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Cited by 244Stress Responses and CortisolHormonal Regulation and HypertensionAdrenal Hormones and Disorders

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11β-Hydroxysteroid dehydrogenases and the brain: From zero to hero, a decade of progress

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Wyrwoll, Caitlin S., Holmes, Megan C., Seckl, Jonathan R.·2011·Frontiers in Neuroendocrinology
DOI 10.1016/j.yfrne.2010.12.001PMC PMC3149101
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Abstract

Glucocorticoids have profound effects on brain development and adult CNS function. Excess or insufficient glucocorticoids cause myriad abnormalities from development to ageing. The actions of glucocorticoids within cells are determined not only by blood steroid levels and target cell receptor density, but also by intracellular metabolism by 11β-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD1 regenerates active glucocorticoids from their inactive 11-keto derivatives and is widely expressed throughout the adult CNS. Elevated hippocampal and neocortical 11β-HSD1 is observed with ageing and causes cognitive decline; its deficiency prevents the emergence of cognitive defects with age. Conversely, 11β-HSD2 is a dehydrogenase, inactivating glucocorticoids. The major central effects of 11β-HSD2 occur in development, as expression of 11β-HSD2 is high in fetal brain and placenta. Deficient feto-placental 11β-HSD2 results in a life-long phenotype of anxiety and cardiometabolic disorders, consistent with early life glucocorticoid programming.

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Fig. 1 The enzymatic actions of 11β-hydroxysteroid dehydrogenase (11β-HSD) in inter-conversion of active and inactive glucocorticoids in rodents. Active glucocorticoid (corticosterone) is metabolised by 11β-HSD2 to its inactive form (11-dehydrocorticosterone) while regeneration can occur via 11β-HSD1.
Fig. 1 The enzymatic actions of 11β-hydroxysteroid dehydrogenase (11β-HSD) in inter-conversion of active and inactive glucocorticoids in rodents. Active glucocorticoid (corticosterone) is metabolised by 11β-HSD2 to its inactive form (11-dehydrocorticosterone) while regeneration can occur via 11β-HSD1.CC BY · PubMed Central
Fig. 2 Orientation of 11β-HSD1 in the endoplasmic reticulum and its relationship with H6PDH. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is located on the luminal side of endoplasmic reticulum (ER) and the N-terminus is embedded into the membrane of the ER. The system comprising the glucose-6-phosphate (G6P) transporter and hexose-6-phosphate dehydrogenase (H6PDH) is crucial for transport of G6P to the H6PDH enzyme. G6P binds to the H6PDH to form 6-phospho-gluconolactone (G6P=O) resulting in generation of NADPH inside the lumen of the ER. The NADPH thus produced is utilised by 11β-HSD1 for the reduction of 11-dehydrocorticosterone to corticosterone.
Fig. 2 Orientation of 11β-HSD1 in the endoplasmic reticulum and its relationship with H6PDH. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is located on the luminal side of endoplasmic reticulum (ER) and the N-terminus is embedded into the membrane of the ER. The system comprising the glucose-6-phosphate (G6P) transporter and hexose-6-phosphate dehydrogenase (H6PDH) is crucial for transport of G6P to the H6PDH enzyme. G6P binds to the H6PDH to form 6-phospho-gluconolactone (G6P=O) resulting in generation of NADPH inside the lumen of the ER. The NADPH thus produced is utilised by 11β-HSD1 for the reduction of 11-dehydrocorticosterone to corticosterone.CC BY · PubMed Central
Fig. 3 The effects of diurnal rhythm and voluntary exercise on 5-HT 2CR mRNA expression in 11β-HSD1−/− (KO) and wild type mice (WT). Animals were kept in a constant light-dark cycle with lights on at 06:00 and lights off at 18:00. Mice were sacrificed at 06:00 (6), 12:00 (12), 18:00 (18), or after two months of voluntary wheel-running at 06:00 (W6). 5-HT 2CR mRNA expression was detected by in situ hybridisation histochemistry. Diurnal variation was seen in 11β-HSD1−/−, but not in wild type animals in (A) retrosplenial cortex (KO: P = 0.022, WT: P = 0.698) and (B) choroids plexus (KO: P = 0.001, WT: P = 0.232). (C) In the mediodorsal thalamus a tendency towards diurnal variation was observed in 11β-HSD1−/−, but not in wild type animals (KO: P = 0.090, WT: P = 0.596). (D) Representative photomicrographs. n = 4–6 for each condition. Values are mean ± SEM. +P < 0.05 compared to corresponding 06:00 value.
Fig. 3 The effects of diurnal rhythm and voluntary exercise on 5-HT 2CR mRNA expression in 11β-HSD1−/− (KO) and wild type mice (WT). Animals were kept in a constant light-dark cycle with lights on at 06:00 and lights off at 18:00. Mice were sacrificed at 06:00 (6), 12:00 (12), 18:00 (18), or after two months of voluntary wheel-running at 06:00 (W6). 5-HT 2CR mRNA expression was detected by in situ hybridisation histochemistry. Diurnal variation was seen in 11β-HSD1−/−, but not in wild type animals in (A) retrosplenial cortex (KO: P = 0.022, WT: P = 0.698) and (B) choroids plexus (KO: P = 0.001, WT: P = 0.232). (C) In the mediodorsal thalamus a tendency towards diurnal variation was observed in 11β-HSD1−/−, but not in wild type animals (KO: P = 0.090, WT: P = 0.596). (D) Representative photomicrographs. n = 4–6 for each condition. Values are mean ± SEM. +P < 0.05 compared to corresponding 06:00 value.CC BY · PubMed Central
Fig. 4 The effects of diurnal rhythm and voluntary exercise on 11-HSD1 mRNA expression in the cortex and hippocampus of wild type mice (C57BL/6J). Animals were kept in a constant light-dark cycle with lights on at 06:00 and lights off at 18:00. Mice were sacrificed at 06:00 (6), 12:00 (12), 18:00 (18), or after two months of voluntary wheel-running at 06:00 (W6). Gene expression was detected by in situ hybridisation histochemistry. 11-HSD1 mRNA expression in (A) cortex and (B) CA3 of wild type animals. n = 4–6 for each condition, except where a number above the bar indicates the n for that condition. Values are mean ± SEM.
Fig. 4 The effects of diurnal rhythm and voluntary exercise on 11-HSD1 mRNA expression in the cortex and hippocampus of wild type mice (C57BL/6J). Animals were kept in a constant light-dark cycle with lights on at 06:00 and lights off at 18:00. Mice were sacrificed at 06:00 (6), 12:00 (12), 18:00 (18), or after two months of voluntary wheel-running at 06:00 (W6). Gene expression was detected by in situ hybridisation histochemistry. 11-HSD1 mRNA expression in (A) cortex and (B) CA3 of wild type animals. n = 4–6 for each condition, except where a number above the bar indicates the n for that condition. Values are mean ± SEM.CC BY · PubMed Central
Fig. 5 Behaviour of 11β-HSD1−/− (KO) and wild type (WT) mice in the object recognition test. Two identical objects were presented to the mice in a learning session (L). In test sessions after 1 (T 1), 4 (T 4) or 24 (T 24) hours, the same (old) object and a new object were shown to the animals. (A) Distance travelled by 11β-HSD1−/− and wild type animals (n = 12 per genotype) in experiment 1. ANOVA reveals a significant effect of genotype (P = 0.017) and a decrease in activity over sessions in 11-HSD1−/− animals only (P = 0.022). (B and C) Exploration time of 11β-HSD1−/− and wild type mice (n = 12 per genotype) in experiment 1. (B) 11β-HSD1−/− mice show increased total exploration time compared to wild types, confirmed by ANOVA (genotype effect, P = 0.019). (C) No significant preference for the novel object over the old object was seen in either genotype. ANOVA reveals a significant session:genotype interaction effect (P = 0.010). (D and E) Exploratory behaviour of naïve wild type mice (n = 12) in experiment 2. Significant preference for the novel object was seen (D) in terms of absolute exploratory behaviour, confirmed by ANOVA (P = 0.005), but not (E) in terms of the percentage of total exploration time spent exploring the novel object. Dashed line indicates chance level. (F) Exploration time of naïve wild type mice (n = 15) in experiment 3. Values are mean ± SEM. *P < 0.05 compared to corresponding wild type animals.
Fig. 5 Behaviour of 11β-HSD1−/− (KO) and wild type (WT) mice in the object recognition test. Two identical objects were presented to the mice in a learning session (L). In test sessions after 1 (T 1), 4 (T 4) or 24 (T 24) hours, the same (old) object and a new object were shown to the animals. (A) Distance travelled by 11β-HSD1−/− and wild type animals (n = 12 per genotype) in experiment 1. ANOVA reveals a significant effect of genotype (P = 0.017) and a decrease in activity over sessions in 11-HSD1−/− animals only (P = 0.022). (B and C) Exploration time of 11β-HSD1−/− and wild type mice (n = 12 per genotype) in experiment 1. (B) 11β-HSD1−/− mice show increased total exploration time compared to wild types, confirmed by ANOVA (genotype effect, P = 0.019). (C) No significant preference for the novel object over the old object was seen in either genotype. ANOVA reveals a significant session:genotype interaction effect (P = 0.010). (D and E) Exploratory behaviour of naïve wild type mice (n = 12) in experiment 2. Significant preference for the novel object was seen (D) in terms of absolute exploratory behaviour, confirmed by ANOVA (P = 0.005), but not (E) in terms of the percentage of total exploration time spent exploring the novel object. Dashed line indicates chance level. (F) Exploration time of naïve wild type mice (n = 15) in experiment 3. Values are mean ± SEM. *P < 0.05 compared to corresponding wild type animals.CC BY · PubMed Central
Fig. 6 Hippocampal GR mRNA expression during early post-natal period in 11β-HSD2 transgenic mice. Effect of 11β-HSD2 genotype (+/+ ■, −/− □) on glucocorticoid receptor (GR) mRNA expression in the (a) CA1, (b) CA2, (c) CA3 and (d) dentate gyrus (DG) hippocampal subfields. Expression levels were measured in 1-week (P7), 2-week (P14) and 3-week (P21) old mice by optical densitometry of in situ hybridisation autoradiographs. Data are expressed as mean ± SEM in arbitary units (AU) and analysed by two-way ANOVA with SNK post-hoc testing for each subfield; n = 5–10 per group. *P < 0.05, #P < 0.01.
Fig. 6 Hippocampal GR mRNA expression during early post-natal period in 11β-HSD2 transgenic mice. Effect of 11β-HSD2 genotype (+/+ ■, −/− □) on glucocorticoid receptor (GR) mRNA expression in the (a) CA1, (b) CA2, (c) CA3 and (d) dentate gyrus (DG) hippocampal subfields. Expression levels were measured in 1-week (P7), 2-week (P14) and 3-week (P21) old mice by optical densitometry of in situ hybridisation autoradiographs. Data are expressed as mean ± SEM in arbitary units (AU) and analysed by two-way ANOVA with SNK post-hoc testing for each subfield; n = 5–10 per group. *P < 0.05, #P < 0.01.CC BY · PubMed Central
Fig. 7 Total Igf2 expression in liver of 11β-HSD2+/+, 11β-HSD2+/- and 11β-HSD2−/− fetuses at E15. Total Igf2 expression was measured by real-time RT-PCR in offspring generated from heterozygous 11β-HSD2 matings. Data are expressed as mean ± SEM; n = 6 per group. *P < 0.05.
Fig. 7 Total Igf2 expression in liver of 11β-HSD2+/+, 11β-HSD2+/- and 11β-HSD2−/− fetuses at E15. Total Igf2 expression was measured by real-time RT-PCR in offspring generated from heterozygous 11β-HSD2 matings. Data are expressed as mean ± SEM; n = 6 per group. *P < 0.05.CC BY · PubMed Central
Fig. 8 Expression and function of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. 11β-HSD1 is widely expressed throughout the adult CNS and is key to HPA axis function and cognitive decline during ageing. Conversely, the major central effects of 11β-HSD2 are seen in development, as expression of 11β-HSD2 is high in fetal tissues including the neonate brain and placenta. Loss of 11β-HSD2 from the fetus and fetally-derived tissues results in a life-long phenotype of anxiety, consistent with developmental programming.
Fig. 8 Expression and function of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and 2. 11β-HSD1 is widely expressed throughout the adult CNS and is key to HPA axis function and cognitive decline during ageing. Conversely, the major central effects of 11β-HSD2 are seen in development, as expression of 11β-HSD2 is high in fetal tissues including the neonate brain and placenta. Loss of 11β-HSD2 from the fetus and fetally-derived tissues results in a life-long phenotype of anxiety, consistent with developmental programming.CC BY · PubMed Central

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Metadata

Authors
Wyrwoll, C. S., Holmes, M. C., & Seckl, J. R.
Affiliations
The Queen's Medical Research Institute (GB)
Corresponding author
Wyrwoll, Caitlin S.
ORCID
Venue
Frontiers in Neuroendocrinology
Publisher
Elsevier BV
Published
2011-08
Volume
32
Issue
3
Pages
265-286
ISSN
0091-3022 (ISSN-L)
DOI
10.1016/j.yfrne.2010.12.001
PMC
PMC3149101
OpenAlex
W2133069858
Cited by
244
References
336
Citations by year
2026: 9 · 2025: 12 · 2024: 10 · 2023: 17 · 2022: 12 · 2021: 18 · 2020: 18 · 2019: 22 · 2018: 12 · 2017: 15 · 2016: 20 · 2015: 17 · 2014: 22 · 2013: 23 · 2012: 12
FWCI
1.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Neuroendocrinology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UWA Profiles and Research Repository (UWA) (submittedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Wellcome Trust
  • MRC
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
11β-hydroxysteroid dehydrogenase, 11β-hydroxysteroid dehydrogenase type 1, 11β-hydroxysteroid dehydrogenase type 2, glucocorticoids, brain development, cognitive aging, hippocampus, neocortex, placenta, fetal programming, anxiety, cardiometabolic disease, glucocorticoid metabolism
MeSH terms
Aging, Animals, Brain, Glucocorticoids, Humans, Isoenzymes, Signal Transduction, Gene Expression Regulation, Enzymologic, 11-beta-Hydroxysteroid Dehydrogenase Type 1, 11-beta-Hydroxysteroid Dehydrogenase Type 2

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