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Endocrine Unit, Queen’s Medical Research Institute, Centre for Cardiovascular Sciences, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
¹ Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, UK

(Requests for offprints should be addressed to K E Chapman; Email: karen.chapman{at}ed.ac.uk)

Proopiomelanocortin (POMC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fat accretion in Pomc^–/–mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc^–/– mice show exaggerated responses, including excessive fat accumulation, hyperleptinaemia and insulin resistance. To investigate the peripheral mechanisms underlying this glucocorticoid hypersensitivity, we examined the expression levels of key determinants and targets of glucocorticoid action in adipose tissue and liver. Despite lower basal expression of 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11ß-HSD1 mRNA levels was more pronounced in adipose tissues of Pomc^–/–mice. Similarly, CORT treatment increased lipoprotein lipase mRNA levels in all fat depots in Pomc^–/– mice, consistent with exaggerated fat accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal fat of Pomc^–/– mice but were corrected by CORT in the latter depot. In liver, CORT increased phosphoenolpyruvate carboxykinase mRNA levels specifically in Pomc^–/– mice, consistent with their insulin-resistant phenotype. Furthermore, CORT induced hypertension in Pomc^–/–mice, independently of adipose or liver renin–angiotensin system activation. These data suggest that CORT-inducible 11ß-HSD1 expression in fat contributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.

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				S. Sai, C. L. Esteves, V. Kelly, Z. Michailidou, K. Anderson, A. P. Coll, Y. Nakagawa, T. Ohzeki, J. R. Seckl, and K. E. Chapman Glucocorticoid Regulation of the Promoter of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Is Indirect and Requires CCAAT/Enhancer-Binding Protein-{beta} Mol. Endocrinol., September 1, 2008; 22(9): 2049 - 2060. [Abstract] [Full Text] [PDF]