Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice.
Wray, Jonathan R
The Endocrine Society
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Sefton, C., Davies, A., Allen, T., Wray, J. R., Shoop, R., Adamson, A., Humphreys, N., et al. (2019). Metabolic Abnormalities of Chronic High-Dose Glucocorticoids Are Not Mediated by Hypothalamic AgRP in Male Mice.. Endocrinology, 160 (5), 964-978. https://doi.org/10.1210/en.2019-00018
Glucocorticoids (Gcs) are potent and widely used medicines, but often cause metabolic side effects. A murine model of corticosterone (Cort) treatment results in increased hypothalamic expression of the melanocortin antagonist AgRP in parallel with obesity and hyperglycaemia. This study investigates how these adverse effects develop over time with particular emphasis on hypothalamic involvement. Wild type and Agrp-/- male mice were treated with Cort for three weeks. Phenotypic, biochemical, protein and mRNA analysis was undertaken on central and peripheral tissues including white and brown adipose tissue, liver and muscle to determine the metabolic consequences. Cort treatment induced hyperphagia within one day in wild type mice and this persisted for three weeks. Despite this early increase in food intake, body weight only started to rise after ten days. Hyperinsulinaemia occurred at day one, and although after two days there were alterations in genes often associated with insulin resistance in several peripheral tissues, hyperglycaemia only developed at three weeks. Throughout there was a sustained elevation in hypothalamic Agrp expression. Mice with Agrp deleted (using CRISPR-Cas9, Agrp-/-) were partially protected against Cort-induced hyperphagia. However, Agrp-/- mice still had similar Cort-induced increases in body weight and adiposity to Agrp+/+ mice. Loss of AgRP did not diminish Cort-induced hyperinsulinaemia or correct changes in hepatic gluconeogenic genes. Chronic Gc treatment in mice mimics many of the metabolic side effects seen in patients and leads to a robust increase in Agrp. However, AgRP does not appear to be responsible for the majority of the Gc-induced adverse metabolic effects.
Hypothalamus, Adipose Tissue, Animals, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Mice, Knockout, Obesity, Body Weight, Corticosterone, Leptin, Glucocorticoids, Gene Expression Regulation, Eating, Male, Agouti-Related Protein
External DOI: https://doi.org/10.1210/en.2019-00018
This record's URL: https://www.repository.cam.ac.uk/handle/1810/290054