Abstract
Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects. These may occur through direct actions of GCs on peripheral organs, but could also be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Therefore, the aim of this study was to examine the metabolic effects of chronic treatment with the GC corticosterone (Cort, 75 μg/ml in drinking water) in mice lacking the glucocorticoid receptor (GR) on AgRP neurons. Female AgRP-GR KO mice had delayed onset of Cort-induced hyperphagia. However, AgRP-GR KO had little impact on the increased body weight or adiposity seen with 3 weeks Cort treatment. Cort caused hepatic steatosis in control mice, but in Cort treated female AgRP-GR KO mice there was a 25% reduction in liver lipid content and lower plasma triglycerides. Additionally, Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test. In conclusion, these data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment.
Highlights
Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects
The present study has demonstrated that GCs acting on AgRP neurons contribute to the Cort-induced hyperinsulinaemia and hepatic steatosis in female mice
It seems likely that these changes contribute to the reductions in hepatic steatosis and hyperinsulinaemia in the AgRP-glucocorticoid receptor (GR) KO mice
Summary
Glucocorticoids (GCs) are widely prescribed anti-inflammatory medicines, but their use can lead to metabolic side-effects These may occur through direct actions of GCs on peripheral organs, but could be mediated by the hypothalamic AgRP neurons, which can increase food intake and modify peripheral metabolism. Cort treatment led to hyperinsulinaemia, but compared to controls, Cort-treated AgRP-GR KO mice had both lower fasting insulin levels and lower insulin levels during a glucose tolerance test These data indicate that GCs do act through AgRP neurons to contribute, at least in part, to the adverse metabolic consequences of chronic GC treatment. Perturbation of heat production in BAT has the potential to reduce energy expenditure and enhance the development of obesity Another major metabolic side-effect of GCs is disrupted glucose homeostasis. The direct actions of GCs on a range of peripheral tissues such as skeletal muscle, adipose tissue, liver and pancreas are well known to contribute to glucose intolerance and a reduction in insulin sensitivity (reviewed in Pasieka et al 201619 and Rafacho et al 2 01420)
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