The effects of proopiomelanocortin deficiency on murine adrenal development and responsiveness to adrenocorticotropin.
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.
Coll
Anthony P
AP
Department of Medicine, Box 232, Addenbrooke's Hospital, Cambridge CB2 2QR, United Kingdom.
Challis
Benjamin G
BG
Yeo
Giles S H
GS
Snell
Katherine
K
Piper
Sarah J
SJ
Halsall
David
D
Thresher
Rosemary R
RR
O'Rahilly
Stephen
S
D000302:Adrenal Cortex / Q000187:drug effects / Q000473:pathology; D000311:Adrenal Glands / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism; D003366:Cosyntropin / Q000494:pharmacology*; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000172:deficiency*
D003366:Cosyntropin; D011333:Pro-Opiomelanocortin; D003345:Corticosterone