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Rudolf Magnus Institute for Neurosciences, Department of Medical Pharmacology, Utrecht University, 3508 TA Utrecht, The Netherlands; and the Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, Department of Medicine, and the Tupper Research Institute, Tufts University School of Medicine and New England Medical Center Hospitals (M.L.E., J.B.T.), Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Dr. Roger A. H. Adan, Rudolf Magnus Institute for Neurosciences, Department of Medical Pharmacology, Utrecht University, P.O. Box 80040, 3508 TA Utrecht, The Netherlands. E-mail: R.A.H.Adan{at}med.ruu.nl
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH and ACTH-related peptides) influence the
physiological functions of certain peripheral organs, including
exocrine and endocrine glands. This study was designed to determine the
identity and anatomical localization of the melanocortin receptors
(MC-R) expressed in these organs in the rat. MC5-R messenger RNA was
found in exocrine glands, including lacrimal, Harderian, preputial, and
prostate glands and pancreas, as well as in adrenal gland, esophagus,
and thymus, as demonstrated by ribonuclease protection assays. In
exocrine glands, MC5-R messenger RNA expression was restricted to
secretory epithelia. MC-R protein was likewise present in secretory
epithelia of exocrine glands, as determined by 125I-labeled
[Nle4,D-Phe7]MSH
([125I]NDP-MSH) binding and autoradiography in tissue
sections. Specific [125I]NDP-MSH binding was also
observed in adrenal cortex, thymus, spleen, and esophageal and
trachealis muscle. MC receptors in these sites are accessible to
circulating MC-R agonists in vivo, as specific binding
of [125I]NDP-MSH was observed in exocrine and adrenal
glands after systemic injection in vivo. Taken together,
these findings show that the MC5 receptor is commonly and selectively
expressed in exocrine glands and other peripheral organs. Based on
these findings and compelling evidence from other studies, a functional
coherence is suggested between central and peripheral actions of
melanocortins and melanocortin receptors in physiological functions,
including thermoregulation, immunomodulation, and sexual behavior. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH and
ACTH are known for their abilities to stimulate pigmentation and
adrenal glucocorticoid secretion, respectively. Melanocortins can also
affect the functions of a wide range of peripheral organs, including
exocrine and endocrine glands and cells of the immune system (1, 2).
Previously, it was demonstrated that a radioiodinated melanocortin
agonist, [Nle4,D-Phe7]MSH
(NDP-MSH), bound specifically in a number of putative peripheral target
organs of rats and mice in vivo, particularly in the
exocrine lacrimal and preputial glands (3). These findings implied the
presence of melanocortin receptors in these organs. In the lacrimal
gland, MSH stimulates acinar secretion (4, 5), and high levels of
adenylate cyclase-coupled melanocortin receptors were demonstrated in
acinar cells by classical methods (6, 7). Furthermore, melanocortins
have trophic and other actions in vivo on exocrine glands,
including the preputial and prostate glands (8, 9, 10). Melanocortin
receptors in these tissues of similar function might provide a common
molecular substrate for a group of related biological actions of
melanocortins.
Five different melanocortin receptor (MC-R) subtypes, designated MC1-R
through MC5-R, have been cloned and characterized. The MC1 and MC2
receptors are believed to be the classical melanocytic MSH and
adrenocortical ACTH receptors, respectively (2, 11, 12). Expression of
MC4-R appears to be restricted to the nervous system (13, 14), and
messenger RNA (mRNA) encoding MC3-R is also principally present in the
brain, although low levels of expression have been reported in placenta
and gut tissues (15, 16, 17). MC5-R is the only MC-R subtype for which
widespread mRNA expression has been detected among peripheral tissues
(18, 19, 20), thus identifying this receptor as a candidate mediator of
many previously recognized peripheral melanocortin actions.
The present studies were designed to identify the subtype of MC-R that may mediate the actions of melanocortins in exocrine glands and several other putative peripheral target tissues of the rat and to determine the anatomical localization within these tissues. The studies focused on organs previously found to exhibit specific NDP-MSH binding (3) and extended to several additional targets of interest, such as the prostate gland, lymphoid organs, and skeletal muscle. The results show that the MC5-R subtype is commonly and selectively expressed in these tissues in the rat. The findings support a potential role of MC5-R in epithelial cell function in exocrine and endocrine glands and support a direct immunomodulatory role of melanocortins in lymphoid organs. Indeed, while this work was in progress, Chen et al. reported the expression of functional MC5-R in exocrine glands of the mouse and exocrine dysfunction after targeted genetic disruption of the MC5-R gene (21). In accordance with those findings, the present studies suggest a functional role for MC5-R in exocrine glands as well as adrenal cortex and certain other tissues in the rat.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P]CTP; 800
Ci/mmol; ICN, Costa Mesa, CA) were transcribed in vitro from
the following templates: a 312-bp rat MC3-R complementary DNA (cDNA)
fragment (from +592 to +904 bp relative to translation initiation), a
180-bp rat MC4-R cDNA fragment (from +426 to +606 bp), a 198-bp rat
MC5-R cDNA fragment (from +402 to +600 bp), and a 55-bp rat
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) cDNA fragment (from
+178 to +233 bp). Total RNA samples (35 µg) were incubated overnight
at 50 C with 5,000 cpm antisense MC-R probe and 50,000 cpm antisense
GAPDH probe. After digestion with RNase Cocktail (Ambion, Houston, TC;
diluted to a final concentration of 40 µg/ml RNase A and 800 U/ml
RNase T1), the samples were analyzed by electrophoresis on
a denaturing 6% polyacrylamide gel and autoradiographed.
In situ hybridization
Cryostat sections (20 µm) on polylysine-coated slides were
fixed in 4% paraformaldehyde in PBS for 5 min, washed, pretreated with
0.25% acetic anhydride in 0.1 M triethanolamine, and
dehydrated in graded ethanol. 35S-Labeled antisense and
sense RNA probes ([-35S]UTP; 800 Ci/mmol; ICN) were
transcribed from the MC receptor cDNA templates described in the
previous section. The sections were hybridized overnight at 55 C with
106 cpm probe in buffer containing 50% formamide and
2 x SSC (standard saline citrate). Slides with adjacent sections
were hybridized with sense probe to determine the specificity of
hybridization. After hybridization, the sections were washed in 50%
formamide-2 x SSC at 65 C, treated with RNase A (20 µg/ml) for
20 min at 37 C, washed in 50% formamide-2 x SSC at 65 C and
0.1 x SSC at room temperature, and dehydrated. The slides were
coated with liquid autoradiography emulsion (NTB-2, Eastman Kodak,
Rochester, NY) and exposed for 2–4 weeks. After development, the
sections were counterstained with cresyl violet.
In vitro [125I]NDP-MSH binding and
autoradiography
In vitro tissue binding and autoradiography were
performed as previously described (6), using the synthetic agonist
[125I]NDP-MSH, which binds with high affinity to MC1-R,
MC3-R, MC4-R, and MC5-R. The results for each organ studied represent a
total of three to seven rats, except for esophagus (n = 1).
Briefly, tissues were rapidly removed, frozen on dry ice, and stored at
-80 C. Serial 8-µm cryostat sections were prepared, mounted, and
dried under vacuum at 4 C. NDP-MSH was radioiodinated (6, 23), and
binding incubations were performed as described previously (6).
Briefly, the unfixed frozen sections were subjected to a preincubation
wash, 2-h exposure to [125I]NDP-MSH (4–7 x
105 dpm/ml) in binding buffer, a series of brief washes to
stop the binding reaction, rapid air-drying, fixation in
paraformaldehyde vapors, and defatting. Autoradiography was performed
by two methods. Slides were exposed directly to x-ray film
[3H-Ultrofilm, LKB (Rockville, MD) or Biomax MR, Kodak] for 1–3
weeks at room temperature, or for visualization of MC-R distribution at
the microscopic level, slides were coated with liquid photographic
emulsion (NTB-2, Kodak) and exposed for 3–21 days at room temperature.
For each slide incubated in the presence of [125I]NDP-MSH
only, a slide containing adjacent serial sections was exposed to
[125I]NDP-MSH in the presence of 1 mM MSH
to determine the specificity of tracer binding, and a slide containing
adjacent sections was subjected to fixation and hematoxylin-eosin
staining for anatomical reference.
In vivo [125I]NDP-MSH tissue distribution
and autoradiographic localization
Rats (n = 6) were anesthetized with sodium pentobarbital
(35 mg/kg) and injected via the left jugular vein with a solution
containing [125I]NDP-MSH (6.7 x 105
dpm) in 200 µl 0.15 M NaCl-10 mM sodium
phosphate, pH 7.4. To determine the specificity of
[125I]NDP-MSH localization, the injectates for half of
the rats (n = 3) also contained 0.5 mg MSH, an amount of the
native agonist sufficient to compensate for both the greater MC-R
binding affinity and the greater in vivo stability of
NDP-MSH. After 10 min, the rats were killed, and the tissues of
interest were harvested rapidly and processed for cryosectioning and
x-ray film autoradiography as described above for in vitro
binding experiments. Sections taken from rats treated with tracer alone
and from rats treated with tracer plus MSH were mounted in
alternating rows on each slide to ensure identical autoradiographic
exposure conditions.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, MC5-R mRNA was detected in exocrine
glands, including the extraorbital lacrimal, Harderian, preputial, and
prostate glands. MC5-R transcripts were also demonstrated in pancreas,
adrenal glands, esophagus, and thymus (Fig. 1A). Among these tissues,
the highest levels of MC5-R mRNA were found in lacrimal, Harderian, and
preputial glands. In contrast, neither MC3-R nor MC4-R mRNA was
detectable in any of the exocrine glands, pancreas, or esophagus (Fig. 1B). In the thymus, MC3-R, but not MC4-R, transcripts were also
detected (Fig. 1B) and appeared to be expressed somewhat more
abundantly than MC5-R mRNA.
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), in contrast with the reported high levels of MC5-R
transcripts in mouse skeletal muscle (19). Nevertheless, MC5-R mRNA was
readily detected in mouse hindlimb muscle using the present assay (data
not shown), indicating that the difference in skeletal muscle MC5-R
mRNA content between mice and rats was due to a true species difference
rather than to interlaboratory differences in technique.
Localization of MC5-R mRNA in exocrine glands
The intraorgan distribution of MC5-R mRNA was determined by
in situ hybridization in tissues shown to contain MC5-R
transcripts by RNase protection assays. In the lacrimal gland, MC5-R
mRNA was abundantly expressed throughout the acinar secretory
epithelium of the entire organ, but was absent from ducts and stromal
elements (Fig. 2, A and B). In the
preputial gland, high level MC5-R hybridization was likewise restricted
to exocrine secretory units (Fig. 2, D and E). In contrast, no
hybridization was detectable in either lacrimal or preputial glands
using a MC3-R probe (Fig. 2, C and F). Using sense MC3-R or MC5-R
probe, no hybridization was detected in either lacrimal or preputial
glands, demonstrating the specificity of hybridization (not shown). In
tissues with relatively low MC5-R mRNA expression, such as prostate or
pancreas, no specific MC5-R hybridization was detected (not shown).
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, left
panel, and Fig. 4). In contrast,
specific [125I]NDP-MSH binding was absent from the
dorsolateral part of the prostate, a histologically similar, but
functionally, distinct tissue (Fig. 4C). In the preputial and prostate
glands (Figs. 3 and 4) and in the lacrimal gland as reported previously
(6, 7) (not shown), the autoradiographic signal was localized over the
secretory epithelial cells and was lacking from the connective tissue
elements and other stroma. A moderate level of specific binding was
also found in pancreas (Fig. 3, left panel), which appeared
to reflect binding to the exocrine portion of the gland because of the
relatively uniform distribution of signal over the tissue and the
scarcity or complete absence of islets in these regions. It was not
determined whether MC-R proteins were present in pancreatic islets.
[125I]NDP-MSH binding in the exocrine glands was
inhibited by excess MSH, demonstrating the specificity of binding
(Fig. 3, right panels). In the Harderian gland, a fairly
high level of [125I]NDP-MSH binding was observed, but
this binding could not be inhibited by excess MSH or NDP-MSH (not
shown). This might be due to the presence of intracellular pigments or
other factors that bind tracer nonspecifically, overriding the specific
binding signal, rather than to an absence of specific melanocortin
receptors. This reasoning is based on the observations that high levels
of MC5-R transcripts and tissue binding were found, and that high
levels of MSH-inhibitable [125I]NDP-MSH localization
were readily demonstrated in Harderian glands of both rats and mice
in vivo (3), a situation in which the integrity of the
plasma membrane prevents direct tracer access to the intracellular
compartment.
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, left
panels). The specificity of adrenal [125I]NDP-MSH
binding was shown by its inhibition in the presence of MSH (Fig. 5, right panels). There was no autoradiographic evidence of
[125I]NDP-MSH binding in the thyroid and parathyroid
glands (not shown). In contrast, in the same tissue sections containing
the thyroid, robust binding of [125I]NDP-MSH was observed
in the longitudinal muscle layer of the esophagus and in the smooth
muscle fibers of the trachealis muscle (Fig. 6, left panel). No binding was
observed in the presence of excess MSH (Fig. 6, right
panel). A low level of specific binding was evident in the
sternothyroid muscle (not shown).
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, A and B,
left panels). In the spleen, specific tracer binding was not
detectable macroscopically by film autoradiography, but at the
microscopic level, emulsion autoradiography revealed scattered foci of
specific [125I]NDP-MSH binding, primarily in the tissue
adjacent to either blood vessels or trabecular septa (Fig. 7C, left panel). The specificity of binding was indicated by
inhibition with excess MSH (Fig. 7, right panels). No
autoradiographic evidence of [125I]NDP-MSH binding was
observed in liver, seminal vesicles, or brown fat (not shown).
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, A and B, left panels),
ventral prostate lobe (not shown), and exocrine pancreas (Fig. 8C, left panel) and was found in the secretory epithelia in each
of these tissues. Specific [125I]NDP-MSH localization
also occurred in the adrenal zona glomerulosa (Fig. 8, D and E,
left panels). The specificity of tracer localization in each
of these sites was indicated by the reduction of autoradiographic
signal in rats that received coinjected MSH (Fig. 8, right
panels).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous in vitro and in vivo studies have shown
that melanocortins influence the functions of exocrine glands. In
lacrimal acinar cells, melanocortins stimulate protein and peroxidase
secretion (4, 5, 7), and in sebaceous, preputial and Harderian glands,
melanocortins stimulate sebum secretion, dermal and preputial
lipogenesis (9, 10), and porphyrin biosynthesis (24), respectively. In
preputial and prostate glands, MSH synergizes with testosterone to
exert a trophic effect (8). The present finding that the MC5-R is
commonly expressed in secretory epithelia of multiple exocrine glands
in rats supports the hypothesis that melanocortins may act directly via
MC5-R at these sites to regulate exocrine functions. Indeed, while the
present study was being completed, it was reported that disruption of
the MC5-R gene in mice resulted in multiple exocrine deficiencies,
demonstrating unequivocally that expression of MC5-R is required for
normal exocrine gland function (21, 25). Thus, the present findings are
in strong agreement with those of Chen et al. (21, 25) and
support a similar role for MC5-R in the regulation or maintenance of
exocrine gland functions in rats.
Taken together, the findings of MC5-R expression (21, 25; present study) and its functional role (21, 25) in multiple exocrine glands of rodents are suggestive of a fairly well conserved role of melanocortins and MC5-R in controlling the functions of certain exocrine glands. However, the present findings demonstrate a marked tissue specificity of MC-R expression even within the secretory epithelia of highly related exocrine tissues, as MC-R were abundant in the ventral lobe, but undetectable in the dorsolateral lobe, of the prostate gland. The latter findings are interesting considering that the ventral and dorsolateral lobes also show dramatic differences in steroid hormone metabolism and in susceptibility to steroid-induced dysplasias and carcinogenesis (26).
The potential of melanocortins to modulate exocrine gland functions directly through MC5-R may reflect a peripheral component that cooperates with central melanocortin actions to influence coordinated homeostatic processes. In mice, targeted genetic disruption of the MC5-R gene produced thermoregulatory insufficiency, attributed to deficient production of hair coat lipids due to sebaceous gland dysfunction (21, 25). Similarly, the release of lipids and pigments from the Harderian gland has been implicated in thermoregulation in gerbils (27). Thus, melanocortin-stimulated and MC5-R-mediated lipogenesis and exocrine secretion from both sebaceous and Harderian glands may similarly play a thermoregulatory role in the rat. The release and spreading over the skin of Harderian secretory products to regulate body temperature require a specific behavioral repertoire, i.e. grooming behavior (27). Grooming itself is stimulated by centrally acting melanocortins, a classical behavioral melanocortin effect that is probably mediated by central MC4-R (28). Furthermore, melanocortins have also been shown to act via MC-R located in the central nervous system to modulate thermoregulation and fever (23). These multiple lines of evidence suggest that melanocortins may act at both peripheral and central levels to cooperatively influence thermoregulation.
Similarly, melanocortins appear to act centrally to influence sexual
behavior (29, 30), and MSH acts peripherally to regulate lipogenesis
and secretion of sexual attractants from the preputial gland (31, 32),
presumably by activating MC5-R expressed in this organ. Indeed,
preputial lipogenesis was decreased in MC5-R-deficient mice (21). Thus,
based on multiple lines of evidence derived from previous in
vivo studies and the present data confirming MC-R expression in
peripheral organs, a functional coherence between peripheral and
central melanocortin actions is suggested for multiple physiological
functions, including temperature regulation and sexual behavior.
The present findings also support a direct role for MC5-R in adrenal
cortical functions. The specific NDP-MSH binding in the zona
glomerulosa probably represents MC5-R protein. MC5-R transcripts were
previously demonstrated in this region in the rat by in situ
hybridization (18), and the present study confirmed the expression of
MC5-R-encoding transcripts in rat adrenal glands. Furthermore,
[125I]NDP-MSH does not bind to MC2-R (33). Therefore,
these findings support the earlier suggestion (18) that
melanocortin-stimulated aldosterone secretion in the zona glomerulosa
(34, 35) may be mediated by MC5-R. In contrast, the lack of detectable
MC-R mRNA and [125I]NDP-MSH binding in the thyroid gland
suggests that MC-R do not mediate the reported thyrotropic effects of
MSH directly (36).
In the thymus, the presence of both MC3-R and MC5-R suggests that melanocortins may have multiple direct immunomodulatory effects. Melanocortins can modulate immune responses in vivo (37), and their suppressive effects on mitogen- and cytokine-induced thymocyte proliferation in vitro exhibit a complex dose-response (38) that might be explained in part by the presence of multiple MC-R subtypes, with different pharmacological properties. As melanocortins can act centrally to influence immune and inflammatory responses (37, 39), the presence of MC-R in lymphoid organs, including thymus and spleen, combined with these earlier findings further support the concept that melanocortins may act cooperatively at both central and peripheral levels to influence physiological processes.
The potential of melanocortins to directly regulate exocrine glands and
other peripheral targets through melanocortin receptors implies the
existence of a physiological source of endogenous melanocortin
agonists. Accordingly, blood-borne pituitary MSH or ACTH, both of
which are potent MC5-R agonists (18, 19, 20), may provide hormonal input to
the peripheral MC-R. Supporting this possibility is our finding that
[125I]NDP-MSH binding to the MC-R in exocrine and
adrenocortical parenchymal cells is blocked by the endogenous MC-R
agonist MSH after iv administration. Alternatively, autocrine or
paracrine release may provide a pathway for stimulation of peripheral
tissue MC-R by endogenous melanocortins. POMC transcripts and
melanocortin immunoreactivity have been described in several
MC5-R-expressing organs, including pancreas, spleen, and thymus
(40, 41, 42).
Strikingly, the present studies and findings by others (18, 21, 25) show that MC5-R are expressed in each of the three tissues that show major functional impairment in Allgrove’s syndrome: adrenal gland, lacrimal gland, and esophagus. This rare multisystem disorder is also known as triple A syndrome due to the combined presence of ACTH resistance, alacrima, and achalasia of the cardia (43). The adrenal ACTH unresponsiveness suggests a defect in MC-R function. However, ACTH (MC2) receptor defects are not the underlying cause of this disease, as no mutations could be identified in the ACTH receptor-coding region in patients with triple A syndrome (44, 45). Rather, the robust expression of MC5-R in each of the affected tissues in the rat suggests a potential involvement of MC5-R-regulated pathways in the pathogenesis of triple A syndrome. In adrenal cortex and lacrimal gland, the loss of a trophic or secretagogue function of endogenous melanocortins due to MC-R dysfunction might lead to impaired development or secretion, thus contributing to adrenal insufficiency and alacrima. Similarly, the localization of MC5-R in the longitudinal skeletal muscle of the esophagus suggests that functional defects in MC-R might contribute to achalasia. Triple A syndrome has recently been mapped to chromosome 12q13 (46). This indicates that the MC5-R, which maps to human chromosome 18p11.2 (47), is not the locus of the primary genetic defect in triple A syndrome, but, rather, that its function may be impaired by mutations in signaling or regulating factors. In this respect, adenylate cyclase type 6, which maps to chromosome 12q13 (48), might be an interesting candidate gene for triple A syndrome, because all MC receptors couple to adenylate cyclase.
In conclusion, the present findings support a direct role for MC5-R in the function of exocrine glands in the rat, in strong agreement with the recent demonstration of a functional role of the MC5-R in exocrine glands of mice (21, 25). In addition, MC5-R may be involved in other peripheral actions of melanocortins, including adrenal corticosteroid secretion. These results combined with previous lines of evidence support the concept of a functional continuity between the central and peripheral actions of melanocortins in regulating certain physiological functions, e.g. thermoregulation, sexual behavior, and immunity.
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Acknowledgments |
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Footnotes |
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Received October 27, 1997.
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