Abstract
Chronically elevated glucocorticoid levels impair cognition and are pro-inflammatory in the brain. Deficiency or inhibition of 11β-hydroxysteroid dehydrogenase type-1 (11β-HSD1), which converts inactive into active glucocorticoids, protects against glucocorticoid-associated chronic stress- or age-related cognitive impairment. Here, we hypothesised that 11β-HSD1 deficiency attenuates the brain cytokine response to inflammation. Because inflammation is associated with altered energy metabolism, we also examined the effects of 11β-HSD1 deficiency upon hippocampal energy metabolism.Inflammation was induced in 11β-HSD1 deficient (Hsd11b1Del/Del) 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 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 11β-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.
Highlights
In the absence of an inflammatory challenge, 11b-HSD1 deficiency had no effect on markers of peripheral or brain inflammation, with undetectable Tnfa, Il1b and Il6 mRNA in the hippocampus of Hsd11b1Del/Del and C57BL/6 control mice and no difference in circulating neutrophil and monocyte numbers between genotypes (Supplementary Fig. 4A–C)
In the hippocampus there was no difference between naïve Hsd11b1Del/Del and C57BL/6 control mice in mRNAs encoding a range of metabolic transporters and enzymes: Slc2a1 and Slc2a3 mRNA, encoding the GLUT-1 and GLUT-3 transporters responsible for glucose uptake in glial and neuronal cells, respectively; Slc16a1, Slc16a7 and Slc16a4 mRNA encoding, respectively, the MCT-1 and MCT-2 transporters responsible for lactate uptake in glial and neuronal cells, and the MCT-4 transporter responsible for lactate export from glial cells; key enzymes of glycolysis, the pentose phosphate pathway and mitochondrial oxidative phosphorylation (Supplementary Fig. 4D–H)
These results suggest there is no inherent hippocampal inflammation in mice of either genotype, nor is the capacity for energy substrate transport and metabolism altered in the brains of naive Hsd11b1Del/Del mice
Summary
11b-HSD1-deficiency or inhibition is protective against age and/or stress related cognitive decline in rodents (Sooy et al, 2010; Yau et al, 2007, 2001, 2011; Mohler et al, 2011), associated with reduced intra-hippocampal levels of corticosterone (Yau et al, 2015, 2015). 11b-HSD1-deficiency alters intermediary metabolism and cellular glucose uptake (Morton et al, 2001, 2004; Wamil et al, 2011) These effects are marked when circulating glucocorticoid levels are elevated (Morgan et al, 2014). Recent evidence has highlighted the importance of a metabolic switch from oxidative respiration to aerobic glycolysis in stress-related inflammation or the aging brain (Currais, 2015) These findings suggest that 11b-HSD1 may alter brain energy metabolism, especially when the hypothalamic–pitui taryadrenal (HPA) axis is activated.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
