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Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
Open accessAbstract
Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II-mediated hypertension. Taken together, our findings suggest that overexpression of 11beta-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11beta-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder.
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“Expression of 11β-hydroxysteroid dehydrogenase (11β-HSD) in adipose tissue results in a mouse with abdominal obesity that develops hypertension (225).”
From Cardiac remodeling in obesity (2008) · cites this paper as [225]
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Franckhauser, S., & Bosch, F. (2005) · Elsevier eBooks · doi:10.1016/b978-84-8174-892-5.50004-8
Calcitriol and the Renin Angiotensin System, and Adipose Tissue Inflammation
Caserio, C. M. (2009)
Estrogen and Glucocorticoid Metabolism
Andersson, T. (2010) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Michailidou, Z. (2008) · ERA
11β‐Hydroxysteroid Dehydrogenase Type 1 as a Therapeutic Target for Type 2 Diabetes
Hale, C., & Jean, D. J. S. (2011) · doi:10.1002/9780470910016.ch16
Kim, Y., Kang, S. K., Lee, G. B., Lee, K. M., Jaladi, A. K., Kim, K. Y., Rhee, S. D., Joo, J., Bae, M. A., Lee, W. K., et al. (2015) · MedChemComm · doi:10.1039/c5md00096c
Metadata
- Authors
- Masuzaki, H., Yamamoto, H., Kenyon, C. J., Elmquist, J. K., Morton, N. M., Paterson, J. M., Shinyama, H., Sharp, M. G. F., Fleming, S., Mullins, J. J., Seckl, J. R., & Flier, J. S.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- University of Edinburgh (GB)
- University of Dundee (GB)
- Corresponding author
- Flier, Jeffrey S.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2003-07-01
- Volume
- 112
- Issue
- 1
- Pages
- 83-90
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC162290
- OpenAlex
- W2127764698
- Cited by
- 434
- References
- 76
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 5 · 2020: 3 · 2019: 10 · 2018: 4 · 2017: 20 · 2016: 17 · 2015: 20 · 2014: 16 · 2013: 30 · 2012: 21
- FWCI
- 26.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Eli Lilly and Company
- Wellcome Trust
- National Institutes of Health (5r01dk059751-02)
- National Institute of Diabetes and Digestive and Kidney Diseases (P01DK056116, DK56116, DK 59751)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Renin-Angiotensin System Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- 11β-hydroxysteroid dehydrogenase type 1, adipose tissue, hypertension, salt-sensitive hypertension, renin-angiotensin system, angiotensin II, aldosterone, metabolic syndrome, obesity, transgenic mice
- MeSH terms
- Adipose Tissue, Animals, Glucocorticoids, Hydroxysteroid Dehydrogenases, Hypertension, Kidney, Male, Mice, Transgenic, Renin-Angiotensin System, Sodium Chloride, 11-beta-Hydroxysteroid Dehydrogenases, Mice
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