Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice
Hiroaki Masuzaki, … , Jonathan R. Seckl, Jeffrey S. Flier
Hiroaki Masuzaki, … , Jonathan R. Seckl, Jeffrey S. Flier
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):83-90. https://doi.org/10.1172/JCI17845.
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Categories: Article Endocrinology

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Abstract

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 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-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.

Authors

Hiroaki Masuzaki, Hiroshi Yamamoto, Christopher J. Kenyon, Joel K. Elmquist, Nicholas M. Morton, Janice M. Paterson, Hiroshi Shinyama, Matthew G.F. Sharp, Stewart Fleming, John J. Mullins, Jonathan R. Seckl, Jeffrey S. Flier

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Figure 1

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(a) Daily profile of MAP in aP2-HSD1 mice at 23 weeks of age. MAP was mo...
(a) Daily profile of MAP in aP2-HSD1 mice at 23 weeks of age. MAP was monitored closely by telemetry transmitters implanted in the left carotid artery. Values are expressed as mean ± SEM of 60 data points each hour. Throughout the day, MAP in Tg mice (n = 17, filled squares) was significantly elevated (by 10–30 mmHg, P < 0.04) compared with that of non-Tg mice (n = 14, open circles). (b) In situ hybridization analysis of adrenal glands from aP2-HSD1 mice. Adrenal gland tissue from non-Tg (n = 5) and Tg mice (n = 3) was hybridized with 35S-labeled cRNA probes for aldosterone synthetase and 11β-hydroxylase. Images of five or six sections from each gland were quantified and statistically evaluated (d). Results are expressed as arbitrary units. The ratio of aldosterone synthetase to 11β-hydroxylase (Aldo/11β) in each sample was also determined. *P < 0.02 versus non-Tg. (c) Effect of specific AT-1 receptor antagonist GA0113 on MAP in aP2-HSD1 mice at 27 weeks of age. GA0113 was administered orally once per day (0.1 mg/kg body weight, at 1500 hours) for 4 days, and the effect of drug administration was evaluated by telemetry on day 5. Filled circles, non-Tg (n = 5) initial (untreated) values; open circles, non-Tg treated; filled squares, Tg (n = 6) initial (untreated); open squares, Tg treated. *P < 0.05 vs. Tg untreated. Telemetry monitoring was continued for 4 days after the final administration to observe that MAP in both sets of mice returned to initial values.