Endocrine Abstracts (2015) 38 P239 | DOI: 10.1530/endoabs.38.P239

Hypothalamic glucocorticoid levels increase in an in vivo model of glucocorticoid-induced obesity and hyperinsulinaemia

Charlotte Sefton1, Erika Harno1, Alison Davies1, Helen Small2, Tiffany-Jayne Allen1, Jonathan Wray1, Thanuja Gali Ramamoorthy1, Anthony P Coll3 & Anne White1

1University of Manchester, Manchester, UK; 2Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK; 3University of Cambridge Metabolic Research Laboratories, Cambridge, UK.

Glucocorticoid (Gc) excess, either endogenously produced (Cushing’s syndrome) or as a result of exogenous steroid treatment, can cause metabolic disorders such as obesity and hyperglycaemia. The contribution of centrally acting corticosterone in the development of these metabolic disorders is unknown. Gcs regulate the anorexigenic and orexigenic neuropeptides (POMC and AgRP) within the arcuate nucleus of the hypothalamus to modulate energy balance. This study investigated the effects of exogenous corticosterone treatment on central corticosterone levels and evaluated the consequences on Gc-target genes and genes regulating Gc levels. Mice were administered corticosterone (75 μg/ml, CORT) or ethanol (1%, Veh) in their drinking water with high fat diet (HFD, 60% energy from fat diet) or chow for 4 weeks. The CORT and CORT/HFD generated a metabolic syndrome-like phenotype. Increased circulating corticosterone levels were found at the nadir and peak, and caused ablation of the corticosterone diurnal rhythm. LC-MS/MS analysis showed increased hypothalamic corticosterone levels in both the CORT and CORT/HFD groups. POMC and GR mRNA expression levels remained unchanged in the pituitary indicating the increases in corticosterone levels are a result of exogenous administration. There was a twofold decrease in the glucocorticoid receptor (GR) mRNA in the hypothalamus, and in situ hybridisation indicated that this was in a region other than the ARC or PVN. The GR was still active as CORT caused greater than twofold increase in both glucocorticoid-induced leucine zipper (GILZ) and fkbp5 expression. Exogenous CORT treatment resulted in a decrease in mRNA expression of 11β-hydroxysteroid dehydrogenase (11βHSD1), the enzyme which regenerates active Gcs, while the expression of the efflux transporter MDR-PGP was unaltered. In summary, exogenous Gc treatment increases hypothalamic corticosterone and this results in increases in Gc target genes, which in turn may be associated with the development of metabolic disturbances seen with GC excess.