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Original Studies |
-Melanocyte-Stimulating Hormone1
Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine, New England Medical Center (E.M., C.F., J.B.T., R.M.L.), Boston, Massachusetts 02111; Department of Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences (C.F., Z.L.), 1083 Budapest, Hungary; Department of Pathology (Neuropathology Division), Brown University School of Medicine/Rhode Island Hospital (E.G.S.), Providence, Rhode Island 02903; and Department of Neuroscience, Tufts University School of Medicine (R.M.L.), Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Division of Endocrinology, Box No. 268, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}lifespan.org
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH, are
contained in axon terminals that heavily innervate hypophysiotropic TRH
neurons in the rat brain and may contribute to the altered set-point of
the hypothalamo-pituitary-thyroid axis during fasting. To determine
whether a similar regulatory system exists in human brain, we performed
a series of immunohistochemical studies using antisera against NPY,
AGRP, MSH, and TRH in adult hypothalami obtained within 15 h of
death. Numerous small to medium-sized, fusiform and multipolar NPY-,
AGRP-, and MSH-immunoreactive (-IR) cells were widely distributed
throughout the rostro-caudal extent of the infundibular (arcuate)
nucleus. A similar distribution pattern was found for NPY- and AGRP-IR
neurons in the arcuate nucleus, whereas MSH-IR cells appeared to
form a separate cell population. By double labeling fluorescent
immunohistochemistry, 82% of NPY neurons cocontained AGRP, and 87% of
AGRP neurons coexpressed NPY. No colocalization was found between
MSH- and AGRP-IR neurons. NPY-, AGRP-, and MSH-containing axons
densely innervated the hypothalamic paraventricular nucleus and were
found in close juxtaposition to TRH-synthesizing cell bodies and
dendrites. These studies demonstrate that in man, the NPY-, AGRP-, and
MSH-IR neuronal systems in the infundibular and paraventricular
nuclei are highly reminiscent of that observed in the rat and may
similarly be involved in regulating the hypothalamo-pituitary-thyroid
axis in the human brain. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH, a cleavage product of POMC, is also
contained in axon terminals that innervate TRH neurons in the rat PVN
and has a stimulatory effect on pro-TRH gene expression when injected
into the cerebrospinal fluid (21), we have further proposed that MSH
may be responsible for the restoration of pro-TRH mRNA in PVN neurons
of fasting animals treated with leptin.
To determine whether regulatory control of hypophysiotropic TRH neurons
in man are similar to that observed in the rat, we performed a series
of immunohistochemical studies on adult human hypothalami using
specific antisera to NPY, AGRP, MSH, and TRH, looking primarily at
the infundibular nucleus, the human equivalent of the rat arcuate
nucleus, and the PVN. A preliminary report of these findings has been
presented in abstract form (22).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hypothalami from three adults with no history of neurological or
endocrinological impairment were obtained at routine autopsies (Table 1
). Tissue samples were taken within
15 h of death. The diencephalic blocks were fixed in 4%
paraformaldehyde for 48–72 h at 4 C, then cryoprotected in 30%
sucrose and frozen on dry ice. Serial 30-µm thick coronal sections
were cut parallel to the lamina terminalis on a cryostat (2800
Frigocut-E, Reichert-Jung, Vienna, Austria) and stored in
phosphate-buffered saline (PBS) containing 0.2% sodium azide at 4 C
until immunohistochemical or immunofluorescent processing.
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Single and double label immunohistochemistry was performed at
the light microscopic level to establish the distribution of neuronal
perikarya and fibers containing NPY, AGRP, MSH, and TRH in the
hypothalamic infundibular and paraventricular nucleus and the possible
relationships among them. Hypothalamic sections were pretreated with
3% hydrogen peroxide and 0.45% Triton X-100 (Sigma, St.
Louis, MO) in PBS for 15 min to reduce endogenous peroxidase activity
and improve antibody penetration, respectively, and then were immersed
in 10% normal horse serum in PBS for 30 min to abolish nonspecific
antibody binding. Tissue sections were then incubated with one of the
following primary antibodies: rabbit anti-NPY (1:50,000;
Peninsula Laboratories, Inc., Belmont, CA), rabbit
anti-AGRP (1:20,000; Phoenix Pharmaceuticals, Inc.,
Mountain View, CA), or sheep anti-MSH (1:150,000; raised in our
laboratory) (23), each for 48 h at 4 C. After washing in PBS,
sections were incubated in biotinylated donkey antirabbit IgG or
biotinylated donkey antisheep IgG (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA) at 1:500, depending on the
first antibody, for 2 h at room temperature. Both primary and
secondary antisera were diluted in 2.5% normal horse serum and 0.2%
sodium azide containing PBS. After further rinsing in PBS, the sections
were immersed in avidin-biotin complex (1:100; Vector Elite Kit,
Vector Laboratories, Inc., Burlingame, CA) for 2 h,
rinsed, and then developed in 0.05% diaminobenzidene-0.15% nickel
ammonium sulfate-0.005%
H2O2 in 0.05 mol/L Tris
buffer, pH 7.6, for approximately 5 min. The reaction was stopped by
immersion of tissue sections in 0.05 mol/L Tris buffer, washed in 2%
sodium acetate (pH 7.2), and then silver intensified (24) to obtain a
black reaction product. After additional washes in PBS, the tissue
sections for double label immunohistochemistry were transferred to
rabbit anti-TRH antiserum (25) (diluted 1:4,000) for 2 days at 4 C.
Biotinylated donkey antirabbit IgG (The Jackson Laboratory, Bar Harbor, ME) was used as the second antibody
(diluted 1:500), and after further washes and incubation in
avidin-biotin complex Elite reagent (1:100; Vector Laboratories, Inc.), the tissue was reacted with 0.025%
diaminobenzidene-0.0036%
H2O2 in PBS to yield a
contrasting brown reaction product.
The sections were mounted onto SuperFrost slides (Fisher Scientific, Pittsburgh, PA), air-dried, dehydrated in an ascending series of alcohol, cleared in Histosol (National Diagnostics, Atlanta, GA), and then coverslipped with DPX (Fluta, Ronkonkoma, NY). Some of the double labeled sections were embedded in Epon-resin for preparation of semithin sections. The resin was polymerized at 56 C for 2 days, then the region of interest was cut out with a razor blade, glued onto a Durcupan (Fluta) block, and sectioned on an MT 6000 ultramicrotome (RML, Inc., Tucson, AZ).
The distribution of NPY, AGRP, and MSH perikarya in the arcuate
nucleus and the innervation of the PVN by these systems were analyzed
by light microscopic examination using a Carl Zeiss
Axioskop 2 epifluorescent microscope (New York, NY). The
percentage of TRH neurons receiving contacts on their perikarya
and first order dendrites by immunoreactive axon terminals of
each peptide, respectively, was determined. The data are presented as
the mean ± SEM.
The specificity of immunostaining with NPY, MSH, and TRH antisera
was demonstrated by the loss of immunoreactivity after preabsorption of
the diluted antisera with an excess of synthetic NPY
(10-5 mol/L), MSH
(10-5 mol/L), and TRH
(10-3 mol/L) peptides,
respectively. The specificity of the AGRP antiserum has been previously
reported (15). In addition, no specific staining could be detected by
omission of each primary or secondary antiserum.
Immunofluorescence
To determine whether NPY, AGRP, and MSH are expressed in the
same neurons, a double labeling immunofluorescence method was used.
Tissue sections were immersed in 1% sodium acetate for 1 min, then
treated in graded solutions of acetone (50%, 70%, 90%, 100%, and
90%) for 5 min each, washed in 70% ethanol, and treated with 0.3%
Sudan black in 70% ethanol for 30 min to reduce autofluorescence (26).
After differentiation in 70% ethanol, sections were washed in PBS,
pretreated with 10% normal horse serum in PBS, and incubated in one of
the following mixtures: 1) rabbit anti-AGRP (1:3000; Phoenix Pharmaceuticals, Inc.) and sheep anti-NPY (1:1000; Chemicon
International, Inc., Temecula, CA), 2) rabbit anti-AGRP (1:3000) and
sheep anti-MSH (1:5000), 3) rabbit anti-NPY (1:5000; Peninsula Laboratories, Inc.) and sheep anti-MSH (1:5000),
respectively, for 4 days at 4 C. After washes in PBS, tissues were
immersed in a mixture containing biotinylated donkey antirabbit IgG
(1:500; The Jackson Laboratory) and Texas Red-conjugated
antisheep IgG (1:40; The Jackson Laboratory) for 1 day at
4 C. Sections were washed in PBS and further incubated in fluorescein
isothiocyanate-avidin D cell-sorting grade (Vector Laboratories, Inc.; diluted at 1:250) for 1 day at 4 C. After
washes, sections were mounted on SuperFrost slides (Fisher Scientific, Pittsburgh, PA), coverslipped with Vectashield
(Vector Laboratories, Inc.), and analyzed under a
Carl Zeiss Axioskop 2 epifluorescent microscope using the
following filter sets: Texas Red (excitation, 540–590 nm; bandpass,
595 nm; emission, 600–660) and fluorescein isothiocyanate (excitation,
460–500 nm; bandpass, 505 nm; emission, 510–560 nm). Thus, AGRP
appeared green, and NPY or MSH, respectively, appeared red by
fluorescent microscopy in the AGRP and NPY or MSH colocalization
study, whereas NPY appeared green, and MSH appeared red when
colocalization of NPY with MSH was studied. Images were captured
with a Spot digital camera (Diagnostic Instruments, Inc., Sterling
Heights, MI), the same field was double exposed by switching the filter
sets for each fluorochrome, and the images were superimposed using
Adobe Photoshop 5.0 and a Macintosh G3 computer (Apple Computer, Inc.,
Cupertino, CA). Only the brightness and contrast were adjusted
in the final digitized image.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH-immunoreactive (IR) neurons
in the hypothalamic infundibular nucleus
NPY- and AGRP-IR neurons were present throughout the rostro-caudal
extent of the infundibular nucleus embedded in a dense NPY- or AGRP-IR
fiber network, respectively (Fig. 1, A–F). Occasional neurons extended further laterally in the neuropil of
the hypothalamus. Single label immunohistochemistry revealed that the
size, shape and distribution of NPY- and AGRP-IR neurons were similar;
both were small to medium sized and fusiform or multipolar in shape
(Fig. 1, A–F). NPY- and AGRP-IR perikarya were observed mainly in the
medial part of the infundibular nucleus at the rostral level of the
nucleus (Fig. 1, A and D). At the midlevel of the infundibular nucleus,
they organized into two distinct groups, one in the medial portion and
a second in the lateral portion of the infundibular nucleus, with a
relative paucity of immunoreactive cells in the central part of the
nucleus (Fig. 1, B and E), whereas in the caudal regions, NPY- and
AGRP-producing cells showed higher concentrations laterally (Fig. 1, C and F).
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MSH-IR perikarya were also dispersed throughout the rostro-caudal
extent of the infundibular nucleus, but were concentrated in the
lateral portions of the nucleus at the anterior and caudal levels (Fig. 1
, G and I). At the midlevel of the nucleus, however, the distribution
pattern of MSH-positive neurons was similar to that seen for NPY-
and AGRP-IR perikarya; MSH-containing neurons were located in medial
and lateral portions of nucleus, with the lack of immunostaining in the
central part (Fig. 1H). Morphologically, these cells were distinct from
NPY- and AGRP- containing cells, being medium sized and
multipolar.
Colocalization of AGRP, NPY, and MSH immunoreactivity in
infundibular nucleus neurons
By double labeling immunofluorescence, AGRP and NPY
immunoreactivity appeared to be cocontained in the majority of the same
infundibular nucleus neurons (Fig. 2, A
and B). Cell counts throughout the rostro-caudal extent of the
infundibular nucleus revealed that approximately 86.5 ± 1.3% of
AGRP neurons cocontained NPY. Colocalization was particularly apparent
at the anterior level of the nucleus, where nearly 100% of AGRP-IR
neurons were double labeled. The majority of single labeled AGRP-IR
neurons were located at the midlevel of the arcuate nucleus in the
medial portion. Conversely, 81.8 ± 6.4% of NPY-synthesizing
perikarya in the infundibular nucleus contained AGRP; however, the
majority of colocalized neurons were located at the mid- and caudal
levels of the nucleus. No colocalization of AGRP or NPY with MSH was
seen in any infundibular nucleus neuron (Fig. 2, C and D).
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MSH-containing fibers in the
PVN
The PVN contained a high density of strongly stained NPY-IR fibers
throughout the nucleus (Fig. 3, A–C).
The thin varicose fibers formed a rich network within the nucleus, and
some pericellular baskets were also seen. Both parvo- and magnocellular
parts were innervated. Occasionally, small NPY-positive perikarya were
identified in both parvo- and magnocellular subdivisions. AGRP-IR
beaded fibers were also dispersed throughout the PVN, although their
distribution varied somewhat from that observed for NPY- containing
fibers. The periventricular part of the anterior PVN exhibited a higher
concentration of immunoreactive fibers, whereas the mid- and caudal PVN
received uniform innervation (Fig. 3, D–F). A medium density of
MSH-IR fibers was found throughout the PVN. The lateral region of
the nucleus exhibited the densest pattern of labeled, large varicose
fibers (Fig. 3, H–J). Immunoreactivity for all three peptides,
respectively, was identified just lateral to the PVN and above the
fornix in the dorsal hypothalamic area and appeared to enter the
PVN.
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MSH-containing fibers
TRH-positive cells were observed throughout the PVN, but were
mostly concentrated in the medial region of the midlevel of the nucleus
(Fig. 4, A–C). The majority of the cells
were small, multipolar, and round in shape, but some scattered large
neurons were also seen. NPY axon varicosities were found in close
juxtaposition to 77.9 ± 3.2% of TRH-containing perikarya and
dendrites (Fig. 5A). This close
relationship was particularly apparent in the anterior and midlevel of
the nucleus. AGRP-IR terminals were closely apposed to approximately
60.6 ± 3.1% of TRH-synthesizing neurons, uniformly throughout
the nucleus (Fig. 5B). In some instances the AGRP-IR innervation was so
intense that varicosities formed fiber baskets around the TRH neurons,
outlining the cell surface. MSH-positive fibers were closely apposed
to approximately 58.5 ± 10.5% of TRH-IR perikarya (Fig. 5C),
making contacts with both dendritic processes and soma of TRH neurons.
Close appositions of NPY-, AGRP-, and MSH-IR axon varicosities to
TRH-synthesizing perikarya were also found in semithin sections (Fig. 5, D–F).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MSH-containing axon terminals (15, 16, 21, 27). Since the
major origin of the innervation of TRH neurons in the PVN by all three
of the above peptides in the rat is the arcuate nucleus (15, 16, 21),
we first examined the relative distributions of neurons containing NPY,
AGRP, and MSH in the human infundibular nucleus using highly
specific antiserum and single and double labeling immunocytochemistry.
Both NPY- and AGRP-IR neurons were identified in the hypothalamic
infundibular nucleus, contained in the perikarya of small and
medium-sized neurons throughout the medial part of the nucleus, but
also in basolateral portions of the nucleus in mid- and caudal levels.
Double labeling immunofluorescent studies demonstrated that
approximately 82% of NPY-containing neurons also contained AGRP,
whereas 87% of AGRP-containing neurons coexpressed NPY, indicating
that, as in the rat brain (14), these two peptides are substantially
colocalized in the same infundibular nucleus neurons. In contrast,
MSH immunostaining was located in a morphologically distinct group
of neurons and was located predominantly in the lateral regions of the
infundibular nucleus. It was not surprising, therefore, that, similar
to other animal species (14), double labeling immunofluorescence in the
human brain demonstrated that MSH-containing neurons and
NPY-/AGRP-containing neurons form separate cell populations in the
infundibular nucleus. Within the PVN, however, all three peptides were present in axon terminals that heavily inundated the nucleus. The substantial overlap between AGRP- and NPY-containing axons in the PVN is consistent with these two peptides arising from the same infundibular nucleus neurons. The NPY innervation of the PVN, however, was more extensive than the AGRP innervation. Similarly, whereas both NPY- and AGRP-IR axon varicosities were found in close juxtaposition to the majority of TRH-containing cell bodies in the PVN, in some instances outlining the entire surface and first order dendrites with numerous contacts, a greater percentage of TRH neurons was contacted by NPY- than AGRP-containing axons. If AGRP in the human brain originates exclusively from the arcuate nucleus, as in the rat and mouse (15, 28), one might presume that the more extensive NPY innervation of TRH neurons suggests a more widespread origin of NPY-containing axons from neuronal populations in the regions of the brain in addition to the arcuate nucleus. Potential sources of NPY from regions that have known projection pathways to the PVN in the rat and human include the lateral and dorsomedial medulla, where NPY colocalizes with catecholamines (29, 30, 31), the bed nucleus of the stria terminalis (32), and the lateral geniculate (33).
MSH-containing axons also heavily inundated TRH neurons in the PVN,
outlining soma and dendrites of approximately 58% of the TRH neurons.
As both MSH- and AGRP-containing axons innervate the majority of TRH
neurons, the likelihood that at least a subpopulation of TRH neurons
are innervated by both peptides would appear strong. The potential
significance of dual innervation by AGRP and MSH is implicit in the
demonstration that these two peptides antagonize each other at the same
receptor. Thus, in mouse skin, the homologue of AGRP, agouti, and
MSH both bind to the melanocortin-1 receptor (MC-1R) to regulate
skin color (34). Similarly, in the brain, AGRP competes with MSH for
binding to the MC-4R, inhibiting the anorectic effects of MSH and
inducing feeding behavior (10, 35). Thus, the dual innervation of TRH
neurons in the PVN of the human brain by AGRP- and MSH-containing
axons would suggest opposing actions of these two peptides on the
regulation of hypophysiotropic TRH.
AGRP/NPY and MSH mRNA levels are affected by nutritional status.
Thus, during starvation, when circulating leptin levels fall, arcuate
nucleus-derived AGRP and NPY mRNA levels increase, POMC mRNA decreases
(17, 19, 20, 36, 37, 38, 39), and pro-TRH gene expression in hypophysiotropic
neurons decreases (40, 41, 42). These changes are associated with low or
inappropriately normal circulating TSH and reduction of thyroid hormone
levels, characteristic of the nonthyroidal illness syndrome (41, 43).
Recent studies from our laboratories (40) have demonstrated that the
systemic administration of leptin to fasting rats, which inhibits AGRP
and NPY mRNA and stimulates MSH gene expression (9, 17, 19, 20),
restores circulating thyroid hormone levels to normal. In addition,
infusion of MSH to fasting rats prevents the fasting-induced
suppression of pro-TRH mRNA in the PVN (21). We presume, therefore,
that AGRP and NPY may exert inhibitory effects on TRH neurons,
whereas the effect of MSH may be stimulatory. However, mice with
deletion in NPY gene show a similar reduction in
T4 levels during fasting (44), raising the
possibility that AGRP may have a compensatory role in these animals or
that additional mechanisms are called into play.
On the basis of the above observations, we conclude that in the human
brain, NPY, AGRP, and MSH are anatomically situated to exert
regulatory control over hypophysiotropic TRH neurons in the PVN. We
propose, therefore, that the human hypothalamic-pituitary-thyroid axis
has retained similar homeostatic mechanisms present in the rodent
brain, centrally mediated by the opposing effects of NPY/AGRP and
MSH on hypophysiotropic TRH neurons in the PVN (15, 16, 18, 21).
Thus, during fasting or other disorders that result in the nonthyroidal
illness syndrome (43) the seemingly paradoxic fall in pro-TRH mRNA
levels in the PVN in both man and experimental animals (45, 46, 47, 48), when
circulating thyroid hormone levels are low, may be explained at least
in part by the increased secretion of NPY/AGRP and/or the decreased
secretion of MSH to reduce thyroid thermogenesis and conserve
peripheral energy stores.
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Footnotes |
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Received November 10, 1999.
Revised February 25, 2000.
Accepted March 22, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-melanocyte stimulating hormone in
vivo. Endocrinology. 139:4428–4431.-melanocyte-stimulating hormone on LH release in the
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