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Department of Medical Anatomy, University of Copenhagen (N.V., P.J.L., M.T.-C.), Blegdamsvej 3, 2200 Copenhagen; and Department of Histology, Novo Nordisk A/S (P.K., M.-T.C.), 2880 Bagsvaerd, Denmark
Address all correspondence and requests for reprints to: Niels Vrang, M.D., Department of Medical Anatomy, B, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: n.vrang{at}mai.ku.dk
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Introduction |
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CART mRNA was originally isolated by PCR differential display techniques from rat striatum as a mRNA acutely up-regulated by cocaine and amphetamine administration (3). In the untreated rat, however, the majority of CART-synthesizing cells are found in the hypothalamus (3, 4, 5). Also, CART mRNA is expressed in the brain stem and spinal cord (3, 6), the anterior pituitary gland (6), the adrenal gland (6), and D cells in the pancreatic islet of Langerhans (7), pointing to widespread roles of CART in neuroendocrine and endocrine regulation. Based on the cDNA sequence, the rat CART gene yields two different transcripts (3) encoding either a short (89 residues) or a long (102 residues) peptide. However, after purification and isolation of CART peptide from different rat tissues, only forms of the short peptide were found (8). The processing of CART seems to be tissue specific, in that hypothalamic and pituitary extracts contain CART-(42–89) and CART-(49–89), whereas adrenal extracts contain CART-(1–89) and CART-(10–89) (8).
We have recently identified a naturally occurring form of hypothalamic
CART involved in regulating food intake, as intracerebroventricular
(icv) administration of recombinant CART-(42–89) inhibits food intake
in the rat (1, 9). Also, it has been reported that a synthetic peptide
fragment of CART inhibits food intake in rats (10). Supporting a
physiological role for CART peptides in regulating feeding behavior is
the observation that CART mRNA levels in the arcuate nucleus (Arc) are
influenced by metabolic state, in that fasting reduces the expression
of CART in the Arc (1). Also, in animal models of impaired leptin
signaling (ob/ob and db/db mice), CART expression
in the Arc is virtually absent. Leptin treatment of ob/ob
mice partially restores CART expression in the Arc, suggesting that
these neurons may participate in central pathways mediating the effects
of leptin on feeding, thyroid, and gonadal axis (1). The complexity of
the neurocircuitry underlying the anorectic properties of CART is
emphasized by the observation that the majority of CART-containing
neurons in the Arc also synthesize POMC (5, 11), whereas
CART-immunoreactive (-ir) neurons in the lateral hypothalamic area
costore melanin-concentrating hormone (5). The POMC-derived peptide
MSH has been shown to inhibit food intake, whereas
melanin-concentrating hormone stimulates food intake (12, 13).
As the CART receptor remains to be identified, we have mapped potential central sites of action of CART using the immediate early gene c-fos as a marker of neuronal activity (9). Central administration of CART-(42–89) induced c-Fos immunoreactivity in several hypothalamic and brain stem nuclei that play a role in autonomic and endocrine regulation, including the paraventricular nucleus of the hypothalamus (PVN) (9). Notably, CART induced expression of c-Fos immunoreactivity in areas of the PVN housing both magnocellular neurosecretory neurons as well as hypophysiotropic CRH neurons (9). These data prompted us to investigate the effects of CART on the activation of the hypothalamic-pituitary adrenal (HPA) axis as well as on the secretion of the neurosecretory peptides vasopressin (AVP) and oxytocin (OT). In addition, we have characterized phenotypically (by double and triple immunohistochemistry) the hypothalamic neurons activated by central administration of recombinant CART (42–89).
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Materials and Methods |
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Exp 1: effect of CART icv on hormone secretion and blood
glucose
Intracerebroventricular injections of CART or vehicle were
performed in the morning (between 0800–0900 h) to freely moving
conscious rats. Animals were injected with either 5 µl vehicle (KPBS;
50 mM PBS containing 0.02% potassium) or 0.5 µg CART
dissolved in 5 µl vehicle. Animals killed at time zero were not
injected and served as baseline controls. The dose of CART was chosen
on the basis of its ability to significantly inhibit food intake (5).
At 10, 20, 40, 60, 120, and 240 min after the injection of vehicle or
CART-(42–89), animals were decapitated, and trunk blood was collected
in heparinized plastic tubes. Blood glucose was measured in tail blood
obtained from rats immediately before decapitation (One Touch,
Johnson & Johnson, Miopitas, CA). The timespan from
removal of the animals from their home cages to decapitation was
approximately 1 min. Blood samples were centrifuged (3000 rpm for 10
min), and plasma was frozen until analysis of OT, AVP, and
corticosterone was performed. Plasma corticosterone was measured using
a commercially available RIA kit (Corticosterone rat, Diagnostic Products, San Diego, CA). AVP and OT were measured by RIA of
plasma extracted by means of C18 Sep-Pak
(Waters Corp., Milford, MA) cartridges according to
a previously described procedure (14). Synthetic AVP (mol wt, 1083;
Peninsula Laboratories, Inc., Belmont, CA) and synthetic
OT (mol wt, 1006; Peninsula Laboratories, Inc., Belmont,
CA) served as reference preparations. For the AVP assay, the least
detectable quantity was 0.1–0.3 pmol/liter plasma, and the intra- and
interassay coefficients of variations were 8% and 12%, respectively.
For the OT assay the least detectable quantity was 4–6 pmol/liter
plasma, and the intra- and interassay coefficients of variations were
8% and 12%, respectively.
Exp 2: c-Fos induction
On the day of the study, rats were injected icv with either
vehicle or 0.5 µg CART in 5 µl vehicle, and food was removed from
the cages (injections performed in the morning between 0800–0900 h).
Initial experiments showed no differences in the pattern of c-Fos-ir in
either the SON or the PVN across time (60–240 min postinjection) (9).
We therefore arbitrarily chose the 120 min point in the present study.
At 120 min after injection animals were anesthetized and perfused
transcardially, first with heparinized (15,000 IU/liter) KPBS, followed
by Stephanini fixative (2% paraformaldehyde in KPBS containing picric
acid, pH 7.4) for 10 min. After removal and 24 h of postfixation
in the same fixative, the brains were transferred to 30% sucrose for 2
days before being cut in the coronal plane (6 series of 40-µm thick
sections) on a freezing microtome.
Immunohistochemistry
All reactions were carried out on free floating sections. The
protocol and data for single immunohistochemistry for c-Fos have been
described in detail previously (5). The double staining procedure used
to visualize c-Fos and OT or c-Fos and AVP was performed by combining
monoclonal antibodies to OT- or AVP-associated neurophysins diluted
1:100 (provided by Dr. Harold Gainer) with a rabbit polyclonal antibody
to c-Fos diluted 1:1000 (94012; characterized in Ref. 15). A standard
immunohistochemical procedure was employed (5). OT and AVP were
visualized using a fluorescence isothiocyanate-conjugated antimouse
antibody (Jackson ImmunoResearch Laboratories, Inc., West
Grove, PA), and the c-Fos-ir elements were visualized by a sandwich
technique using first a biotinylated antirabbit antibody (Zymed Laboratories, Inc., San Francisco, CA) followed by
streptavidin-conjugated Texas Red (Amersham Pharmacia Biotech, Aylesbury, UK). The double staining procedure used to
visualize CART and OT and that used for CART and AVP were identical,
except that a polyclonal rabbit CART antibody [raised against
CART-(49–89)] was used in conjunction with the above-mentioned
monoclonal antibodies to OT and AVP neurophysins. Characterization of
both CART-recognizing antibodies has been described previously (5).
In brief, the triple immunohistochemical procedure used to visualize CRH, CART, and c-Fos simultaneously was as follows. After rinses in KPBS and blocking in 5% normal swine serum, sections were incubated overnight at 4 C in a cocktail of the primary antibodies. The primary antibodies were diluted in KPBS containing 0.3% Triton X-100 and 1% BSA [sheep anti-CRH diluted 1:25000 (a gift from Dr. Wylie Vale), rabbit anti c-Fos diluted 1:200, and mouse anti-CART diluted 1:100]. After rinses in KPBS containing 0.25% BSA and 0.1% Triton X-100 (KPBS-BT), the sections were incubated for 1 h in a biotinylated antisheep antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA), rinsed three times for 10 min each time in KPBS-BT followed by 1 h in an avidin-biotin-peroxidase complex (Vector Elite Kit, Vector Laboratories, Inc., Burlingame, CA) diluted 1:250 in KPBS-BT. After three 10-min washes in KPBS-BT the sections were incubated in biotinylated tyramide (NEN Life Science Products, Boston, MA; TSA-indirect kit). After rinses in KPBS-BT, the sections were finally incubated for 60 min at room temperature in a mixture of streptavidin-conjugated Cy2 (Amersham Pharmacia Biotech; 1:250, to visualize CRH-ir), Texas Red-conjugated antirabbit antibody (Jackson ImmunoResearch Laboratories, Inc.; 1:100 to visualize c-Fos-ir), and a Cy5-conjugated antimouse antibody (1:100 to visualize CART-ir).
Sections from the double and triple labeling reactions were subsequently mounted in Glycergel (Dakopatts, Copenhagen, DK) and examined with a Carl Zeiss confocal microscope (LSM 510, Carl Zeiss, New York, NY). Image-editing software (Adobe PhotoShop and Adobe Illustrator) were used to combine acquired images into plates that subsequently were printed on a Kodak dye sublimation printer (Eastman Kodak Co., Rochester, NY).
Cell counts and quantification
As the number of c-Fos-ir nuclei in vehicle-injected animals was
very low in both the SON (0.5 ± 0.3 vs. 26.9 ±
5.0, vehicle vs. CART) and PVN (8.3 ± 1.9
vs. 195.7 ± 21.8, vehicle vs. CART),
counting was performed only on material from CART-treated animals. A
cell was counted only if it had a clearly labeled cell body surrounding
a nucleus. So as not to count all cells from each animal containing the
individual transmitters, counting was performed on sections from
identical rostro-caudal levels, making direct comparison between
animals possible. For all areas the number of immunoreactive cells and
double labeled cells were counted bilaterally on one section per
animal, and a mean value for one side was calculated (n = 6 for
all areas and transmitters). In the SON, counting of OT, AVP, and CART
was performed at the level of the suprachiasmatic nucleus
[corresponding to level 22 in the atlas by Swanson (16)]. The OT
neurons in the anterior magnocellular PVN were counted at approximately
the same level. The CRH-ir neurons were counted at the level of the
core of the posterior magnocellular nucleus (level 26) (16). This level
was also chosen for quantification of AVP and OT in the posterior
magnocellular PVN as well as OT neurons in the dorsal parvicellular
PVN.
Statistics
Statistical evaluation of the experiments used two-way ANOVA
followed by Fisher’s post-hoc analysis. Values (hormone
concentrations, number of immunoreactive cells, percent colocalization)
are expressed as the mean ± SEM.
P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, central
administration of 0.5 µg CART caused a robust increase in circulating
corticosterone. The increase was significantly different from the
effect of vehicle 20 min after the injection (Fig. 1; 426 ± 33
vs. 71 ± 16 ng/ml; CART vs. vehicle) and
remained elevated during the first 2 h of the observation period
(Fig. 1; 40 min, 565 ± 15 vs. 55 ± 17 ng/ml; 60
min, 562 ± 167 vs. 67 ± 30 ng/ml; 120 min,
568 ± 17 vs. 44 ± 10 ng/ml; CART vs.
vehicle). Four hours after icv injection of 0.5 µg CART plasma
corticosterone levels declined to baseline levels (Fig. 1: 55 ±
21 vs. 37 ± 11; CART vs. vehicle). CART
significantly increased circulating OT 10 and 20 min after the
injection (Fig. 2a; 10 min, 48.3 ±
14.1 vs. 12.8 ± 2.2 pg/ml; 20 min, 48.1 ± 11
vs. 13.2 ± 2.2 pg/ml), whereas no effect was seen on
plasma levels of AVP (Fig. 2b). As shown in Fig. 3, CART caused a transient increase in
blood glucose significantly different from that in vehicle-injected
animals only at 10 min (6.2 ± 0.2 vs. 5.1 ± 0.1;
CART vs. vehicle).
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shows
the number of cells per side/section (one section at same rostro-caudal
level counted per animal and the mean value used in the analysis;
n = 6 all transmitters and areas) containing OT-, AVP-, CRH-, and
CART-ir as well as the percentage of colocalization with c-Fos-ir in
the various subnuclei of the PVN and SON (mean ±
SEM). Central administration of CART induced c-Fos in a
high proportion of CRH-ir neurons located in the hypophysiotropic part
of the PVN (Fig. 4, A and B). In
contrast, CRH neurons of other nuclei, such as the central nucleus of
the amygdala (Table 1) and bed nucleus of the stria terminalis (data
not shown) were devoid of CART-induced c-Fos expression. Also, the
magnocellular OT-producing neurons of the SON, anterior magnocellular
PVN, and posterior magnocellular PVN were found to contain CART-induced
c-Fos (Table 1 and Fig. 4, C–E). In addition, a high proportion of
parvicellular OT-ir neurons located in the dorsal portion of the PVN
(dpPVN) was found to contain c-Fos-ir after icv CART (Table 1 and Fig. 4E). Only very few AVP-ir magnocellular cells in the PVN and SON were
found to contain c-Fos (Table 1 and Fig. 4F). Finally, the coexistence
of CART-induced c-Fos-ir with endogenous CART in hypothalamic neurons
was assessed. A small proportion of CART cells within the medial and
periventricular parts of the PVN was found to contain c-Fos (Table 1
and Fig. 4, A and B), whereas the CART neurons in the Arc and in the
lateral hypothalamic area did not costore c-Fos (data not shown). The
PVN contains not only CART-ir cell bodies, but also a high number of
CART-ir fibers in close apposition to perikarya of neuroendocrine
neurons. In the mpPVN, CART-ir fibers were seen in close apposition to
CRH-ir cell bodies concomitantly expressing CART-induced c-Fos-ir (Fig. 5, A–C). In separate experiments we
investigated, by double immunohistochemistry, the distribution of
CART-ir fibers in relation to either OT or AVP neurons in the PVN. In
the magnocellular PVN we found CART-ir fibers with boutons en passage
and terminal boutons in close apposition to OT-containing (Fig. 5D) as
well as AVP-containing neurons (Fig. 5F). The dorsal parvicellular
portion of the PVN contained a dense plexus of CART-ir fibers, many of
which formed basket-like plexuses surrounding parvicellular OT-ir
neurons (Fig. 5E).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As the CART receptor is as yet unidentified, we initially used the
immediate early gene c-fos as a tool to map potential sites
of action of CART (Ref. 9 and the present study). Numerous studies have
shown that c-fos gene expression in most neurons is closely
coupled to cellular excitation and functional activation (for review,
see Ref. 17), and several groups have used c-fos expression
as a marker of activation of neuroendocrine neurons after different
acute or chronic stressors (19, 20). The triple immunohistochemical
procedure used to simultaneously visualize CRH, CART, and c-Fos
demonstrated that icv injection of 0.5 µg CART-(42–89) induced
c-Fos-ir in the vast majority of medial parvicellular CRH neurons
(
90%). The low level of peptide present in the hypophysiotropic CRH
neurons renders immunohistochemical detection of these neurons
difficult in conventionally paraformaldehyde fixed tissue (21). In the
present study, the use of a different fixative preserving CRH-ir (22),
as well as the use of the highly sensitive tyramide amplification
technique (23) enabled us to visualize the majority of PVN CRH neurons
(as well as CRH neurons in other sites: medial preoptic area, central
nucleus of the amygdala, and bed nucleus of the stria terminalis). It
should be noted that albeit the tyramide amplification enhances CRH-ir
in the PVN, part of the population requires colchicine pretreatment of
animals before immunohistochemical visualization is possible (24). The
actual percentage of CRH-ir neurons containing c-Fos after CART could
therefore be either higher or lower than that observed in the present
study.
The triple staining method allowed detailed examination of the anatomical relationship between CART- and CRH-ir elements in the PVN. The presence of CART-ir fibers endowed with both terminal boutons and boutons en passage in close apposition to c-Fos containing CRH-ir neurons within the PVN suggests that hypothalamic-pituitary-adrenal axis motor-neurons are directly innervated by CART-containing axons. Although the origin of the CART-ir fibers contacting the CRH-ir neurons remains elusive, it is tempting to speculate that Arc neurons contribute to this pathway. Firstly, the Arc contains a large population of CART-producing neurons, the vast majority of which (>95%) costore POMC (5, 11). Secondly, the POMC neurons of the Arc have been shown to project to the PVN (25, 26, 27), and synaptic contacts between POMC-containing fibers in the PVN and CRH here have been demonstrated (28). However, other areas must contribute with CART-ir fibers to the PVN, as animals with neurochemical monosodium glutamate lesions of the Arc (29) still contain a considerable amount of CART-ir fibers and cell bodies in the PVN (our unpublished observations). Further neuroanatomical tracing studies will have to be conducted to determine whether the residual CART fibers in Arc-lesioned animals originate from CART neurons contained within the PVN proper or from CART neurons in other hypothalamic sites.
The increase in plasma corticosterone levels induced by central CART administration as well as the triple immunohistochemical data showing CART-ir fibers juxtaposed to CRH-ir cell bodies containing c-Fos point to a possible direct action of CART on the hypophysiotropic CRH neurons. However, it should be stressed that the demonstration of CART-ir fibers close to activated CRH-ir neurons by no means excludes the possibility that the exogenously administered CART activates the PVN CRH neurons via other (indirect) routes. Also, the exact connectivity of CART-activated CRH-ir cell bodies in the PVN is uncertain. At least three possible routes are followed by CRH-ir axons of parvicellular PVN neurons. The medial parvicellular PVN perikarya give off intranuclear collaterals before giving rise to the ventrolaterally directed projection bundle innervating the external zone of the median eminence. The lateral and dorsal parvicellular subnuclei, comprising the caudal complex of the PVN, harbor CRH-ir perikarya, giving rise to descending projections innervating preganglionic autonomic motoneurons (30). Thus, CART potentially influences both hypophysiotropic and autonomic CRH-ir neurons having an impact on such diverse functions as the hypothalamo-pituitary-adrenocortical axis as well as overall sympathetic tone. In further support of central CART-induced activation of descending pathways to the sympathetic outflow neurons are acutely elevated blood glucose levels, although further studies are needed to elucidate whether CART also influences cardiovascular parameters such as arterial mean blood pressure and cardiac output. It is worthy of mention that changes in arterial blood pressure induce c-Fos expression in the PVN, substantiating that activation of some of the parvicellular neurons may have been secondary to CART-induced excursions of mean arterial blood pressure (31). Presently, we abstained from quantifying CART-induced c-Fos in CRH neurons located in PVN subnuclei other than the medial parvicellular PVN. The vast majority of CRH-ir neurons in the medial parvicellular PVN are hypophysiotropic, whereas the projectional patterns of CRH-ir cells in other parvicellular PVN subnuclei are diverse and different to segregate anatomically from the hypophysiotropic CRH population (30). Therefore, proper analysis of c-Fos activation of efferent CRH projections originating in the lateral and dorsal parvicellular PVN requires the use of combined c-Fos immunohistochemistry with neuronal tracing techniques.
A number of compounds with anorectic properties can stimulate central OT neurons. These include transmitters that have been associated with satiety (cholecystokinin and CRH) as well as compounds causing visceral discomfort when injected ip (lithium chloride and hypertonic saline) (for review, see Ref. 32). Systemic administration of cholecystokinin (33, 34) and central administration of CRH (35) both activate magnocellular OT neurons, leading to increased levels of circulating OT. However, this peripheral rise in circulating OT has no effect on food intake (36), but, rather, reflects a concomitant activation of central oxytocinergic systems, as central administration of OT antagonists can block the inhibitory effects on feeding behavior elicited by both compounds (32, 37, 38). In support of a role of central descending oxytocinergic pathways in mediating CART-induced anorexia is our observation that a high proportion of parvicellular OT-ir cells in the dorsal parvicellular PVN contained c-Fos-ir nuclei. The dorsally located group of parvicellular OT neurons constitute a distinct and easily recognized group of neurons in the PVN (39). The dorsal parvicellular PVN consists of a dense relatively homogeneous group of neurons projecting directly to the preganglionic sympathetic neurons in the spinal cord (39, 40, 41). Besides OT, this paraventriculo-spinal tract contains a variety of other transmitters, notably AVP (10, 39, 41, 42, 43, 44). OT-ir fibers have been shown to make synaptic contacts with preganglionic neurons of the intermediolateral cell column (IML) (45), and a direct excitatory action of OT on IML neurons in the spinal cord has been described (46). Our data showing activation of parvicellular OT neurons in the PVN and a high number of putative contacts between CART-ir fibers and OT cells in this part of the PVN therefore suggests that CART activates the autonomic preganglionic neurons. Although we have no direct measurements of autonomic activation, we propose that the rapid and transient increase in blood glucose levels seen after central administration of CART is due to activation of the sympathetic branch of the autonomic nervous system. It should be noted that CART itself has been demonstrated in fibers innervating the IML (11, 47), and that part of this projection comes from CART-ir cell bodies located in the rostral part of the Arc (11). Therefore, a direct action of centrally administered CART at this distant site cannot be excluded, and future studies will have to determine whether local injections of CART in the spinal cord have effects on sympathetic activity. Nevertheless, it is possible that CART can influence autonomic balance via several separate routes.
In conclusion, we have shown that intracerebroventricular administration of recombinant CART-(42–89) peptide, one of the naturally occurring forms of hypothalamic CART, stimulates circulating levels of OT and corticosterone. Furthermore, CART induces c-Fos expression in CRH-containing neurons in the PVN, possibly via a direct action on these, as CART-ir fibers were found in close apposition to c-Fos-containing CRH-ir neurons. Also, CART induces c-Fos in both magnocellular and parvicellular OT neurons of the PVN. As the majority of parvicellular OT neurons in the PVN project to preganglionic sympathetic neurons in the spinal cord, we suggest that this activation increases sympathetic outflow. This final suggestion is supported by the observation that CART elicits a rise in blood glucose levels.
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Acknowledgments |
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Received June 21, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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