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Estrogen upregulates 11β-hydroxysteroid dehydrogenase type 1 in adipose tissues via estrogen receptor β
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. (Tommy Olsson)
Endocrine Unit, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
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(English)Manuscript (preprint) (Other academic)
Keyword [en]
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: urn:nbn:se:umu:diva-33163OAI: oai:DiVA.org:umu-33163DiVA: diva2:310268
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
In thesis
1. Estrogen and Glucocorticoid Metabolism
Open this publication in new window or tab >>Estrogen and Glucocorticoid Metabolism
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
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:nbn:se:umu:diva-33165 (URN)978-91-7264-973-6 (ISBN)
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

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