Previous Article |
Table of Contents
| Next Article 
Proc. Natl. Acad. Sci. USA
Vol. 94,
pp. 14924-14929,
December 1997
* Centre for Genome Research, University of Edinburgh, Kings
Buildings, West Mains Road, Edinburgh EH 9 3JQ, Scotland, UK;
Communicated by Keith R. Yamamoto, University of California, San
Francisco, CA, October 20, 1997 (received for review May 15, 1997)
Glucocorticoid hormones, acting via nuclear receptors, regulate
many metabolic processes, including hepatic gluconeogenesis. It
recently has been recognized that intracellular glucocorticoid concentrations are determined not only by plasma hormone levels, but
also by intracellular 11
Physiology
11
-Hydroxysteroid dehydrogenase type 1 knockout mice show
attenuated glucocorticoid-inducible responses and resist hyperglycemia
on obesity or stress
,,,,,, and Molecular Endocrinology Laboratory, Molecular Medicine Centre,
University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU,
Scotland, UK; and § Department of Obstetrics and Gynaecology,
Ninewells Hospital and Medical School, University of Dundee, Dundee DD1
9SY, Scotland, UK
-hydroxysteroid dehydrogenases (11-HSDs), which interconvert active corticosterone (cortisol in humans) and inert
11-dehydrocorticosterone (cortisone in humans). 11-HSD type 2, a
dehydrogenase, thus excludes glucocorticoids from otherwise nonselective mineralocorticoid receptors in the kidney. Recent data
suggest the type 1 isozyme (11-HSD-1) may function as an 11-reductase, regenerating active glucocorticoids from circulating inert 11-keto forms in specific tissues, notably the liver. To examine
the importance of this enzyme isoform in vivo, mice were produced with targeted disruption of the 11-HSD-1 gene. These mice
were unable to convert inert 11-dehydrocorticosterone to corticosterone
in vivo. Despite compensatory adrenal hyperplasia and
increased adrenal secretion of corticosterone, on starvation homozygous
mutants had attenuated activation of the key hepatic gluconeogenic
enzymes glucose-6-phosphatase and phosphoenolpyruvate carboxykinase,
presumably, because of relative intrahepatic glucocorticoid deficiency.
The 11-HSD-1 
/ mice were found to resist hyperglycamia provoked by obesity or stress. Attenuation of hepatic 11-HSD-1 may
provide a novel approach to the regulation of gluconeogenesis.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg What's this?
This article has been cited by other articles in HighWire Press-hosted journals:
|
|
 |
|
  D. P Macfarlane, S. Forbes, and B. R Walker Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome J. Endocrinol., May 1, 2008; 197(2): 189 - 204. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I J Bujalska, L L Gathercole, J W Tomlinson, C Darimont, J Ermolieff, A N Fanjul, P A Rejto, and P M Stewart A novel selective 11{beta}-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis J. Endocrinol., May 1, 2008; 197(2): 297 - 307. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Bujalska, K. N. Hewitt, D. Hauton, G. G. Lavery, J. W. Tomlinson, E. A. Walker, and P. M. Stewart Lack of Hexose-6-Phosphate Dehydrogenase Impairs Lipid Mobilization from Mouse Adipose Tissue Endocrinology, May 1, 2008; 149(5): 2584 - 2591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. De Sousa Peixoto, S. Turban, J. H. Battle, K. E. Chapman, J. R. Seckl, and N. M. Morton Preadipocyte 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Is a Keto-Reductase and Contributes to Diet-Induced Visceral Obesity in Vivo Endocrinology, April 1, 2008; 149(4): 1861 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Lavery, E. A. Walker, N. Turan, D. Rogoff, J. W. Ryder, J. M. Shelton, J. A. Richardson, F. Falciani, P. C. White, P. M. Stewart, et al. Deletion of Hexose-6-phosphate Dehydrogenase Activates the Unfolded Protein Response Pathway and Induces Skeletal Myopathy J. Biol. Chem., March 28, 2008; 283(13): 8453 - 8461. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shapiro, M. Matheny, Y. Zhang, N. Tumer, K.-Y. Cheng, E. Rogrigues, S. Zolotukhin, and P. J. Scarpace Synergy Between Leptin Therapy and a Seemingly Negligible Amount of Voluntary Wheel Running Prevents Progression of Dietary Obesity in Leptin-Resistant Rats Diabetes, March 1, 2008; 57(3): 614 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Liu, F. Park, J. L. Pietrusz, G. Jia, R. J. Singh, B. C. Netzel, and M. Liang Suppression of 11{beta}-hydroxysteroid dehydrogenase type 1 with RNA interference substantially attenuates 3T3-L1 adipogenesis Physiol Genomics, February 19, 2008; 32(3): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. P. Gomez-Sanchez, D. G. Romero, A. F. de Rodriguez, M. P. Warden, Z. Krozowski, and C. E. Gomez-Sanchez Hexose-6-Phosphate Dehydrogenase and 11{beta}-Hydroxysteroid Dehydrogenase-1 Tissue Distribution in the Rat Endocrinology, February 1, 2008; 149(2): 525 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. G. Bhat, N. Hosea, A. Fanjul, J. Herrera, J. Chapman, F. Thalacker, P. M. Stewart, and P. A. Rejto Demonstration of Proof of Mechanism and Pharmacokinetics and Pharmacodynamic Relationship with 4'-Cyano-biphenyl-4-sulfonic Acid (6-Amino-pyridin-2-yl)-amide (PF-915275), an Inhibitor of 11 -Hydroxysteroid Dehydrogenase Type 1, in Cynomolgus Monkeys J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 299 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Lavery, D. Hauton, K. N. Hewitt, S. M. Brice, M. Sherlock, E. A. Walker, and P. M. Stewart Hypoglycemia with Enhanced Hepatic Glycogen Synthesis in Recombinant Mice Lacking Hexose-6-Phosphate Dehydrogenase Endocrinology, December 1, 2007; 148(12): 6100 - 6106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Nuotio-Antar, D. L. Hachey, and A. H. Hasty Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1517 - E1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Y. Zhang and R. A. Daynes Macrophages from 11beta-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Exhibit an Increased Sensitivity to Lipopolysaccharide Stimulation Due to TGF-beta-Mediated Up-Regulation of SHIP1 Expression J. Immunol., November 1, 2007; 179(9): 6325 - 6335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Arai, H. Masuzaki, T. Tanaka, T. Ishii, S. Yasue, N. Kobayashi, T. Tomita, M. Noguchi, T. Kusakabe, J. Fujikura, et al. Ceramide and Adenosine 5'-Monophosphate-Activated Protein Kinase Are Two Novel Regulators of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity in Cultured Preadipocytes Endocrinology, November 1, 2007; 148(11): 5268 - 5277. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Berthiaume, M. Laplante, W. T. Festuccia, K. Cianflone, L. P. Turcotte, D. R. Joanisse, G. Olivecrona, R. Thieringer, and Y. Deshaies 11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues Am J Physiol Endocrinol Metab, October 1, 2007; 293(4): E1045 - E1052. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. W. Yau, K. M. McNair, J. Noble, D. Brownstein, C. Hibberd, N. Morton, J. J. Mullins, R. G. M. Morris, S. Cobb, and J. R. Seckl Enhanced Hippocampal Long-Term Potentiation and Spatial Learning in Aged 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Knock-Out Mice J. Neurosci., September 26, 2007; 27(39): 10487 - 10496. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Walker, A. Ahmed, G. G. Lavery, J. W. Tomlinson, S. Y. Kim, M. S. Cooper, J. P. Ride, B. A. Hughes, C. H. L. Shackleton, P. McKiernan, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function J. Biol. Chem., September 14, 2007; 282(37): 27030 - 27036. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wiegand, A. Richardt, T. Remer, S. A Wudy, J. W Tomlinson, B. Hughes, A. Gruters, P. M Stewart, C. J Strasburger, and M. Quinkler Reduced 11{beta}-hydroxysteroid dehydrogenase type 1 activity in obese boys Eur. J. Endocrinol., September 1, 2007; 157(3): 319 - 324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Aslanidi, V. Kroutov, G. Philipsberg, K. Lamb, M. Campbell-Thompson, G. A. Walter, S. Kurenov, J. Ignacio Aguirre, P. Keller, K. Hankenson, et al. Ectopic expression of Wnt10b decreases adiposity and improves glucose homeostasis in obese rats Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E726 - E736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Michailidou, A. P Coll, C. J Kenyon, N. M Morton, S. O'Rahilly, J. R Seckl, and K. E Chapman Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone J. Endocrinol., July 1, 2007; 194(1): 161 - 170. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Buren, S.-A. Bergstrom, E. Loh, I. Soderstrom, T. Olsson, and C. Mattsson Hippocampal 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Messenger Ribonucleic Acid Expression Has a Diurnal Variability that Is Lost in the Obese Zucker Rat Endocrinology, June 1, 2007; 148(6): 2716 - 2722. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Wake, R. H. Stimson, G. D. Tan, N. Z. M. Homer, R. Andrew, F. Karpe, and B. R. Walker Effects of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} Agonists on 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1848 - 1856. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Berthiaume, M. Laplante, W. Festuccia, Y. Gelinas, S. Poulin, J. Lalonde, D. R. Joanisse, R. Thieringer, and Y. Deshaies Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Endocrinology, May 1, 2007; 148(5): 2391 - 2397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Kim, K. A. Temple, S. A. Jones, K. N. Meredith, J. L. Basko, and M. J. Brady Differential Modulation of 3T3-L1 Adipogenesis Mediated by 11beta-Hydroxysteroid Dehydrogenase-1 Levels J. Biol. Chem., April 13, 2007; 282(15): 11038 - 11046. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Tomlinson, M. Sherlock, B. Hughes, S. V. Hughes, F. Kilvington, W. Bartlett, R. Courtney, P. Rejto, W. Carley, and P. M. Stewart Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity in Vivo Limits Glucocorticoid Exposure to Human Adipose Tissue and Decreases Lipolysis J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 857 - 864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Paterson, M. C. Holmes, C. J. Kenyon, R. Carter, J. J. Mullins, and J. R. Seckl Liver-Selective Transgene Rescue of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in 11{beta}-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice Endocrinology, March 1, 2007; 148(3): 961 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nammi, K. Dembele, and B. L. G. Nyomba Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1101 - R1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. J Bujalska, O. M Durrani, J. Abbott, C. U Onyimba, P. Khosla, A. H Moosavi, T. T Q Reuser, P. M Stewart, J. W Tomlinson, E. A Walker, et al. Characterisation of 11{beta}-hydroxysteroid dehydrogenase 1 in human orbital adipose tissue: a comparison with subcutaneous and omental fat J. Endocrinol., February 1, 2007; 192(2): 279 - 288. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Subramanian, M. A. DeRosa, C. Bernal-Mizrachi, N. Laffely, W. T. Cade, K. E. Yarasheski, P. E. Cryer, and C. F. Semenkovich PPAR{alpha} activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1365 - E1371. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. R WALKER and R. ANDREW Tissue Production of Cortisol by 11beta-Hydroxysteroid Dehydrogenase Type 1 and Metabolic Disease Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 165 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E CHAPMAN, A. COUTINHO, M. GRAY, J. S GILMOUR, J. S SAVILL, and J. R SECKL Local Amplification of Glucocorticoids by 11beta-Hydroxysteroid Dehydrogenase Type 1 and Its Role in the Inflammatory Response Ann. N.Y. Acad. Sci., November 1, 2006; 1088(1): 265 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Wake, N. Z. M. Homer, R. Andrew, and B. R. Walker Acute In Vivo Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity by Insulin and Intralipid Infusions in Humans J. Clin. Endocrinol. Metab., November 1, 2006; 91(11): 4682 - 4688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Basu, D. S. Edgerton, R. J. Singh, A. Cherrington, and R. A. Rizza Splanchnic Cortisol Production in Dogs Occurs Primarily in the Liver: Evidence for Substantial Hepatic Specific 11{beta} Hydroxysteroid Dehydrogenase Type 1 Activity Diabetes, November 1, 2006; 55(11): 3013 - 3019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Darmon, F. Dadoun, S. Boullu-Ciocca, M. Grino, M.-C. Alessi, and A. Dutour Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity Am J Physiol Endocrinol Metab, November 1, 2006; 291(5): E995 - E1002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.-C. Alessi and I. Juhan-Vague PAI-1 and the Metabolic Syndrome: Links, Causes, and Consequences Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2200 - 2207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Mariniello, V. Ronconi, S. Rilli, P. Bernante, M. Boscaro, F. Mantero, and G. Giacchetti Adipose tissue 11{beta}-hydroxysteroid dehydrogenase type 1 expression in obesity and Cushing's syndrome Eur. J. Endocrinol., September 1, 2006; 155(3): 435 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. S. Densmore, N. M. Morton, J. J. Mullins, and J. R. Seckl 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Induction in the Arcuate Nucleus by High-Fat Feeding: A Novel Constraint to Hyperphagia? Endocrinology, September 1, 2006; 147(9): 4486 - 4495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. U Onyimba, N. Vijapurapu, S J. Curnow, P. Khosla, P. M Stewart, P. I Murray, E. A Walker, and S. Rauz Characterisation of the prereceptor regulation of glucocorticoids in the anterior segment of the rabbit eye. J. Endocrinol., August 1, 2006; 190(2): 483 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Gilmour, A. E. Coutinho, J.-F. Cailhier, T. Y. Man, M. Clay, G. Thomas, H. J. Harris, J. J. Mullins, J. R. Seckl, J. S. Savill, et al. Local amplification of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J. Immunol., June 15, 2006; 176(12): 7605 - 7611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bruley, V. Lyons, A. G. F. Worsley, M. D. Wilde, G. D. Darlington, N. M. Morton, J. R. Seckl, and K. E. Chapman A Novel Promoter for the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Gene Is Active in Lung and Is C/EBP{alpha} Independent Endocrinology, June 1, 2006; 147(6): 2879 - 2885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. G. Lavery, E. A. Walker, N. Draper, P. Jeyasuria, J. Marcos, C. H. L. Shackleton, K. L. Parker, P. C. White, and P. M. Stewart Hexose-6-phosphate Dehydrogenase Knock-out Mice Lack 11beta-Hydroxysteroid Dehydrogenase Type 1-mediated Glucocorticoid Generation J. Biol. Chem., March 10, 2006; 281(10): 6546 - 6551. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Piccirella, I. Czegle, B. Lizak, E. Margittai, S. Senesi, E. Papp, M. Csala, R. Fulceri, P. Csermely, J. Mandl, et al. Uncoupled Redox Systems in the Lumen of the Endoplasmic Reticulum: PYRIDINE NUCLEOTIDES STAY REDUCED IN AN OXIDATIVE ENVIRONMENT J. Biol. Chem., February 24, 2006; 281(8): 4671 - 4677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. McCormick, X. Wang, and G. J. Mick Evidence That the 11 {beta}-Hydroxysteroid Dehydrogenase (11 {beta}-HSD1) Is Regulated by Pentose Pathway Flux: STUDIES IN RAT ADIPOCYTES AND MICROSOMES J. Biol. Chem., January 6, 2006; 281(1): 341 - 347. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. B. Zemel The Role of Dairy Foods in Weight Management J. Am. Coll. Nutr., December 1, 2005; 24(suppl_6): 537S - 546S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Grino Prenatal nutritional programming of central obesity and the metabolic syndrome: role of adipose tissue glucocorticoid metabolism Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1233 - R1235. [Full Text] [PDF]
|
|
|
|
|
|
M. Baserga, M. A. Hale, R. A. McKnight, X. Yu, C. W. Callaway, and R. H. Lane Uteroplacental insufficiency alters hepatic expression, phosphorylation, and activity of the glucocorticoid receptor in fetal IUGR rats Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1348 - R1353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Gnanalingham, A. Mostyn, M. E. Symonds, and T. Stephenson Ontogeny and nutritional programming of adiposity in sheep: potential role of glucocorticoid action and uncoupling protein-2 Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2005; 289(5): R1407 - R1415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Paterson, J. R. Seckl, and J. J. Mullins Genetic manipulation of 11{beta}-hydroxysteroid dehydrogenases in mice Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2005; 289(3): R642 - R652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Small, P. W. F. Hadoke, I. Sharif, A. R. Dover, D. Armour, C. J. Kenyon, G. A. Gray, and B. R. Walker Preventing local regeneration of glucocorticoids by 11{beta}-hydroxysteroid dehydrogenase type 1 enhances angiogenesis PNAS, August 23, 2005; 102(34): 12165 - 12170. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Hermanowski-Vosatka, J. M. Balkovec, K. Cheng, H. Y. Chen, M. Hernandez, G. C. Koo, C. B. Le Grand, Z. Li, J. M. Metzger, S. S. Mundt, et al. 11{beta}-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice J. Exp. Med., August 15, 2005; 202(4): 517 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Arampatzis, B. Kadereit, D. Schuster, Z. Balazs, R. A S Schweizer, F. J Frey, T. Langer, and A. Odermatt Comparative enzymology of 11{beta}-hydroxysteroid dehydrogenase type 1 from six species J. Mol. Endocrinol., August 1, 2005; 35(1): 89 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Draper and P. M Stewart 11{beta}-Hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action J. Endocrinol., August 1, 2005; 186(2): 251 - 271. [Abstract] [Full Text] [PDF]
|
|
