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The Effects of Proopiomelanocortin Deficiency on Murine Adrenal Development and Responsiveness to Adrenocorticotropin

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.

	Abstract

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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.

	Introduction

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ONCE FULLY DEVELOPED, the glucocorticoid-producing elements of the adrenal cortex are clearly dependent upon proopiomelanocortin (POMC) peptides produced by pituitary corticotrophs to maintain normal structure and function (1). Thus, hypophysectomy or down-regulation of corticotroph activity secondary to exogenous glucocorticoid both result in adrenal atrophy (1, 2). Of the POMC-derived peptides, ACTH is the classic adrenocorticotropic hormone and is the most important pituitary-derived peptide controlling steroidogenesis in the adult adrenal.

Additionally, there is evidence that POMC-derived peptides may play a role in the control of adrenal development, with exposure to these peptides during fetal and neonatal life being a potential requirement for the development of a functionally competent adrenal cortex. Yaswen et al. (3) reported that Pomc-null mice have no discernible adrenals macroscopically, only rudimentary adrenal glands microscopically, and undetectable circulating levels of both glucocorticoid and mineralocorticoid. Congenital deficiency of POMC in humans also results in hypocortisolemia and a markedly disrupted adrenal cortex (4, 5). A crucial role for ACTH in the development of the adrenal is highlighted by the anatomical findings in humans affected by familial glucocorticoid deficiency (6). Familial glucocorticoid deficiency is caused by loss of function mutations in the melanocortin 2 receptor, the endogenous ACTH receptor, resulting in adrenal unresponsiveness to ACTH and severe glucocorticoid deficiency (6). Affected adrenal glands are atrophic and have a disordered zona glomerulosa with no evidence of fasciculata or reticularis cells within the adrenal cortex.

However, evidence that POMC-derived peptides other than ACTH may be involved in the control of adrenal growth and development is also accumulating (7, 8, 9, 10, 11). In particular, some studies have proposed that a potent adrenal mitogenic peptide resides within the N-terminal 16-kDa fragment of POMC (N-POMC) (7, 8, 9, 10, 11). This large peptide is itself nonmitogenic and would require postsecretional cleavage to release the smaller active fragment. The recent description of an adrenal serine protease that can specifically cleave rat N-POMC to generate a small peptide has given considerable weight to this hypothesis (12).

We have examined the adrenal phenotype in an independent mouse model of POMC deficiency (Pomc^–/–) lacking all POMC-derived peptides. In addition, we have used mice heterozygous for this null mutation in the Pomc allele to determine whether Pomc haploinsufficiency (Pomc^+/–) results in adrenal hypofunction. Finally, we have treated these mice with a specific ACTH analog to determine whether it is capable of acting alone to restore adrenal structure and function.

	Materials and Methods

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Animal studies
POMC-deficient mice were generated on a 129/SvEv background as previously described (13). Pomc^–/– mice used in this study were offspring of either heterozygous matings or female Pomc^+/– mice/male Pomc^–/– matings. As we have previously reported (13), heterozygous matings resulted in Pomc^–/– mice being born at a frequency of 8%, rather than the 25% expected for a recessive disorder, indicating that POMC deficiency is associated with substantial prenatal lethality. Genotypes were determined by PCR of DNA from tail tissue as previously described (13). Mice were maintained under controlled temperature (22 C) and light (12 h light from 0700–1900 h) and had ad libitum access to water and standard chow (4.5% fat chow; Special Diet Services, Witham, UK). Animals were individually caged and handled daily for 1 wk before peptide administration and/or blood collection, unless otherwise stated. Trunk blood was collected within 1 min of initial handling in all experiments. All animal protocols used in these studies were approved by the United Kingdom Home Office.

Unstimulated hormone levels
Blood for corticosterone was collected at the indicated clock time. All sampling done in dark cycle was collected using a dark room red light to minimize stress to the mice. Blood for aldosterone was collected between 1600 and 1700 h.

CRH test
Two-month-old male wild-type and Pomc^+/– mice were subcutaneously injected at 0900 h with either 1 µg of CRH (Sigma-Aldrich, Poole, UK) or saline. Blood was collected after 30 min.

ACTH test
Two-month-old male wild-type and Pomc^+/– mice were ip injected at 0900 h with either ACTH_1–24 (Sigma-Aldrich) at a dose of 10 mg/kg or saline. Blood was collected after 60 min.

Depot ACTH administration
Three-month-old male wild-type and Pomc^–/– mice were sc injected once daily at 1800 h for 10 d with either 30 µg of Depot Synacthen (Alliance Pharmaceuticals, Wiltshire, UK) or saline (sham injection). Blood was collected at 0900 h on the day after the last injection.

Histology and immunohistochemistry
Adrenal glands were rapidly dissected, cleaned of fat, and weighed. Glands that were to be used for histology were left uncleaned and attached to kidney and placed in 4% paraformaldehyde overnight at 4 C. Tissues were dehydrated and embedded in paraffin, and 7-µm sections were cut and stained with hematoxylin and eosin using standard protocols.

For proliferative cell nuclear antigen (PCNA) immunohistochemistry, paraffin-embedded sections were rehydrated, boiled in 10 nM sodium citrate (pH 6.0) for 5 min, blocked with 0.3% hydrogen peroxide in methanol for 10 min, and incubated at 4 C overnight with a rabbit polyclonal antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) at a dilution of 1:100 in a blocking buffer. Bound antibody was detected using the Immunocruz Kit (Santa Cruz Biotechnology) according to the manufacturer’s protocol. Sections were counterstained with hematoxylin.

To assess response to ACTH, hematoxylin and eosin-stained adrenal glands were examined under standard light microscopy using x400 magnification. Cell nuclei within the cortical region of three independent sections from three different animals per group were counted.

Hormone assays
Plasma corticosterone and aldosterone were determined using commercially available kits according to the manufacturers’ protocols (corticosterone, OCTEIA kit; Immunodiagnostic Systems Limited, Tyne and Wear, UK; and aldosterone, ¹²⁵I RIA kit; Diagnostics Products Corp., Los Angeles, CA).

Statistics
All data reported are mean ± SEM unless otherwise reported. Analysis was by paired or unpaired Student’s t test using Prism software (GraphPad Software Inc., San Diego, CA). Diurnal variation was analyzed by two-way ANOVA. Results were considered statistically significant at P < 0.05.

	Results

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Pomc^–/– mice have small adrenal glands with disordered cortical architecture
Three-month-old Pomc^–/– mice all had macroscopically detectable adrenal glands, but they were significantly smaller than those found in wild-type littermates (mean weight of gland, 0.5 ± 0.1 vs. 2.1 ± 0.1 mg, respectively; P < 0.001; Fig. 1A). Microscopically, they had a distinct cortex and medulla, although the normal cortical architecture was lost with no clearly distinguishable zona fasciculata or glomerulosa (Fig. 1F). On hematoxylin and eosin staining, the adrenal medulla was clearly present in Pomc^–/– mice, although reduced in size compared with wild-type mice. Pomc^+/– mice also had smaller glands than wild-type animals (1.8 ± 0.1 vs. 2.1 ± 0.1 mg, respectively; P < 0.05; Fig. 1A), but the gross histological appearance was identical to that of wild-type mice.

View larger version (91K): [in this window] [in a new window]   FIG. 1. A, Mean size of adrenal gland in 3-month-old male mice (*, P < 0.05; **, P < 0.01). Appearance of wild-type (B–D) and mutant (E–G) adrenal gland. Macroscopic (B and E; magnification, x20; scale bar, 1 mm) and microscopic hematoxylin and eosin staining (C and F: magnification, x200; and D and G: magnification, x400; scale bar, 1 mm).

View larger version (13K): [in this window] [in a new window]   FIG. 2. A, Diurnal variation in wild-type and heterozygous 2-month-old male mice. Each point represents data from six mice. Plasma corticosterone in Pomc–/– was below detectable limit of assay. B, Basal plasma aldosterone in wild-type, heterozygous, and mutant mice (+/+, n = 7; +/–, n = 7; and –/–, n = 6; *, P < 0.05; **, P < 0.01; ***, P < 0.001).

View larger version (11K): [in this window] [in a new window]   FIG. 3. Corticosterone response after CRH (A) or ACTH (B) in wild-type (clear bar) or heterozygous (dark bar) 2-month-old male mice. Each bar represents data from six mice. *, P < 0.05.

View larger version (31K): [in this window] [in a new window]   FIG. 4. Adrenal response to ACTH. A, Weight of single adrenal gland after sham or ACTH treatment in wild-type and mutant mice (n = 4 in each group; *, P < 0.05). Macroscopic (B; magnification, x20) and microscopic (C; magnification, x200) appearance of adrenal gland from Pomc–/– mouse after 10 d of depot ACTH. Scale bar, 1 mm. cx, Cortex; m, medulla; zf, zona fasciculata; zg, zona glomerulosa.

View larger version (84K): [in this window] [in a new window]   FIG. 5. A, Cell count of hpf within zona fasciculata of adrenals from wild-type and mutant mice after sham and ACTH treatment. *, P < 0.05. Immunohistochemistry for proliferative marker PCNA in wild-type (B and D) and knockout (C and E) mice after sham injection (B and C) or ACTH (D and E). Arrows indicate positively stained nuclei. zg, Zona glomerulosa; zf, zona fasciculata.

View larger version (10K): [in this window] [in a new window]   FIG. 6. Plasma corticosterone after ACTH treatment in Pomc–/– mice. Plasma corticosterone in sham-treated Pomc–/– mice was below the detection limit of assay (n = 4 in each group; **, P < 0.01). nd, Not detectable; ns, not significant.

	Discussion

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The adrenal phenotype in the strain of Pomc-null mice described here differs significantly from previous reports of congenital POMC deficiency in mice (3, 14). All the homozygous mutant mice we examined had visible adrenal glands, which, despite being markedly small and highly dysmorphic, clearly had both cortex and medulla. The mice reported by Yaswen et al. (3) had no macroscopically visible adrenal tissue, and the rudimentary gland that was seen microscopically had no clearly discernible cortical and medullary zones. One relatively trivial potential reason for the differences between the two studies is the fact that these mice develop progressive and severe obesity, and the large amount of abdominal fat can make adrenals hard to locate. Our study used younger mice than Yaswen et al. (3 vs. 6 months, respectively) that would have been less obese, and this may have made localization easier. Indeed, since their first report in 1999, Hochgeschwender et al. (15) have subsequently reported the presence of adrenal glands in these mice, with reduced size and altered cellular composition at pre- and early postnatal stages.

The absence of corticosterone in our Pomc-null mice is consistent with the findings of Yaswen et al. (3) and is not unexpected given the central role of ACTH and the melanocortin 2 receptor in glucocorticoid biosynthesis. However, the presence of detectable circulating aldosterone contrasts with the previous knockout mouse model, which reported undetectable aldosterone, a finding that might be thought to support the concept of a failure of adrenal development in mice congenitally deficient in POMC because it is known that the major regulators of aldosterone production from the mature adrenal are not POMC derived. Humans affected by congenital POMC deficiency are hypocortisolemic but have normal aldosterone levels (5), which is indicative of a normally functioning zona glomerulosa. Further, postmortem studies in such subjects have revealed structurally intact zona glomerulosa and adrenal medulla but an absence of zona fasciculata and reticularis (5). Thus, the presence in our mice of discernible adrenal tissue with a disordered cortex but a clear cortical/medullary demarcation and detectable mineralocorticoid suggest that the structural and functional sequelae of congenital POMC deficiency seen in our knockout model resemble much more closely those seen in humans. Why the two POMC knockout models differ in terms of aldosterone levels is not entirely clear but may relate to issues such as assay type, timing of samples, and age of mice at time of study.

Of note, we have demonstrated that Pomc haploinsufficiency significantly reduces corticosterone production throughout the diurnal cycle, indicating that for fully normal function, the HPA axis requires two full copies of the Pomc gene. In addition, we have demonstrated that Pomc heterozygosity significantly blunts the response of the HPA axis to both CRH and ACTH. Yaswen et al. (3) also reported that heterozygous mice have a reduced corticosterone level, although it is uncertain at what time of day these samples were taken.

An important question that has not previously been answered with confidence is the extent to which there is a developmental period during which the creation of a functionally competent adrenal cortex is dependent on exposure to POMC-derived peptides. A second related question is whether or not ACTH alone is capable of promoting the growth and development of an adrenal gland or whether there might be an additional requirement for other peptides derived from POMC. Smart and Low (14) have recently back-crossed the Pomc mutant allele from the 129/SvEv strain used by Yaswen et al. onto a C57BL/6 background. These mice had undetectable corticosterone but did have identifiable, severely hypoplastic adrenals, indicative of the effect genetic background can have on phenotype. However, when these mice were treated with 1 µg of ACTH_1–24 twice daily by ip injection for 2 wk, there was no increase in corticosterone production. This result led these authors to conclude that the development of a functionally competent adrenal cortex might be dependent on exposure to POMC-derived peptides in fetal and or neonatal life. In contrast to Smart and Low, the administration of a highly selective ACTH analog (Depot Synacthen) to our Pomc^–/– mice for 10 d resulted in the development of an adrenal gland that was indistinguishable from wild-type gland in terms of size, morphology, and glucocorticoid production. This difference may be because the ACTH in our study was administered at a higher dose and in the form of a sc depot preparation.

Histological and immunohistochemical analysis show this response as being primarily hypertrophy rather than hyperplasia, which is indicative of a role for ACTH in adrenocortical differentiation of cells already present in the Pomc-null adrenal. However, at present, it is unknown whether more prolonged treatment could also result in cell proliferation.

Nevertheless, our data show that in mice that lack all endogenous POMC-derived peptides throughout uterine and postnatal life, ACTH alone can transform previously dysmorphic, hypofunctional adrenals into glands capable of synthesizing corticosterone at levels close to those of wild-type mice. The finding that plasma aldosterone levels were detectable but reduced in Pomc-null animals but that these levels did not increase after ACTH administration is intriguing and requires further exploration.

Finally, recent studies by Bicknell et al. (12) strongly suggest that adrenal growth, at least under certain circumstances, may require not only ACTH but also a peptide or peptides derived from the N terminus of POMC, whose bioactivity is liberated by the actions of an adrenal-specific protease. This phenomenon was demonstrated to be particularly involved in situations such as the compensatory growth of the remaining adrenal in response to unilateral adrenalectomy. Although our studies were not designed to test the hypothesis that compensatory adrenal growth might require N-terminal POMC-derived peptides, it is notable that we were able to restore structure and function to the adrenal gland in the absence of any POMC-derived peptide other than a highly specific ACTH analog. The POMC-deficient model will be very useful in the future to more directly test hypotheses regarding the requirement for other peptide elements of the Pomc gene in adrenal structure, growth, and function.

	Footnotes

 
This work was supported by the United Kingdom Medical Research Council and a Raymond and Beverly Sackler Fellowship (to A.P.C.).

Abbreviations: HPA, Hypothalamic-pituitary-adrenal; hpf, high-power field; PCNA, proliferative cell nuclear antigen; POMC, proopiomelanocortin.

Received April 16, 2004.

Accepted for publication June 23, 2004.

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