The metabolic abnormalities of chronic high dose glucocorticoids are not mediated by hypothalamic AgRP in male mice

Research output: Contribution to journalArticle

  • External authors:
  • Tiffany-Jayne Allen
  • Jonathan Wray
  • Rosemary Shoop
  • Neil Humphreys
  • Anthony P Coll

Abstract

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 centraland 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 appearto be responsible for the majority of the Gc-induced adverse metabolic effects.

Bibliographical metadata

Original languageEnglish
JournalEndocrinology
Early online date22 Feb 2019
DOIs
Publication statusPublished - 22 Feb 2019