Endocrine Abstracts

Chronically elevated glucocorticoid (GC) levels alter cognition and increase cardio-metabolic disease risk. Negative feedback suppression of the hypothalamic–pituitary–adrenal (HPA) axis, including at the hippocampus, maintains low/basal circulating GC levels. Intracellular GC can be increased, without alteration in circulating levels, by the activity of 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1). In some tissues, 11β-HSD1 expression is increased by pro-inflammatory cytokines and by GC themselves. We hypothesized that 11β-HSD1 in the brain will be regulated during inflammation by pro-inflammatory cytokines and/or GC and will modulate local inflammation induced effects on HPA axis activity and energy homeostasis. To investigate whether 11β-HSD1 influences brain metabolism basally and whether 11β-HSD1 in the hippocampus and/or the hypothalamus is regulated during inflammation, levels of mRNA encoding enzymes and transporters relevant to energy homeostasis were quantified in whole brain of 11β-HSD1−(KO) and C57BL/6 (WT) mice by qPCR. Inflammation was induced in an experimental model of arthritis (i.p. injection of arthritogenic K/BxN serum) or lung inflammation (i.t. administration of Staphylococcus aureus). 11β-HSD1 mRNA levels were quantified at day15 (K/BxN arthritis) and 24 h post inoculation (Staphylococcus aureus). Lactate transporter, Mct1, mRNA levels were higher in KO (1.3-fold; P<0.05) suggesting increased lactate uptake. Levels of Pfk-1 and Ldh-b mRNA (encoding glycolytic enzymes) were lower in KO (0.75– to 0.82-fold; P<0.05) suggesting increased glycolysis. KO had higher mitochondrial DNA content and mRNA encoding mitochondrial enzymes, Cs and Cox6c (1.3–,1.2 to 1.3-fold, respectively; P<0.05) suggesting increased mitochondrial number. Arthritis or lung inflammation increased hippocampal and hypothalamic Tnf-α mRNA levels (P<0.05), reduced hippocampal 11β-HSD1 mRNA levels (P<0.001) with a similar, though non-significant trend, in hypothalamus. These data suggest that 11β-HSD1 deficiency increases glycolysis and energy substrate (lactate) in brain. Following inflammation, 11β-HSD1 mRNA levels are reduced in brain, in contrast to the up-regulation previously described in peripheral tissues suggesting a possible mechanism to increase brain glycolysis in response to inflammation.