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Elevated hypothalamic glucocorticoid levels are associated with obesity and hyperphagia in male mice.
Sefton, C Harno, E Davies, A Small, Helen F Allen, T Wray, J Lawrence, C Coll, A White, A
Sefton, C
Harno, E
Davies, A
Small, Helen F
Allen, T
Wray, J
Lawrence, C
Coll, A
White, A
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Abstract
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognised to cause adverse metabolic side effects. The Gc receptor (GR) is widely expressed throughout the body, including brain regions such as the hypothalamus. However the extent to which chronic Gcs affect Gc concentrations in the hypothalamus and impact on GR and target genes is unknown. To investigate this, we used a murine model of corticosterone-induced obesity, and analysed corticosterone levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered corticosterone (75μ g/ml, Cort) or ethanol (1%, vehicle) in drinking water for 4 weeks. Cort-treated mice had increased body weight, food intake and adiposity. As expected, Cort increased plasma corticosterone levels at both ZT=1 and ZT=13, ablating the diurnal rhythm. LC-MS/MS revealed a 4-fold increase in hypothalamic corticosterone, which correlated with circulating levels and concentrations of corticosterone in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme which regenerates active Gcs, while efflux transporter Abcb1 mRNA was unaltered. In addition, while Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the glucocorticoid-induced leucine zipper (Tsc22d3) mRNA increased which indicated elevated GR activation. In keeping with the development of hyperphagia and obesity, Cort increased Agrp, but there were no changes in Pomc, Npy or Cart mRNA in the hypothalamus. In summary, chronic Cort treatment causes chronic increases in hypothalamic corticosterone levels, and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
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2016-09-20
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Elevated hypothalamic glucocorticoid levels are associated with obesity and hyperphagia in male mice. 2016, 157(11):4257–4265 Endocrinology