Session: SAT 1-25-Glucocorticoid Actions & HPA Axis
Poster Board SAT-16
11-DHC was administered in drinking water for 5 weeks to wild-type mice (WT, 25µg/ml and 50µg/ml) and mice lacking 11β-HSD1 globally (GKO, 25µg/ml and 50µg/ml) or only in the liver (LKO, 25µg/ml). 11-DHC raised circulating corticosterone in both WT (25.2±5.2 vs. 169.1±32.2 nM) and LKO mice (20.2±2.6 vs. 162.7±44.6 nM), but not in GKO mice (23.9±3.9 vs. 13.6±2.4 nM). This indicates that corticosterone regenerated from 11-DHC enters the circulation and that liver 11β-HSD1 is not the main source of the regenerated steroid. Treatment with 11-DHC increased body weight and adiposity in WT mice, but not in LKO or GKO mice. This suggests that regenerated corticosterone can drive body weight gain. However, given the LKO data it is corticosterone regenerated by the liver which acts on fat tissue to increase adiposity. Food intake was increased (12.5±1.9%) when 11-DHC was administered to WT mice but not when administered to GKO mice. 11-DHC treatment also led to insulin resistance in WT mice, but not in LKO or GKO mice, suggesting that corticosterone regenerated by hepatic 11β-HSD1 is important in induction of insulin resistance. In contrast, circulating corticosterone derived from 11-DHC influenced HPA axis function, as increased corticosterone in WT and LKO mice resulted in reductions in ACTH, POMC and adrenal weight. These HPA axis markers were unaffected by 11-DHC treatment in GKO mice.
Together, these results demonstrate that 11β-HSD1 regenerated corticosterone can cause a metabolic syndrome-like phenotype in mice. While extra-hepatic (likely adipose tissue) 11β-HSD1 is largely responsible for the regeneration of corticosterone that enters the circulation, liver 11β-HSD1 appears key in the regulation of insulin sensitivity and body weight.
Disclosure: ESH: Researcher, Astra Zeneca. AVT: Employee, Astra Zeneca, Employee, Astra Zeneca. BL: Employee, Astra Zeneca, Employee, Astra Zeneca. Nothing to Disclose: ECC, BGK, AW
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