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

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@article{818faabdeee44851a8166cae44f5ab3b,
title = "11β-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 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 atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.",
keywords = "11-beta-Hydroxysteroid Dehydrogenase Type 1, Adipose Tissue, Animals, Anti-Inflammatory Agents, Blood Pressure, Cushing Syndrome, Disease Models, Animal, Fatty Acids, Nonesterified, Gene Expression Regulation, Glucocorticoids, Glucose Intolerance, Glucose Tolerance Test, Hydrocortisone, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Regeneration, Triglycerides",
author = "Morgan, {Stuart A} and McCabe, {Emma L} and Gathercole, {Laura L} and Hassan-Smith, {Zaki K} and Larner, {Dean P} and Bujalska, {Iwona J} and Stewart, {Paul M} and Tomlinson, {Jeremy W} and Lavery, {Gareth G}",
year = "2014",
month = jun
day = "17",
doi = "10.1073/pnas.1323681111",
language = "English",
volume = "111",
pages = "E2482--91",
journal = "National Academy of Sciences. Proceedings",
issn = "1091-6490",
publisher = "National Academy of Sciences",
number = "24",

}

RIS

TY - JOUR

T1 - 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

AU - Morgan, Stuart A

AU - McCabe, Emma L

AU - Gathercole, Laura L

AU - Hassan-Smith, Zaki K

AU - Larner, Dean P

AU - Bujalska, Iwona J

AU - Stewart, Paul M

AU - Tomlinson, Jeremy W

AU - Lavery, Gareth G

PY - 2014/6/17

Y1 - 2014/6/17

N2 - 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 atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

AB - 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 atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.

KW - 11-beta-Hydroxysteroid Dehydrogenase Type 1

KW - Adipose Tissue

KW - Animals

KW - Anti-Inflammatory Agents

KW - Blood Pressure

KW - Cushing Syndrome

KW - Disease Models, Animal

KW - Fatty Acids, Nonesterified

KW - Gene Expression Regulation

KW - Glucocorticoids

KW - Glucose Intolerance

KW - Glucose Tolerance Test

KW - Hydrocortisone

KW - Liver

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Regeneration

KW - Triglycerides

U2 - 10.1073/pnas.1323681111

DO - 10.1073/pnas.1323681111

M3 - Article

C2 - 24889609

VL - 111

SP - E2482-91

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

SN - 1091-6490

IS - 24

ER -