levels in subcutaneous than visceral adipose tissue of estradiol-treated animals (P < 0.05 for both), opposite the pattern in ovariectomized rats not treated with estradiol (P < 0.001 for mRNA expression). Thus, estrogen modulates fat distribution, at least in part, through effects on tissue-specific glucocorticoid metabolism, suggesting that estrogen replacement therapy could influence obesity related morbidity in postmenopausal women.

Identifiers
urn:nbn:se:umu:diva-30991 (URN)10.1038/oby.2009.294 (DOI)19763091 (PubMedID)
Available from: 2010-01-26 Created: 2010-01-26 Last updated: 2013-01-10Bibliographically approved
3. Estrogen upregulates 11β-hydroxysteroid dehydrogenase type 1 in adipose tissues via estrogen receptor β
Open this publication in new window or tab >>Estrogen upregulates 11β-hydroxysteroid dehydrogenase type 1 in adipose tissues via estrogen receptor β
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(English)Manuscript (preprint) (Other academic)
Keyword
Estrogen, 11β-Hydroxysteroid Dehydrogenase Type 1, Estrogen Receptor β, adipose tissue, cortisol, menopause, rat, obesity
National Category
Endocrinology and Diabetes
Research subject
Medicine
Identifiers
urn:nbn:se:umu:diva-33163 (URN)
Note
T.A. and K.M. contributed equally to this work.Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2011-04-26Bibliographically approved

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