11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation
| Autor: | Thorsten Forster, Manu Verma, Tak Yung Man, Megan C. Holmes, Zhenguang Zhang, Natalie Z.M. Homer, Tiina Kipari, Karen E. Chapman, Jonathan R. Seckl |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Male Neutrophils medicine.medical_treatment OAA oxaloacetic acid SDHA DHAP dihydroxyacetone phosphate Systemic inflammation Hippocampus Monocytes Behavioral Neuroscience Mice Glucocorticoid metabolism 11-beta-Hydroxysteroid Dehydrogenase Type 1 Glycolysis Illness Behavior Mice Knockout Behavior Animal 3PGA 3-phosphoglyceraldehyde HPA hypothalamicpituitary-adrenal 11β-hydroxysteroid dehydrogenase 11-DHC 11-dehydrocorticosterone 3. Good health Mitochondria Cytokine LPS lipopolysaccharide lipids (amino acids peptides and proteins) medicine.symptom Glucocorticoid hormones hormone substitutes and hormone antagonists medicine.drug 11β-HSD1 11β-hydroxysteroid dehydrogenase type-1 medicine.medical_specialty Immunology TCA tricarboxylic acid Inflammation Biology Neuroprotection Article 03 medical and health sciences Internal medicine medicine Animals Endocrine and Autonomic Systems Energy metabolism Mice Inbred C57BL 030104 developmental biology Endocrinology Anaerobic glycolysis Corticosterone |
| Zdroj: | Verma, M, Kipari, T, Zhang, Z, Man, T Y, Forster, T, Homer, N Z M, Seckl, J R, Holmes, M C & Chapman, K E 2017, ' 11β-hydroxysteroid dehydrogenase-1 deficiency alters brain energy metabolism in acute systemic inflammation ', Brain, Behavior, and Immunity . https://doi.org/10.1016/j.bbi.2017.11.015 Brain, Behavior, and Immunity |
| DOI: | 10.1016/j.bbi.2017.11.015 |
| Popis: | Highlights • 11β-HSD1-deficiency reduces the hippocampal inflammatory response to LPS. • This happens despite similar peripheral inflammation. • 11β-HSD1-deficiency favours a “Warburg” like response to LPS in the hippocampus. • LPS increases hippocampal fumarate levels in 11β-HSD1-deficient mice. • Fumarate accumulation can cause pseudo-hypoxia. 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. |
| Databáze: | OpenAIRE |
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