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

Stuart A Morgan; Emma L McCabe; Laura L Gathercole; Zaki K Hassan-Smith; Dean P Larner; Iwona J Bujalska; Paul M Stewart; Jeremy W Tomlinson; Gareth G Lavery

doi:10.1073/pnas.1323681111

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

Stuart A Morgan, Emma L McCabe, Laura L Gathercole, Zaki K Hassan-Smith, Dean P Larner, Iwona J Bujalska, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery

Research output: Contribution to journal › Article › peer-review

147 Citations (Scopus)

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.

Original language	English
Pages (from-to)	E2482-91
Journal	National Academy of Sciences. Proceedings
Volume	111
Issue number	24
Early online date	2 Jun 2014
DOIs	https://doi.org/10.1073/pnas.1323681111
Publication status	Published - 17 Jun 2014

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

Access to Document

10.1073/pnas.1323681111

Centre for Musculoskeletal Ageing Research (linked to 18289 & 19482)
Lord, J. (Principal Investigator), Buckley, C. (Co-Investigator), Duda, J. (Co-Investigator), Dunn, W. (Co-Investigator), Miall, C. (Co-Investigator) & Greig, C. (Co-Investigator)
Medical Research Council
1/08/12 → 31/07/17
Project: Research Councils
Glucocorticoid Metabolism and the Control of Metabolic Phenotype
Tomlinson, J. (Principal Investigator)
Medical Research Council
1/10/09 → 30/09/14
Project: Research Councils
Investigating Hexose-6-Phosphate Dehydrogenase in the Control of Skeletal Muscle Function and Carbohydrate Metabolism
Lavery, G. (Principal Investigator)
Biotechnology & Biological Sciences Research Council
1/09/09 → 31/08/14
Project: Research Councils

Cite this

@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",

}

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

SN - 1091-6490

VL - 111

SP - E2482-91

JO - National Academy of Sciences. Proceedings

JF - National Academy of Sciences. Proceedings

IS - 24

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Projects

Centre for Musculoskeletal Ageing Research (linked to 18289 & 19482)

Glucocorticoid Metabolism and the Control of Metabolic Phenotype

Investigating Hexose-6-Phosphate Dehydrogenase in the Control of Skeletal Muscle Function and Carbohydrate Metabolism

Cite this