Endocrine Abstracts (2015) 38 P218 | DOI: 10.1530/endoabs.38.P218

Glucocorticoid excess increases hypothalamic AgRP and results in obesity and hyperinsulinaemia in mice

Jonathan Wray1, Erika Harno1, Alison Davies1, Charlotte Sefton1, Thanuja Gali Ramamoorthy1, Tiffany-Jayne Allen1, Anthony P Coll2 & Anne White1

1The University of Manchester, Manchester, UK; 2University of Cambridge Metabolic Research Laboratories, Cambridge, UK.

Glucocorticoids (Gcs) are widely prescribed to treat a number of conditions, such as arthritis and asthma. However, patients receiving Gcs often develop metabolic complications such as obesity and hyperglycaemia. The aim of this study was to investigate the molecular mechanisms in the hypothalamus which drive these adverse effects. Male C57BL/6J mice were given ad libitum access to either corticosterone (CORT; 75 μg/ml) or vehicle (V; 1% ethanol) in their drinking water in combination with chow (C) or high fat (HF) diet (60% of calories from fat). Exogenous Gcs in the drinking water produced a robust and reproducible metabolic syndrome-like phenotype. After 4 weeks, body weight was increased to a similar extent in CORT-C, CORT-HF and V-HF animals compared to V-C mice. These three groups all had increased adiposity with a shift from epididymal to inguinal and mesenteric deposition with CORT. CORT treatment led to fed (25-fold) and fasting (fivefold) hyperinsulinaemia. Similarly, postprandial hyperglycaemia was present in CORT-C and CORT-HF groups (approximately twofold); however this only progressed to fasting hyperglycaemia (80% increase) in CORT-HF mice. Food intake was increased in the CORT-C group, leading us to assess the expression levels of hypothalamic neuropeptides known to control food intake. NPY and POMC remained unaffected, but AgRP increased (threefold) in the CORT-C group, providing a likely explanation for the increased food intake. In summary, we have demonstrated that a metabolic syndrome-like phenotype can be rapidly induced in mice using exogenous CORT treatment, and this is exacerbated when combined with HF diet. This suggests that Gcs acting in the hypothalamus contribute to the overall development of metabolic complications seen with Gc therapy.

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