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11?-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

ABSTRACT: The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11?-hydroxysteroid dehydrogenase type 1 (11?-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11?-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11?-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11?-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11?-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11?-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

SUBMITTER: Morgan SA

PROVIDER: S-EPMC4066483 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other

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11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

Morgan Stuart A SA McCabe Emma L EL Gathercole Laura L LL Hassan-Smith Zaki K ZK Larner Dean P DP Bujalska Iwona J IJ Stewart Paul M PM Tomlinson Jeremy W JW Lavery Gareth G GG

Proceedings of the National Academy of Sciences of the United States of America 20140602 24

The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atro ...[more]

PMID: 24889609

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Project description:BackgroundAdrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess.MethodsWe performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis.ResultsPrimary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients.ConclusionOur data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism.FundingMedical Research Council UK, Wellcome Trust, European Commission.

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11?-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

Publications

11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.

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