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Central Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Neuron-Specific Proopiomelanocortin-Deficient Mice

Vollum Institute (J.L.S., V.T., V.O.-C., M.J.L.), Center for the Study of Weight Regulation and Associated Disorders (V.T., V.O.-C., M.J.L.), and Department of Behavioral Neuroscience (M.J.L.), Oregon Health & Science University, Portland, Oregon 97239

Address all correspondence and requests for reprints to: Malcolm J. Low, 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. E-mail: low{at}ohsu.edu.

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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