SFEBES2018 Poster Presentations Obesity & metabolism (24 abstracts)
Glucocorticoid-induced metabolic syndrome: establishing the role of AgRP
Charlotte Sefton 1 , Erika Harno 1 , Alison Davies 1 , Tiffany-Jayne Allen 1 , Jonathan R Wray 1 , Anthony P Coll 2 & Anne White 1
1University of Manchester, Manchester, UK; 2University of Cambridge Metabolic Research Laboratories and MRC Metbaolic Diseases Unit, Wellcome-MRC Institute of Metabolic Science, Cambridge, UK.
Glucocorticoid (Gc) excess, either from endogenous overproduction in disorders of the hypothalamic-pituitary-adrenal axis or exogenous medical therapy, is recognized to cause adverse metabolic side effects including obesity, hyperphagia, and hyperglycemia. The Gc receptor (GR) is widely expressed in the brain including the hypothalamus which is known to regulate energy balance. We have previously established through the administration of corticosterone (Cort) in the drinking water, that exogenous Cort delivery increases hypothalamic Gc levels1. This chronic elevation was associated with increases in AgRP mRNA expression and hyperphagia. The aim of this study was therefore to establish the role of AgRP in the development of Gc-induced obesity, hyperphagia, and hyperglycemia. CRISPR technology was used to create a novel model of AgRP knock down, deleting all three coding exons of the AgRP gene (AgRP−/−). Corticosterone (75 μg/ml) or vehicle (1% ethanol) was administered in the drinking water to AgRP−/− and AgRP+/+ mice across 3 weeks. Cort increased food intake in AgRP+/+ mice after 3 days, and this remained elevated at 3 weeks. However, AgRP−/− mice were partially protected from Cort-induced hyperphagia. In comparison, both AgRP+/+ mice and AgRP−/− mice treated with Cort had increased body weight between days 10 and 14 which then remained elevated for 3 weeks. In addition, at the end of the 3 week study, both AgRP+/+ mice and AgRP−/− mice treated with Cort were hyperglycemic and hyperinsulinemic. These results indicate that although AgRP partially mediates Cort-induced hyperphagia, other non-AgRP related mechanisms play a role in driving the development of Cort-induced obesity and hyperglycemia.
Reference
1Sefton et al., Endocrinology (2016):157,(11) 4257.
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Endocrine Abstracts
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