Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2021) 73 S11.3 | DOI: 10.1530/endoabs.73.S11.2

ECE2021 Symposia Symposium 11: Thyroid hormones, regulation of metabolism and energy balance (3 abstracts)

Chronic glucocorticoid treatment causes metabolic abnormalities: The role of hypothalamic glucocorticoids and DIO2

Erika Harno


University of Manchester, School of Medical Sciences, Manchester, United Kingdom


Synthetic glucocorticoids (GCs) are widely used in clinical practise to treat various inflammatory disorders including rheumatoid arthritis, asthma and some malignancies. Although generally well tolerated, long-term, especially high dose use can lead to metabolic side effects. We have developed a mouse model of GC treatment in drinking water, using corticosterone (Cort, the endogenous GC in rodents), which recapitulates many of the side-effects in patients treated with GCs. After 24 h treatment we observe hyperphagia, leading to increased body weight from day 10 of treatment. There are changes in gene expression consistent with insulin resistance from day 2 of Cort treatment and hyperglycaemia develops by day 21. Although GCs signal peripherally, there is growing evidence that peripheral metabolic effects can be mediated by GCs acting on the neurons of the arcuate nucleus of the hypothalamus (ARC). To investigate these potential central effects, we treated with Cort for 2 days and then carried out global transcriptomic analysis of the ARC, to identify novel GC target genes. Genes which were altered included well known target genes, such as Fkbp5 and Agrp. However, we also identified novel GC target genes and interestingly, GCs upregulated type II iodothyronine deiodinase (Dio2), suggesting that GCs might increase the conversion of T4 to T3. Dio2 was of particular interest, due to its discreet localisation in the tanycytes and astrocytes of the ARC, and because elevated T3, like glucocorticoids, can influence hyperphagia and energy balance, potentially by activating AgRP neurons. Therefore, we knocked down Dio2 by injecting AAV-CRISPR-Cas9 guide RNAs bilaterally into the ARC. In these knockdown mice, we found little effect on the GC-induced metabolic phenotype. However, we observed a reduction in GC-induced Agrp expression, indicating that GC effects in the hypothalamus may be mediated in part by their actions on Dio2.

Volume 73

European Congress of Endocrinology 2021

Online
22 May 2021 - 26 May 2021

European Society of Endocrinology 

Browse other volumes

Article tools

My recent searches

No recent searches.