Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2015) 38 P196 | DOI: 10.1530/endoabs.38.P196

SFEBES2015 Poster Presentations Obesity, diabetes, metabolism and cardiovascular (108 abstracts)

Evidence for 11β-HSD1 regulation of brain energy metabolism following systemic inflammation

Manu Verma 1 , Tiina Kipari 2 , Jonathan Seckl 1 , Megan Holmes 1 & Karen Chapman 1


1University/BHF Centre for Cardiovascular Sciences, University of Edinburgh, Edinburgh, UK; 2MRC Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.

Background: Chronically elevated brain glucocorticoid (GC) levels impair cognition. In rodents, raised GC levels prior to lipopolyaccharide (LPS) administration potentiate neuroinflammation although GC suppresses neuroinflammation if administered after LPS. 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) activity can increase intracellular GC levels, including in the brain, without alteration in circulating levels. 11β-HSD1 deficiency/inhibition protects against age-related cognitive impairment. However, the underlying mechanism remains unclear. 11β-HSD1 activity is coupled to hexose-6-phosphate dehydrogenase activity, itself dependent on cellular energy status. Processes affected by deficiency/inhibition of 11β-HSD1 (e.g. acute inflammation, angiogenesis) are associated with increased aerobic glycolysis.

Hypothesis: 11β-HSD1 deficiency alters hippocampal energy homeostasis following inflammation.

Methods: Sterile peritonitis was induced (i.p. injection of 100 μg/kg LPS or 0.9% saline; culled 3, 6 or 9 h later) in male Hsd11b1−/− and C57BL/6 mice. A burrowing test was performed prior to cull to assess ‘sickness’ behaviour5. Levels of transcripts encoding inflammatory markers, metabolic transporters and enzymes were quantified by qRT-PCR. Inflammatory cells, plasma cytokines and GC levels were quantified by flow cytometry, ELISA and RIA respectively.

Results: Peripheral inflammation (inflammatory cells numbers in blood, plasma cytokine levels and ‘sickness’ behaviour) did not differ between genotypes (P>0.05; n=3–8). However, the brain inflammatory response differed between genotype with lower expression of Tnfa, Il1b and Il6 in Hsd11b1−/−mice (P<0.05, n=7) 3 h post LPS. At 6 h (peak of brain inflammatory response), hippocampal Tnfa, Il1b and Il6 expression levels did not differ between genotype (P>0.05; n=7–8) but principal component analysis of mRNA encoding 18 key metabolic transporters and enzymes showed a distinct cluster for Hsd11b1−/− mice post LPS (reduced glucose transporters and increased mitochondrial enzymes mRNA levels) (cumulative variance=54%). Hippocampal Hsd11b1 was itself down-regulated in C57BL/6 mice (P<0.05; n=7–8) 9 h following inflammation.

Conclusion: These data suggest that 11β-HSD1 deficiency reduces the hippocampal cytokine response and attenuates the switch to aerobic glycolysis following peripheral inflammation.

Volume 38

Society for Endocrinology BES 2015

Edinburgh, UK
02 Nov 2015 - 04 Nov 2015

Society for Endocrinology 

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