Endocrine Abstracts

Glucocorticoids (Gcs) are used in the treatment of inflammatory disorders including asthma and rheumatoid arthritis. However, long-term use can cause metabolic side-effects including obesity and diabetes. Previous studies have shown that Gcs increase Agrp expression and that AgRP/NPY/GABA (ANG) neurons can regulate appetite and insulin sensitivity. To investigate the effects of chronic Gc treatment directly on ANG neurons, we crossed AgRP-IRES-Cre with GR^Flox/Flox mice to generate AgRP-Cre/GR^Flox/Flox (GR/ANG KO) mice where GR is deleted in ANG neurons only. Female GR/ANG KO mice, their AgRP-Cre/GR^Flox/+ (Cre) and GR^Flox/Flox (GR Flox) littermates (controls) were treated with corticosterone (Cort-) or vehicle-supplemented drinking water for 3 weeks after which phenotypic, biochemical and neurohormonal characteristics were assessed. Mice with GR deleted from ANG neurons did have increased Agrp expression, which was present in control strains. Further, although Cort increased food intake in both GR Flox and Cre strains compared to their vehicle controls, GR/ANG KO mice were partially protected from Cort-induced hyperphagia. Cort increased body weight and adiposity in control strains and GR/ANG KO mice to a similar extent. However, Cort-treated GR/ANG KO mice had reduced hepatic lipid accumulation compared to Cort-treated control mice and although control mice were hyperinsulinaemic after 3 weeks, circulating insulin was not elevated in GR/ANG KO mice. Additionally, in Cort-treated GR/ANG KO mice there was no decrease in skeletal muscle Irs1 expression or increase in expression of P85a in skeletal muscle or liver, in contrast to the controls. Loss of the glucocorticoid receptor on ANG neurons ameliorates the acute hyperphagia induced by Cort. In addition, the changes in circulating insulin, liver and muscle seen in GR/ANG KO mice suggest that ANG neurons appear to have a role in mediating Gc-induced hyperinsulinemia and insulin resistance.