Peripheral mechanisms contributing to the glucocorticoid hypersensitivity in proopiomelanocortin null mice treated with corticosterone

Proopiomelanocortin (POMAC) deficiency causes severe obesity through hyperphagia of hypothalamic origin. However, low glucocorticoid levels caused by adrenal insufficiency mitigate against insulin resistance, hyperphagia and fit accretion in Pomc(-)/(-) mice. Upon exogenous glucocorticoid replacement, corticosterone-supplemented (CORT) Pomc (-)/(-) mice show exaggerated responses, including excessive fit 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 11 beta-hydroxysteroid dehydrogenase type I (11 beta-HSD1), which generates active glucocorticoids within cells, CORT-mediated induction of 11 beta-HSD1:)l mRNA levels was more pronounced in adipose tissues of Pomc (-)/(-) mice. Similarly, COR-T treatment increased lipoprotein lipase mRNA levels in all fit depots in Pomc (-)/(-) mice, consistent with exaggerated fit accumulation. Glucocorticoid receptor (GR) mRNA levels were selectively elevated in liver and retroperitoneal tat 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 insulinresistant phenotype. Furthermore, CORT induced hypertension in Pomc(-)/(-) mice, independently of adipose or liver reninangiotensin system activation. These data suggest that CORT- inducible 11 beta-HSD1 expression in fit con tributes to the adverse cardiometabolic effects of CORT in POMC deficiency, whereas higher GR levels may be more important in liver.