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Endocrine Abstracts (2016) 44 OC1.2 | DOI: 10.1530/endoabs.44.OC1.2

SFEBES2016 Oral Communications Early Career Oral Communications (6 abstracts)

11β-HSD1 deficiency modulates brain energy homeostasis during acute systemic inflammation

Manu Verma 1 , Tiina Kipari 2 , Tak Yung Man 1 , Thorsten Forster 3 , Natalie Homer 1, , Jonathan Seckl 1 , Megan Holmes 1 & Karen Chapman 1

1University/BHF Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK; 2MRC Centre For Inflammation Research, University of Edinburgh, Edinburgh, UK; 3Division of Infection and Pathway Medicine, University of Edinburgh, Edinburgh, UK; 4Edinburgh Clinical Research Facility Mass Spectrometry, University of Edinburgh, Edinburgh, UK.

Chronically elevated glucocorticoid (GC) level impairs cognition. In rodents, elevated plasma GC levels, prior to an inflammatory challenge, potentiates neuroinflammation that is abolished by GR but not MR antagonism. 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1) increases intracellular GC levels by regenerating active GCs from inert forms. Inhibition/deficiency of 11β-HSD1 is protective against age-related cognitive decline presumably by lifelong reduced brain exposure to GC, especially during stress/aging. We hypothesised that 11β-HSD1 deficiency will attenuate the brain response to inflammation and will be associated with an attenuated switch to aerobic glycolysis. C57BL/6 and Hsd11b1−/− mice were injected (i.p.) with 100 μg/kg LPS or 0.9% saline and culled 3, 6 or 9 h later. Sickness behaviour was assayed 2 h prior to cull. Pro-inflammatory responses and energy metabolising pathways in the brain were investigated. Compared to controls, Hsd11b1−/− mice showed a quicker recovery from sickness behaviour, post-LPS (P<0.01; n=7–8). Post-LPS, circulating neutrophil and Ly6C+ monocyte numbers were reduced (P<0.05; n=4–10) and plasma corticosterone levels were increased (P<0.05; n=6–9) equally in both genotypes, suggesting similar peripheral inflammatory responses. However, 11-dehydrocorticosterone (11β-HSD1 substrate) levels were higher in Hsd11b1−/− mice, compared to controls (P<0.01; n=6–9;). Post-LPS, the increase in hippocampal Tnfa, Il-1b and Il-6 mRNAs were attenuated in Hsd11b1−/− mice (P<0.001; n=7–8;), compared to controls, suggesting reduced inflammation. Principle component analysis of hippocampal level of mRNAs encoding metabolic transporters and enzymes revealed a distinct response in Hsd11b1−/− mice, compared to controls, post-LPS (cumulative variance=54%). Further analysis, revealed an attenuated switch to aerobic glycolysis in Hsd11b1−/− mice, compared to controls (P<0.05; n=6–8). Hippocampal metabolites showed correspondence with mRNA results with an increased fumrate/succinate ratio in Hsd11b1−/− mice, compared to controls (P<0.05; n=7–10) suggesting reduced inflammation and an enhanced hypoxia response. These data suggests an attenuated hippocampal pro-inflammatory response and better metabolic support for neuronal function could, at least in part, underlie the neuroprotection associated with 11β-HSD1 inhibition/deficiency during stress/aging.

Volume 44

Society for Endocrinology BES 2016

Brighton, UK
07 Nov 2016 - 09 Nov 2016

Society for Endocrinology 

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