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Departments of Clinical Biochemistry and Medicine (A.P.C., B.G.C., G.S.H.Y., K.S., S.J.P., D.H., S.O.), Cambridge Institute for Medical Research, Addenbrooke’s Hospital, Cambridge CB2 2XY, United Kingdom; and Paradigm Therapeutics (R.R.T.), Cambridge CB4 0WA, United Kingdom
Address all correspondence and requests for reprints to: Stephen O’Rahilly, University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Cambridge CB2 2QR, United Kingdom. E-mail: sorahill{at}hgmp.mrc.ac.uk.
The mature adrenal cortex is dependent upon proopiomelanocortin (POMC)-derived peptides for the maintenance of its size, structure, and endocrine function. Recent studies in mice genetically deficient in POMC have suggested that early exposure to POMC-derived peptides might also be necessary for the development of a functionally competent adrenal. We examined adrenal morphology and function in an independent line of mice lacking all POMC-derived peptides (Pomc–/–). Adrenal glands were found in all mice, although the glands of Pomc–/– mice had markedly reduced weight compared with control animals (0.5 ± 0.1 vs. 2.1 ± 0.1 mg, respectively; P < 0.05) and had disrupted cortical architecture. In Pomc–/– mice, plasma corticosterone was undetectable, and plasma aldosterone was significantly reduced compared with wild-type mice (498 ± 88 vs. 1845 ± 168 nmol/liter, respectively; P < 0.001). Heterozygous mice (Pomc+/–) had smaller adrenal glands with significantly lower levels of corticosterone both basally and in response to CRH and ACTH than wild-type mice, indicating that two functional copies of the Pomc gene are necessary to support the fully normal function of the hypothalamic-pituitary-adrenal axis. Three-month-old Pomc–/– mice were treated for 10 d with a highly specific ACTH analog. This treatment restored adrenal weight, cortical morphology, and plasma corticosterone to the levels seen in wild-type littermates. In conclusion, murine adrenal glands can develop without exposure to endogenous POMC-derived peptides during fetal and neonatal life. Although such glands are atrophic and hypofunctional, exposure to ACTH alone can restore their size, morphology, and corticosterone secretion.
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