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 longterm 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 saltsensitive 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. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: arterial blood pressure (BP); angiotensinogen (AGT); renin-angiotensin system (RAS); transgenic (Tg); 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); adipocyte fatty acid binding protein (aP2); heart rate (HR); mean arterial pressure (MAP); angiotensin II receptor AT-1 (AT-1 receptor); radioimmunoassay (RIA).

Role of glucocorticoids in the physiopathology of excessive fat deposition and insulin resistance

“…45 Furthermore, angiotensinogen mRNA, which is expressed at low levels in adipose tissue, was strikingly elevated in adipose tissue of aP2-11b-HSD-1 transgenic mice. 46 This observation is likely to explain the marked hypertension seen in these animals. Finally, the animals exhibited a hyperphagia that may result from their leptin resistance (ie elevated leptin levels in the face of hyperphagia).…”

Mechanisms of obesity-induced hypertension

“…Hypertension in aP2-HSD1 mice was abolished by selective Ang II receptor antagonists at a low dose. 74 These findings propose that a local activation of the adipose glucocorticoid action induce an activation of the RAS, which mediates a salt-sensitive form of hypertension in obesity.…”

1α, 25-Dihydroxyvitamin D and corticosteroid regulate adipocyte nuclear vitamin D receptor

“…28 Overexpression of 11b-HSD I specifically in white adipose tissue of transgenic mice recapitulates features of the metabolic syndrome, including central obesity, hypertension, dyslipidemia and insulin resistance, suggesting that tissue-specific dysregulation of glucocorticoid metabolism may promote expansion of adipose tissue stores. 29,30 We have recently reported that 1a, 25-dihydroxyvitamin D increases both 11b-HSD I expression, and cortisol release in cultured human adipocytes demonstrated a key role of 1a, 25-dihydroxyvitamin D in modulating local glucocorticoid production in adipose tissue. 8 These data suggest an interesting positive feedback regulation of glucocorticoid on 1a, 25-dihydroxyvitamin D as described in Figure 5.…”