11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation

Manu Verma; Tiina Kipari; Zhenguang Zhang; Tak Yung Man; Thorsten Forster; Natalie Z. M. Homer; Jonathan R. Seckl; Megan C. Holmes; Karen E. Chapman

doi:10.1016/j.bbi.2017.11.015

11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation

Manu Verma, Tiina Kipari, Zhenguang Zhang, Tak Yung Man, Thorsten Forster, Natalie Z. M. Homer, Jonathan R. Seckl, Megan C. Holmes, Karen E. Chapman

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

Abstract

Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11-hydroxysteroid dehydrogenase type-1 (11B-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11B-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11B-HSD1 deficiency upon hippocampal energy metabolism.
Inflammation was induced in 11B-HSD1 deficient (Hsd11b1Del/Del51 ) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del 54 mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinate
dehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate.

These data suggest 11B-HSD1 deficiency attenuates the hippocampal pro
inflammatory response to LPS, associated with increased capacity for aerobic
glycolysis and mitochondrial ATP generation. This may provide better metabolic
support and be neuroprotective during systemic inflammation or aging.

Original language	English
Journal	Brain, Behavior, and Immunity
Early online date	21 Nov 2017
DOIs	https://doi.org/10.1016/j.bbi.2017.11.015
Publication status	E-pub ahead of print - 21 Nov 2017

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10.1016/j.bbi.2017.11.015

1-s2.0-S0889159117305160-mainFinal published version, 1.7 MBLicence: CC BY

How does 11B-hydroxysteriod dehydrogenase type 1 limit inflammation.
Chapman, K., Gray, M., Savill, J. & Seckl, J.
MRC
1/10/08 → 30/04/12
Project: Research

Karen Chapman
- Centre for Cardiovascular Science
Person: Academic: Research Active

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@article{87e3bca501b44b249959af9148236678,

title = "11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation",

abstract = "Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11-hydroxysteroid dehydrogenase type-1 (11B-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11B-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11B-HSD1 deficiency upon hippocampal energy metabolism.Inflammation was induced in 11B-HSD1 deficient (Hsd11b1Del/Del51 ) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del 54 mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinatedehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate.These data suggest 11B-HSD1 deficiency attenuates the hippocampal proinflammatory response to LPS, associated with increased capacity for aerobicglycolysis and mitochondrial ATP generation. This may provide better metabolicsupport and be neuroprotective during systemic inflammation or aging.",

author = "Manu Verma and Tiina Kipari and Zhenguang Zhang and Man, {Tak Yung} and Thorsten Forster and Homer, {Natalie Z. M.} and Seckl, {Jonathan R.} and Holmes, {Megan C.} and Chapman, {Karen E.}",

note = "We are grateful to the staff at the University of Edinburgh Central Bioresearch Services for their assistance with animal care. We acknowledge financial support of the Wellcome Trust Clinical Research Mass Spectrometry facility from NHS Research Scotland (through the Edinburgh Clinical Research Facility) and from a British Heart Foundation Centre of Excellence award. We thank the staff at the Queen{\textquoteright}s Medical Research Institute flow cytometry facility and Wellcome Trust Clinical Research Mass Spectrometry facility for 617 their assistance. We are grateful to Colm Cunnigham (Trinity College Dublin, Ireland) and Cristina Esteves, Nik Morton and other colleagues at the University of Edinburgh for their advice and helpful discussions. Disclosure statement: JRS: Co-developed and patented in the University of Edinburgh the use of 11B-HSD1 inhibitors. The University licensed this patent to pharmaceutical industry. The funders or the licensee of this patent had no role in study design, analysis or reporting of the current work. JRS has also consulted to the industry for the use of 11B-HSD1 inhibitors. Nothing to disclose: MV, TMJK, ZZ, TYM, TF, NZMH, MCH, KEC FUNDING This work was supported by grants from the Wellcome Trust (WT083184) and Medical Research Council (G0800235). Additional support was provided by funding from the Moray Endowment Fund, University of Edinburgh, the British Society for Neuroendocrinology and a practical skills grant from the Society of Endocrinology (to MV). MV was supported by an International Scholarship from the University of Edinburgh College of Medicine and Veterinary Medicine.",

year = "2017",

month = nov,

day = "21",

doi = "10.1016/j.bbi.2017.11.015",

language = "English",

journal = "Brain, Behavior, and Immunity",

publisher = "Academic Press",

}

TY - JOUR

T1 - 11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation

AU - Verma, Manu

AU - Kipari, Tiina

AU - Zhang, Zhenguang

AU - Man, Tak Yung

AU - Forster, Thorsten

AU - Homer, Natalie Z. M.

AU - Seckl, Jonathan R.

AU - Holmes, Megan C.

AU - Chapman, Karen E.

N1 - We are grateful to the staff at the University of Edinburgh Central Bioresearch Services for their assistance with animal care. We acknowledge financial support of the Wellcome Trust Clinical Research Mass Spectrometry facility from NHS Research Scotland (through the Edinburgh Clinical Research Facility) and from a British Heart Foundation Centre of Excellence award. We thank the staff at the Queen’s Medical Research Institute flow cytometry facility and Wellcome Trust Clinical Research Mass Spectrometry facility for 617 their assistance. We are grateful to Colm Cunnigham (Trinity College Dublin, Ireland) and Cristina Esteves, Nik Morton and other colleagues at the University of Edinburgh for their advice and helpful discussions. Disclosure statement: JRS: Co-developed and patented in the University of Edinburgh the use of 11B-HSD1 inhibitors. The University licensed this patent to pharmaceutical industry. The funders or the licensee of this patent had no role in study design, analysis or reporting of the current work. JRS has also consulted to the industry for the use of 11B-HSD1 inhibitors. Nothing to disclose: MV, TMJK, ZZ, TYM, TF, NZMH, MCH, KEC FUNDING This work was supported by grants from the Wellcome Trust (WT083184) and Medical Research Council (G0800235). Additional support was provided by funding from the Moray Endowment Fund, University of Edinburgh, the British Society for Neuroendocrinology and a practical skills grant from the Society of Endocrinology (to MV). MV was supported by an International Scholarship from the University of Edinburgh College of Medicine and Veterinary Medicine.

PY - 2017/11/21

Y1 - 2017/11/21

N2 - Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11-hydroxysteroid dehydrogenase type-1 (11B-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11B-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11B-HSD1 deficiency upon hippocampal energy metabolism.Inflammation was induced in 11B-HSD1 deficient (Hsd11b1Del/Del51 ) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del 54 mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinatedehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate.These data suggest 11B-HSD1 deficiency attenuates the hippocampal proinflammatory response to LPS, associated with increased capacity for aerobicglycolysis and mitochondrial ATP generation. This may provide better metabolicsupport and be neuroprotective during systemic inflammation or aging.

AB - Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11-hydroxysteroid dehydrogenase type-1 (11B-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11B-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11B-HSD1 deficiency upon hippocampal energy metabolism.Inflammation was induced in 11B-HSD1 deficient (Hsd11b1Del/Del51 ) and C57BL/6 control mice by intraperitoneal injection of lipopolysaccharide (LPS). LPS reduced circulating neutrophil and monocyte numbers and increased plasma corticosterone levels equally in C57BL/6 and Hsd11b1Del/Del 54 mice, suggesting a similar peripheral inflammatory response. However, the induction of pro-inflammatory cytokine mRNAs in the hippocampus was attenuated in Hsd11b1Del/Del mice. Principal component analysis of mRNA expression revealed a distinct metabolic response to LPS in hippocampus of Hsd11b1Del/Del mice. Expression of Pfkfb3 and Ldha, key contributors to the Warburg effect, showed greater induction in Hsd11b1Del/Del mice. Consistent with increased glycolytic flux, levels of 3-phosphoglyceraldehyde and dihydroxyacetone phosphate were reduced in hippocampus of LPS injected Hsd11b1Del/Del mice. Expression of Sdha and Sdhb, encoding subunits of succinatedehydrogenase/complex II that determines mitochondrial reserve respiratory capacity, was induced specifically in hippocampus of LPS injected Hsd11b1Del/Del mice, together with increased levels of its product, fumarate.These data suggest 11B-HSD1 deficiency attenuates the hippocampal proinflammatory response to LPS, associated with increased capacity for aerobicglycolysis and mitochondrial ATP generation. This may provide better metabolicsupport and be neuroprotective during systemic inflammation or aging.

U2 - 10.1016/j.bbi.2017.11.015

DO - 10.1016/j.bbi.2017.11.015

M3 - Article

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation

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