ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2016) 44 P192 | DOI: 10.1530/endoabs.44.P192

RNA-seq of mouse arcuate nuclei reveals pathways perturbed by glucocorticoid treatment

Jonathan Wray1, Erika Harno1, Alison Davies1, Charlotte Sefton1, Tiffany-Jayne Allen1, Brian Y.H. Lam2, Giles S.H. Yeo2 & Anne White1


1Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; 2University of Cambridge Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK.


Glucocorticoids (GCs) are widely prescribed to treat a number of inflammatory and autoimmune conditions. However, patients receiving GCs often develop adverse metabolic effects such as hyperphagia leading to weight gain and hyperglycaemia. Little is known about the central effects of GCs; however they can act in the hypothalamic arcuate nucleus (ARC), a region involved in the integration of other energy regulatory hormones such as leptin, insulin and ghrelin. Therefore, the aim of this study was to identify genes and pathways differentially expressed in the ARC following GC treatment. Male C57BL/6J mice were given ad libitum access to corticosterone (CORT; 75 μg/ml) in their drinking water for 2 days, producing a robust increase in circulating corticosterone. Food intake was increased (~30%) in CORT treated mice from day 1 onwards, but no change in body weight was observed. Following treatment, arcuate nuclei were isolated using laser capture microdissection before RNA was extracted and amplified for RNA-seq. RNA-seq results indicate that of the 15,277 genes identified in the ARC, 224 were differentially expressed (>1.5-fold; P<0.01) with CORT treatment (90 downregulated; 124 upregulated). This subset contained genes already known to be regulated by GCs, including Mt1, Mt2, Cdkn1a, as well as some involved in the control of food intake and energy balance, e.g. Agrp, Ghsr, Lepr. This change in Agrp expression (1.8-fold increase) provides a likely explanation for the observed hyperphagia, as AgRP has potent orexigenic effects. Using Ingenuity Pathway Analysis we revealed effects of GC treatment on genes involved in glucose metabolism, such as Spp1, Bmp2 and Atgr1. These genes are predicted to be regulated by the histone deacetylases (HDACs), with Hdac5 being altered in our dataset (60% decrease). Therefore this study has identified strong candidate genes in the hypothalamus that may be mediating GC induced metabolic dysfunction.

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