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This version published online on July 1, 2004
Endocrinology, doi:10.1210/en.2004-0491
A more recent version of this article appeared on October 1, 2004
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Submitted on April 16, 2004
Accepted on June 23, 2004

The Effects of POMC Deficiency on Murine Adrenal Development and Responsiveness to ACTH

Anthony P. Coll, Benjamin G. Challis, Giles S.H. Yeo, Katherine Snell, Sarah J Piper, David Halsall, Rosemary R. Thresher, and Stephen O'Rahilly*

Departments of Clinical Biochemistry and Medicine, Cambridge Institute for Medical Research, (A.P.C., B.G.C., G.S.H.Y., K.S., S.P., D.H., S.O'R.) Addenbrooke's Hospital, Cambridge, U.K, CB2 2XY and Paradigm Therapeutics (R.R.T.), 214 Cambridge Science Park, Milton Road, Cambridge, CB4 0WA

* To whom correspondence should be addressed. E-mail: sorahill{at}hgmp.mrc.ac.uk.

The mature adrenal cortex is dependent upon pro-opiomelanocortin (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, albeit of markedly reduced weight compared with control animals (0.5 ± 0.1 vs. 2.1 ± 0.1 mg, respectively P < 0.05) and with 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 days 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.
Key words: adrenal • adrenocorticotrophin • pro-opiomelanocortin




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