Central dysregulation of the hypothalamic-pituitary-adrenal axis in neuron-specific proopiomelanocortin-deficient mice.
Endocrinology
; 148(2): 647-59, 2007 Feb.
Article
em En
| MEDLINE
| ID: mdl-17095588
ABSTRACT
Proopiomelanocortin (POMC) is synthesized predominantly in pituitary corticotrophs, melanotrophs, and arcuate hypothalamic neurons. Corticotroph-derived ACTH mediates basal and stress-induced glucocorticoid secretion, but it is uncertain whether POMC peptides produced in the brain also regulate the hypothalamic-pituitary-adrenal axis. To address this question, we generated neuron-specific POMC-deficient mice by transgenic (Tg) replacement of pituitary POMC in a global Pomc(-/-) background. Selective restoration of pituitary POMC prevented the adrenal insufficiency and neonatal mortality characteristic of Pomc(-/-) mice. However, adult Pomc(-/-)Tg/+ mice expressing the pituitary-specific transgene exhibited adrenal cortical hypertrophy, elevated basal plasma corticosterone, elevated basal but attenuated stress-induced ACTH secretion, and inappropriately elevated CRH expression in the hypothalamic paraventricular nucleus. In addition, Pomc(-/-)Tg/+, Pomc(+/-)Tg/+, and Pomc(+/-) mice, which all displayed varying degrees of elevated CRH, frequently developed melanotroph adenomas after 1 yr of age, whereas Pomc(-/-) mice, with maximal CRH expression and glucocorticoid disinhibition, developed corticotroph and melanotroph adenomas. These results indicate that neuronal POMC peptides are necessary to regulate CRH within physiological limits and that a chronic reduction or absence of hypothalamic POMC leads to trophic stimulation of pituitary cells directly or indirectly through elevated CRH levels.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sistema Hipófise-Suprarrenal
/
Encéfalo
/
Pró-Opiomelanocortina
/
Sistema Hipotálamo-Hipofisário
Tipo de estudo:
Etiology_studies
Limite:
Animals
Idioma:
En
Revista:
Endocrinology
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Estados Unidos