Abstract
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized 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 (Cort)-induced obesity and analyzed Cort levels in the hypothalamus and expression of genes relevant to Gc action. Mice were administered Cort (75 μg/mL) 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 Cort levels at both zeitgeber time 1 and zeitgeber time 13, ablating the diurnal rhythm. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11β-hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb1 mRNA was unaltered. In addition, although Cort decreased hypothalamic GR (Nr3c1) expression 2-fold, the Gc-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 Cort levels and a persistent elevation in Agrp, a mediator in the development of metabolic disturbances.
Highlights
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamicpituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects
To determine whether Cort treatment resulted in elevation of Cort in the hypothalamus within 24 hours or whether it gradually accumulated over time, levels were quantified after 24 and 48 hours of Cort treatment
There was increased expression of Tsc22d3 (Gc-induced leucine zipper [GILZ]), a transcription factor known to be regulated by Gcs (P Ͻ .01) (Figure 4B) and a trend towards an increase in FK506binding protein 5 (Fkbp5) within the hypothalamus (Figure 4C), indicating increased Gc activity
Summary
Glucocorticoid (Gc) excess, from endogenous overproduction in disorders of the hypothalamicpituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects. Liquid chromatography dual tandem mass spectrometry revealed a 4-fold increase in hypothalamic Cort, which correlated with circulating levels and concentrations of Cort in other brain regions. This occurred despite decreased 11hydroxysteroid dehydrogenase (Hsd11b1) expression, the gene encoding the enzyme that regenerates active Gcs, whereas efflux transporter Abcb mRNA was unaltered. On a population scale, a much larger burden of Gcinduced metabolic problems occurs as a result of longterm exogenous Gc use for a wide range of inflammatory and malignant conditions Some of these adverse metabolic consequences can be ameliorated, for example, bisphosphonate treatment for steroid-induced osteoporosis, the Gc-induced disorders of increased body weight and abnormal glucose metabolism are often difficult to treat effectively. Gc receptors (GRs) are widely distributed throughout the brain, and yet the contribution of Gc actions in brain regions known to regulate energy balance is often ignored when considering the effects of excess Gcs on metabolic regulation
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