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Title: Peripheral Mechanisms Contributing to the Glucocorticoid Hypersensitivity in
Authors: Michailidou, Zoi
Coll, Anthony P
Kenyon, Christopher J
Morton, Nicholas M
O'Rahilly, Stephen
Seckl, Jonathan R
Chapman, Karen E
Issue Date: 2007
Citation: Journal of Endocrinology (2007) 194, 161-170 
Publisher: Society for Endocrinology
Abstract: 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.
Sponsor(s): Wellcome Trust
Keywords: Cardiovascular science
URI: doi :10.1677/JOE-07-0090
Appears in Collections:Molecular, Genetic and Population Health Sciences publications

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