Central dysregulation of the hypothalamic-pituitary-adrenal axis in neuron-specific proopiomelanocortin-deficient mice.
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.
Smart
James L
JL
Center for the Study of Weight Regulation and Associated Disorders, L-481, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
Tolle
Virginie
V
Otero-Corchon
Veronica
V
Low
Malcolm J
MJ
D000236:Adenoma / Q000209:etiology / Q000473:pathology; D000302:Adrenal Cortex / Q000473:pathology; D000309:Adrenal Insufficiency / Q000209:etiology / Q000401:mortality; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D005260:Female; D006984:Hypertrophy; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology* / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D052717:Melanotrophs / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D010902:Pituitary Gland / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000209:etiology / Q000473:pathology; D010913:Pituitary-Adrenal System / Q000502:physiology* / Q000503:physiopathology; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology
D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D003345:Corticosterone